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RTN1 Reticulon-1 also known as neuroendocrine-specific protein (NSP) is a protein that in humans is encoded by the RTN1 gene. This gene belongs to the family of reticulon-encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. Alternatively spliced transcript variants encoding different isoforms have been identified. Multiple promoters rather than alternative splicing of internal exons seem to be involved in this diversity. # Interactions RTN1 has been shown to interact with BCL2-like 1 and UGCG.

MT-TR Mitochondrially encoded tRNA arginine also known as MT-TR is a transfer RNA which in humans is encoded by the mitochondrial MT-TR gene. # Structure The MT-TR gene is located on the p arm of the non-nuclear mitochondrial DNA at position 12 and it spans 65 base pairs. The structure of a tRNA molecule is a distinctive folded structure which contains three hairpin loops and resembles a three-leafed clover. # Function MT-TR is a small 65 nucleotide RNA (human mitochondrial map position 10405-10469) that transfers the amino acid arginine to a growing polypeptide chain at the ribosome site of protein synthesis during translation. # Clinical significance ## Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) Mutations in MT-TR have been associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). MELAS is a rare mitochondrial disorder known to affect many parts of the body, especially the nervous system and the brain. Symptoms of MELAS include recurrent severe headaches, muscle weakness (myopathy), hearing loss, stroke-like episodes with a loss of consciousness, seizures, and other problems affecting the nervous system. Mutations in MT-TR associated with the disease have included 10450A-G and 10438A-G. ## Cytochrome c oxidase deficiency MT-TR mutations have been associated with complex IV deficiency of the mitochondrial respiratory chain, also known as the cytochrome c oxidase deficiency. Cytochrome c oxidase deficiency is a rare genetic condition that can affect multiple parts of the body, including skeletal muscles, the heart, the brain, or the liver. Common clinical manifestations include myopathy, hypotonia, and encephalomyopathy, lactic acidosis, and hypertrophic cardiomyopathy. A 10437 G>A mutation has been found with a patient with the deficiency.

HAR1F HAR1F is a RNA gene which is part of a human accelerated region of the human genome. HAR1F is found on the long arm of chromosome 20 and the RNA product is expressed in Cajal-Retzius cells, where it colocalizes with the protein reelin. HAR1F was identified in August 2006 when human accelerated regions (HARs) were first investigated. These 49 regions represent parts of the human genome which differ significantly from highly conserved regions of our closest ancestors evolutionarily. Because many of the HARs are associated with genes known to play a role in neurodevelopment, HARs are believed to be responsible for the language, brain size, and complex thought which separate humans from other species. One particularly altered region, HAR1, was found in a stretch of genome with no known protein coding RNA sequences. Two RNA genes, HAR1F and HAR1R were identified partly within the region. The RNA structure of HAR1F has been shown to be stable, with a three–dimensional structure unlike those previously described. HAR1F is active in the developing human brain between the 7th and 18th gestational weeks. It is found in the dorsal telencephalon in fetuses. In adult humans, it is found throughout the cerebellum and forebrain; it is also found in the testes. The function of HAR1F is unknown.

Dimethylarginine dimethylaminohydrolase Dimethylarginine dimethylaminohydrolase (DDAH) is an enzyme found in all mammalian cells. Two isoforms exist, DDAH I and DDAH II, with some differences in tissue distribution of the two isoforms). The enzyme degrades methylarginines, specifically asymmetric dimethylarginine (ADMA) and NG-monomethyl-L-arginine (MMA). The methylarginines ADMA and MMA inhibit the production of nitric oxide synthase. Accordingly, DDAH is important in removing methylarginines, generated by protein degradation, from accumulating and inhibiting the generation of nitric oxide. Inhibition of DDAH activity causes methylarginines to accumulate, blocking nitric oxide(NO) synthesis and causing vasoconstriction. An impairment of DDAH activity appears to be involved in the elevation of plasma ADMA, and impairment of vascular relaxation observed in humans with cardiovascular disease or risk factors (such as hypercholesterolemia, diabetes mellitus, and insulin resistance). The activity of DDAH is impaired by oxidative stress, permitting ADMA to accumulate. A wide range of pathologic stimuli induce endothelial oxidative stress such as oxidized LDL-cholesterol, inflammatory cytokines, hyperhomocysteinemia, hyperglycemia and infectious agents. Each of these insults attenuates DDAH activity in vitro and in vivo. The attenuation of DDAH allows ADMA to accumulate, and to block NO synthesis. The adverse effect of these stimuli can be reversed in vitro by antioxidants, which preserve the activity of DDAH. The sensitivity of DDAH to oxidative stress is conferred by a critical sulfhydryl in the active site of the enzyme that is required for the metabolism of ADMA. This sulfhydryl can also be reversibly inhibited by NO in an elegant form of negative feedback. Homocysteine (a putative cardiovascular risk factor) mounts an oxidative attack on DDAH to form a mixed disulfide, inactivating the enzyme. By oxidizing a sulfhydryl moiety critical for DDAH activity, homocysteine and other risk factors cause ADMA to accumulate and to suppress nitric oxide synthase (NOS) activity. The critical role of DDAH activity in regulating NO synthesis in vivo was demonstrated using a transgenic DDAH mouse. In this animal, the activity of DDAH is increased, and plasma ADMA levels are reduced by 50%. The reduction in plasma ADMA is associated with a significant increase in NOS activity, as plasma and urinary nitrate levels are doubled. The increase in NOS activity translates into a 15mmHg reduction in systolic blood pressure in the transgenic mouse. This study provides evidence for the importance of DDAH activity and plasma ADMA levels in the regulation of NO synthesis. Subsequent studies have shown that DDAH transgenic animals also manifest improvements in endothelial regeneration and angiogenesis, and reduced vascular obstructive disease, in association with the reduced plasma levels of ADMA. These findings are consistent with evidence from a number of groups that nitric oxide plays a critical role in vascular regeneration. By contrast, elevations in ADMA impair angiogenesis. These insights into the role of DDAH in degrading endogenous inhibitors of NOS, and thereby maintaining vascular NO production, may have important implications in vascular health and therapy for cardiovascular disease.

Thromboprophylaxis in Patients With COVID-19 BACKGROUND: Patients hospitalized with COVID-19 often exhibit markers of a hypercoagulable state and have an increased incidence of VTE. In response, CHEST issued rapid clinical guidance regarding prevention of VTE. Over the past 18 months the quality of the evidence has improved. We thus sought to incorporate this evidence and update our recommendations as necessary.STUDY DESIGN AND METHODS:This update focuses on the optimal approach to thromboprophylaxis in hospitalized patients. The original questions were used to guide the search, using MEDLINE via PubMed. Eight randomized controlled trials and one observational study were included. Meta-analysis, using a random effects model, was performed. The panel created summaries using the GRADE Evidence-to-Decision framework. Updated guidance statements were drafted, and a modified Delphi approach was used to obtain consensus.RESULTS:We provide separate guidance statements for VTE prevention for hospitalized patients with acute (moderate) illness and critically ill patients in the ICU. However, we divided each original question and resulting recommendation into two questions: standard prophylaxis vs therapeutic (or escalated dose) prophylaxis and standard prophylaxis vs intermediate dose prophylaxis. This led to a change in one recommendation, and an upgrading of three additional recommendations based upon higher quality evidence. CONCLUSIONS: Advances in care for patients with COVID-19 have improved overall outcomes. Despite this, rates of VTE in these patients remain elevated. Critically ill patients should receive standard thromboprophylaxis for VTE, and moderately ill patients with a low bleeding risk might benefit from therapeutic heparin. We see no role for intermediate dose thromboprophylaxis in either setting. CHEST 2022; 162(1):213-225 KEY WORDS: COVID-19; DIC; DVT; hypercoagulability; pulmonary embolism; VTE ABBREVIATIONS: LMWH = low-molecular-weight heparin; OSFD = organ support-free day; PE = pulmonary embolism; RR = risk ratio; UFH = unfractionated heparin ## Summary of recommendations 1. In hospitalized patients with acute illness with COVID-19 who have low risk of bleeding, with consideration for the remarks below, we suggest therapeutic dose heparin (UFH or LMWH) over current standard dose anticoagulant thromboprophylaxis (Conditional Recommendation, Ungraded Consensus-Based Statement). Remarks: Providers should carefully weigh the risks of thrombosis and bleeding in making this decision. Patients with a significantly elevated D-dimer level (studies have previously defined this as 2-4Â the upper limit of normal), those with prior VTE, or those with other comorbidities known to be associated with VTE may be at increased risk of thrombosis. Patients with high risk of bleeding include, but are not limited to, those with known bleeding within the last 30 days requiring ED presentation or hospitalization, known history of an inherited or acquired bleeding disorder, active dual antiplatelet therapy, recent ischemic stroke, intracranial malignancy, history of bleeding diatheses (eg, hemophilia), history of GI bleeding within previous 3 months, thrombolysis within the previous 7 days, presence of an epidural or spinal catheter, recent major surgery < 14 days, or uncontrolled hypertension (systolic BP > 200 mm Hg, diastolic BP > 120 mm Hg). 2. In hospitalized patients with acute illness with COVID-19 who are not receiving therapeutic dose heparin (UFH or LMWH), we recommend current standard dose anticoagulant thromboprophylaxis over intermediate dose anticoagulation (defined as LMWH bid or increased weight-based dosing that is less than recommended therapeutic doses) (Strong Recommendation, Ungraded Consensus-Based Statement). 3. In critically ill patients with COVID-19, we suggest current standard dose anticoagulant thromboprophylaxis (with UFH or LMWH) over therapeutic dose anticoagulation (Conditional Recommendation, Ungraded Consensus-Based Statement).. In critically ill patients with COVID-19, we suggest current standard dose anticoagulant thromboprophylaxis over intermediate dose anticoagulation (defined as LMWH bid or increased weight-based dosing that is less than recommended therapeutic doses) (Conditional Recommendation, Ungraded Consensus-Based Statement). # Background Within the first few months of the COVID-19 global pandemic, it was recognized that patients hospitalized with SARS-CoV-2 often exhibited markers of a hypercoagulable state and had an increased incidence of VTE. Reports documented significantly elevated D-dimer levels that were associated with increased morbidity and mortality. [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] [bib_ref] Characteristics of emergency patients with markedly elevated D-dimer levels, Tang [/bib_ref] This led many professional societies, including CHEST, [bib_ref] Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019:..., Moores [/bib_ref] to develop rapid guidance documents regarding the optimal strategy for prophylaxis of VTE in these patients. [bib_ref] COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and..., Bikdeli [/bib_ref] [bib_ref] American Society of Hematology 2021 guidelines on the use of anticoagulation for..., Cuker [/bib_ref] [bib_ref] Guidance for the management of patients with vascular disease or cardiovascular risk..., Gerotziafas [/bib_ref] [bib_ref] COVID-19) Treatment Guidelines. National Institutes of Health; 2021. Accessed, Panel [/bib_ref] Initially, evidence was extremely limited and consisted of fewer than 30 retrospective cohort studies of varying size that reported on patients from varied geographic regions and clinical settings. There was no universal approach to screening or diagnosis. Perhaps most importantly, the thromboprophylaxis regimens varied across studies and were sometimes not reported at all. Based upon the limited, low-quality evidence suggesting patients with COVID-19 pneumonia had a higher risk of thrombosis than similarly ill patients without COVID-19, societal guidelines were uniform in their recommendation that all hospitalized patients with COVID-19 pneumonia receive pharmacologic thromboprophylaxis in the absence of a contraindication. Recommendations regarding the optimal dosing, however, varied. Some, including CHEST, recommended standard dose prophylaxis for all patients, while a few suggested that intermediate or therapeutic dosing could be considered, especially in patients admitted to the ICU. [fig_ref] TABLE 1 ]: Early Societal Guidelines Regarding Thromboprophylaxis in COVID-19 [/fig_ref] provides a summary of these early recommendations. Since then, our understanding of the underlying pathophysiologic mechanisms of this prothrombotic state has advanced. While it is beyond the scope of this manuscript to describe these mechanisms in detail, it should be noted that there are two distinct but related processes: a hypercoagulable state that leads to large vessel macrothrombosis and a primary endotheliopathy that results in extensive in situ, immunothrombosis. A more detailed review of these mechanisms has recently been published. [bib_ref] Pulmonary thrombosis and thromboembolism in COVID-19, Poor [/bib_ref] Over the past 15 months, we have also seen the emergence of randomized controlled trials focusing on the optimal dosing for thromboprophylaxis in both moderately ill hospitalized (non-ICU) and critically ill (ICU) patients. Here we provide updated guidance focused on prevention of thrombosis in hospitalized patients. We are not updating any prior guidance related to pre-or posthospital prophylaxis, diagnosis, or treatment. ## Study design and methods The panel followed standard CHEST process for the development of rapid guidance statements, as detailed in the first version of this guideline. [bib_ref] Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019:..., Moores [/bib_ref] Conflict of interest declarations were reviewed for all panelists by the Professional Standards Committee. No panelist required any management for the topic areas being updated. The panel was aware of recently published or studies expected to be published soon regarding optimal thromboprophylaxis and thus chose to limit this update to guidance statements in this topic area. The original Population, Intervention, Comparator, Outcome questions were used to guide the search, using MEDLINE via PubMed. Screening and full text selection were performed in duplicate by pairs of panel members. Additional studies were identified by panel members as they were published. Included studies [bib_ref] Therapeutic versus prophylactic anticoagulation for severe COVID-19: a randomized phase II clinical..., Lemos [/bib_ref] [bib_ref] Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and..., Lopes [/bib_ref] [bib_ref] Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: a..., Perepu [/bib_ref] [bib_ref] Effect of intermediatedose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane..., Sadeghipour [/bib_ref] [bib_ref] Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or..., Sholzberg [/bib_ref] [bib_ref] Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediatedose heparins..., Spyropoulos [/bib_ref] are outlined in. Risk of bias was assessed by the methodologist using Version 2 of the Cochrane risk-of bias tool for randomized trials (RoB 2). [bib_ref] RoB 2: a revised tool for assessing risk of bias in randomised..., Sterne [/bib_ref] Data abstraction was done in duplicate. Any discrepancies were resolved through consensus. Primary outcomes included VTE (pulmonary embolism and DVT), fatal PE, major bleeding, fatal bleeding, mortality, and organ support-free days (OSFDs). As our original guideline focused on VTE, we did not include arterial thrombosis as an outcome. A meta-analysis, using a random effects model, was performed. The panel then created summaries using the GRADE Evidence-to-Decision framework. [bib_ref] GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to..., Alonso-Coello [/bib_ref] These summaries were discussed by the entire group, and updated guidance statements were suggested and voted upon using a modified Delphi approach. This approach utilized several rounds of anonymous voting, with survey results and comments presented to the panel after each round until consensus was achieved. Per CHEST policy, consensus was defined as at least 80% agreement for each recommendation with at least 75% voting participation rate from the panel. Recommendation 1 was controversial and required four rounds of voting (see context comments below). Recommendation 2 reached consensus in three rounds of voting. Recommendations 3 and 4 each reached consensus after two rounds of voting. # Results and recommendations As in the first version of the guideline, we chose to provide separate guidance statements for VTE prevention for hospitalized patients with acute illness (also described as moderately ill, or non-ICU patients) and critically ill patients either hospitalized in the ICU or receiving ICU level care. However, we divided each original Population, Intervention, Comparator, Outcome question and resulting recommendation into two questions: standard prophylaxis vs therapeutic (or escalated dose) prophylaxis and standard prophylaxis vs intermediate dose prophylaxis. ## Hospitalized patients with acute illness Question 1: Should patients with acute illness with COVID-19 be treated with therapeutic anticoagulation or thromboprophylaxis for prevention of VTE? There were four studies reporting on 3,475 patients addressing this question, the largest being the multiplatform ATTACC, ACTIV-4a, and REMAP-CAP studychestjournal.org malignancy, history of bleeding diatheses (eg, hemophilia), history of GI bleeding within previous 3 months, thrombolysis within the previous 7 days, presence of an epidural or spinal catheter, recent major surgery < 14 days, or uncontrolled hypertension (systolic BP > 200 mm Hg, diastolic BP > 120 mm Hg). Context: The panel struggled to come to consensus on this recommendation. From a pure VTE perspective, these trials are consistent with historical trialstherapeutic heparin, either intravenous UFH or full dose LMWH, reduces VTE at the cost of increased bleeding, without any benefit in overall mortality. The reporting of decreased OSFDs in the multiplatform trial 12 deserves notice but is not a typical outcome used in VTE studies. That said, in balance, the benefits of therapeutic vs prophylactic dosing appear to favor the former. Several nuanced issues beyond this were discussed. The ACTION [bib_ref] Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and..., Lopes [/bib_ref] trial, which was the only one to use therapeutic doses of rivaroxaban as opposed to heparin, showed no overall benefit. To explain this, we might invoke that there are additional pleiotropic and/or antiinflammatory effects of heparin that are beneficial beyond the benefits of thromboprophylaxis. While plausible, studies in similarly ill patients without COVID-19 have been inconclusive. The panel also noted the inconsistency in effect between hospitalized patients with acute (moderate) illness and critically ill patients, -Outcomes in moderately ill hospitalized patients receiving therapeutic anticoagulation vs standard thromboprophylaxis. with the OSFD benefit only being seen in the former. This invokes a hypothesis regarding timing of the initiation. Perhaps early administration of therapeutic heparin does indeed affect the underlying pathophysiologic mechanisms in a way that reduces macrothrombosis and microthrombosis, but once patients develop more severe end-organ damage, the harmful effects outweigh any benefit. This is also plausible but not fully studied. Another concern raised was the likelihood of ascertainment bias (patients in the therapeutic arm of an open-label trial may be less likely to undergo diagnostic testing for VTE). Finally, the panel raised concern that the extremely low rate of bleeding in these trials does not match real-world rates, perhaps because patients with high risk of bleeding were excluded, and thus assessment of bleeding risk is paramount in decision-making. Panel members also pointed out the heterogeneous populations included in the trials and the known changes in standard management over time. Given all of this, the panel voted to make a conditional recommendation in favor of therapeutic anticoagulation, while noting in the remarks that the decision should be based upon the risk of thrombosis (those with higher D-dimer levels or other risks for VTE may be at higher risk) and the risk of bleeding (see [fig_ref] TABLE 3 ]: High Bleeding Risk Patients [/fig_ref] for a more extensive list of factors associated with an increased risk of bleeding). Although consensus was reached, one panel member strongly disagreed with this recommendation. There were no randomized trials addressing this question. The only study to inform this question was an observational cohort that reported on rates of VTE stratified by thromboprophylaxis received.The rate of VTE in the intermediate dosing group was 7/33 (21%) and in the prophylactic dose group, 20/67 (30%). Bleeding estimates were not reported. Given our original recommendation against intermediate dosing in these patients, the evidence already presented above for consideration of therapeutic dosing in this cohort, and the lack of any evidence suggesting clear benefit of this approach, the panel voted to endorse the prior recommendation, with consensus reached after one round of voting. 2. In hospitalized patients with acute illness with COVID-19 who are not receiving therapeutic dose heparin (UFH or LMWH), we recommend current standard dose anticoagulant thromboprophylaxis over intermediate dose anticoagulation (defined as LMWH bid or increased weight-based dosing that is less than recommended therapeutic doses) (Strong Recommendation, Ungraded Consensus-Based Statement). Context: Given the lack of randomized controlled trials to address this question, there was unanimous agreement regarding this recommendation. Panel members also noted that "intermediate dose anticoagulation" leaves too much room for error and confusion in clinical practice. ## Critically ill patients Question 3: Should critically ill patients with COVID-19 be treated with therapeutic anticoagulation or thromboprophylaxis for prevention of VTE? For this analysis, we chose to include all studies that compared standard thromboprophylaxis dosing vs "escalated" dosing (intermediate or therapeutic). This was done because the panel recognized that common practice in many ICU settings includes varying escalated dosing protocols. There were five studies to inform this question, which included a total of 1,947 patients. Again, the largest was the multiplatform ATTACC, ACTIV-4a, and REMAP-CAP 13 trial, which accounted for 1,089 patients. Additional studies included the [fig_ref] Question 2: Should patients with COVID-19 hospitalized in the ward setting be treated with... [/fig_ref]. days in the therapeutic dose cohort vs 0 (0-11) ventilator-free days in the prophylactic group, which was significant (P ¼ .028). In the HEP-COVID 20 trial, 10/38 (26.3%) in the therapeutic group required mechanical ventilation compared with 8/35 (22.9%) in the thromboprophylaxis group. Six trials were included in the mortality analysis. In addition to the trials mentioned above, the ACTION 16 trial also included a small number of critically ill patients (n ¼ 39) who were incorporated in the analysis. There was no significant difference in mortality between the two groups (RR, 1.03 [95% CI, 0.91-1.15]) [fig_ref] Question 2: Should patients with COVID-19 hospitalized in the ward setting be treated with... [/fig_ref]. 3. In critically ill patients with COVID-19, we suggest current standard dose anticoagulant thromboprophylaxis (with UFH or LMWH) over therapeutic dose anticoagulation (Conditional Recommendation, Ungraded Consensus-Based Statement). Context: There was no disagreement about the direction of the recommendation. The data supporting thromboprophylaxis for the critically ill are quite robust. Other than the effect on PE seen in the multiplatform trial, there was insufficient evidence to suggest deviation from standard thromboprophylaxis. When all outcomes in the multiplatform trial, and not just PE, are factored in, the case against therapeutic anticoagulation is quite strong. Furthermore, although the risk of VTE is likely lower on therapeutic anticoagulation (absolute risk reduction, approximately 5%), the risk of major bleeding is higher (absolute risk increase, approximately 1%-2%), and there is no effect on mortality. Considering the risk of ascertainment bias for VTE in these open-label trials, the incomplete reporting of VTE events (no DVTs reported) and the high probability of inferiority of therapeutic anticoagulation compared with usual thromboprophylaxis for OSFDs in the multiplatform trial, the data thus far support continued use of existing guidelines. # Discussion and limitations This manuscript serves as a brief update to the original guidance statement. [bib_ref] Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019:..., Moores [/bib_ref] Although we have better quality evidence, many questions remain. Despite this, our panel felt that it was important to share our thoughts regarding the new evidence, especially as one recommendation differs in direction from the original publication, and the others have more evidence to support them. The decision to change the recommendation was not an easy one. While the new trials are higher quality evidence, the interpretation of the results is not without controversy. Progression of respiratory failure due to COVID-19 is a different end point than preventing VTE. In the end, we felt that it was an important end point. Some may question our decision not to include arterial thrombotic events as a primary outcome. These are clearly important to patients and clinicians. Our original publication, however, was focused on VTE, [bib_ref] Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019:..., Moores [/bib_ref] and this was designed as an update to that publication. In addition, a recent meta-analysis that did include these events would not likely have changed our recommendations. [bib_ref] Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and..., Ortega-Paz [/bib_ref] Questions remain and should guide further research. Does the timing of heparin administration affect the ultimate outcome? Should patients admitted to the ICU during their admission continue therapeutic heparin? chestjournal.org Does heparin indeed have antiinflammatory, antiviral, or other pleiotropic effects in COVID-19? Which mechanisms of the prothrombotic state are prominent, and does this influence the optimal approach? Are current standard therapies changing the baseline risk of VTE? Should the approach to vaccinated patients be any different than unvaccinated patients? ## Conclusions and future directions We have learned quite a bit regarding thrombosis in patients with COVID-19 pneumonia. Although advances in care have improved overall outcomes, current evidence supports that the rates of VTE are higher in these patients, at least in the ICU. [bib_ref] Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019:..., Jimenez [/bib_ref] [bib_ref] Venous thromboembolism in COVID-19 compared to non-COVID-19 cohorts: a systematic review with..., Mai [/bib_ref] At this time, we believe critically ill patients should still receive standard thromboprophylaxis for VTE, and moderately ill patients with a low bleeding risk might benefit from therapeutic heparin. We see no role for intermediate dose thromboprophylaxis in either setting. The World Health Organization plans to perform a meta-analysis that includes several small trials along with the studies included here, and their findings may inform practice (PROSPERO registration ID is CRD42020213461). In addition, results from recently published trials examining the effect of pre-and posthospital prophylaxis may lead to additional guideline updates. [fig] 12: patients were excluded, because they did not have confirmed COVID-19. f In REMAP-CAP, levels of oxygen support (including no support) below the level of high-flow nasal cannula were not reported.g Levels of oxygen support below the level of high-flow nasal cannula were not reported. h Levels of oxygen support other than mechanical ventilation were not reported. At baseline, 107 (62%) patients were admitted to an ICU. i A total of 45 of 253 (18%) patients were on either high-flow or noninvasive positive pressure ventilation. j Not listed are 113 patients who were co-enrolled in the REMAP-CAP Antiplatelet Domain (47 in the therapeutic dose anticoagulation group and 66 in the usual care pharmacologic thromboprophylaxis group). k Not listed are 74 patients who were co-enrolled in the REMAP-CAP Antiplatelet Domain (39 in the therapeutic dose anticoagulation group and 35 in the usual-care pharmacologic thromboprophylaxis group). l Treatment during trial period. [/fig] [fig] Question 2: Should patients with COVID-19 hospitalized in the ward setting be treated with intermediate dose anticoagulation or thromboprophylaxis? [/fig] [fig] Figure 2 -: Outcomes in critically ill patients receiving increased-dose anticoagulation vs standard thromboprophylaxis. PPx ¼ prophylaxis or thromboprophylaxis. [/fig] [fig] Figure 3 -: Outcomes in critically ill patients receiving intermediate-dose thromboprophylaxis vs standard thromboprophylaxis. [/fig] [table] TABLE 1 ]: Early Societal Guidelines Regarding Thromboprophylaxis in COVID-19 [/table] [table] TABLE 3 ]: High Bleeding Risk Patients [/table]

GRIA3 Glutamate receptor 3 is a protein that in humans is encoded by the GRIA3 gene. # Function Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. This gene belongs to a family of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. Alternative splicing at this locus results in several different isoforms which may vary in their signal transduction properties. # Interactions GRIA3 has been shown to interact with GRIP1 and PICK1. # RNA editing Several ion channels and neurotransmitters receptors pre-mRNA as substrates for ADARs. This includes 5 subunits of the glutamate receptor: ionotropic AMPA glutamate receptor subunits (Glur2, Glur3, Glur4) and kainate receptor subunits (Glur5, Glur6). Glutamate gated ion channels are made up of four subunits per channel with each subunit contributing to the pore loop structure. The pore loop structure is related to that found in K+ channels (e.g., human Kv1.1 channel). The human Kv1.1 channel pre mRNA is also subject to A to I RNA editing. The function of the glutamate receptors is in the mediation of fast neurotransmission to the brain. The diversity of the subunits is determined, as well as rna splicing by RNA editing events of the individual subunits. This give rise to the necessarily high diversity of these receptors. GluR3 is a gene product of the GRIA3 gene and its pre-mRNA is subject to RNA editing. ## Type A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues while ADAR3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS) ## Location The pre-mRNA of this subunit is edited at one position. The R/G editing site is located in exon 13 between the M3 and M4 regions. Editing results in a codon change from an arginine (AGA) to a glycine (GGA). The location of editing corresponds to a bipartite ligand interaction domain of the receptor. The R/G site is found at amino acid 769 immediately before the 38-amino-acid-long flip and flop modules introduced by alternative splicing. Flip and Flop forms are present in both edited and nonedited versions of this protein. The editing complimentary sequence (ECS) is found in an intronic sequence close to the exon. The intronic sequence includes a 5' splice site. The predicted double stranded region is 30 base pairs in length. The adenosine residue is mismatched in genomically encoded transcript, however this is not the case following editing. Despite similar sequences to the Q/R site of GluR-B, editing at this site does not occur in GluR-3 pre-mRNA. Editing results in the targeted adenosine, which is mismatched prior to editing in the double-stranded RNA structure to become matched after editing. The intronic sequence involved contains a 5' donor splice site. ## Conservation Editing also occurs in rat. ## Regulation Editing of GluR-3 is regulated in rat brain from low levels in embryonic stage to a large increase in editing levels at birth. In humans, 80-90% of GRIA3 transcripts are edited. The absence of the Q/R site editing in this glutamate receptor subunit is due to the absence of necessary intronic sequence required to form a duplex. ## Consequences ### Structure Editing results in a codon change from (AGA) to (GGA), an R to a G change at the editing site. ### Function Editing at R/G site allows for faster recovery from desensitisation. Unedited Glu-R at this site have slower recovery rates. Editing, therefore, allow sustained response to rapid stimuli. A crosstalk between editing and splicing is likely to occur here. Editing takes place before splicing. All AMPA receptors occur in flip and flop alternatively spliced variants. AMPA receptors that occur in the Flop form desenstise faster than the flip form. Editing is also thought to affect splicing at this site.

Sandbox/22 # Gas gangrene # CHF # Hypertension - ↑ Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE; et al. (1986). "Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study". N Engl J Med. 314 (24): 1547–52. doi:10.1056/NEJM198606123142404. PMID 3520315.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL; et al. (2003). "Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme". Lancet. 362 (9386): 759–66. PMID 13678868.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) Review in: ACP J Club. 2004 Mar-Apr;140(2):32-3 - ↑ Naidu SS (2011). "Novel percutaneous cardiac assist devices: the science of and indications for hemodynamic support". Circulation. 123 (5): 533–43. doi:10.1161/CIRCULATIONAHA.110.945055. PMID 21300961. - ↑ Birks EJ, Tansley PD, Hardy J, George RS, Bowles CT, Burke M; et al. (2006). "Left ventricular assist device and drug therapy for the reversal of heart failure". N Engl J Med. 355 (18): 1873–84. doi:10.1056/NEJMoa053063. PMID 17079761.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D; et al. (2009). "Advanced heart failure treated with continuous-flow left ventricular assist device". N Engl J Med. 361 (23): 2241–51. doi:10.1056/NEJMoa0909938. PMID 19920051.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Metra M, Torp-Pedersen C, Cleland JG, Di Lenarda A, Komajda M, Remme WJ, Dei Cas L, Spark P, Swedberg K, Poole-Wilson PA (2007). "Should beta-blocker therapy be reduced or withdrawn after an episode of decompensated heart failure? Results from COMET". European Journal of Heart Failure. 9 (9): 901–9. doi:10.1016/j.ejheart.2007.05.011. PMID 17581778. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ Gissi-HF Investigators. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG; et al. (2008). "Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial". Lancet. 372 (9645): 1223–30. doi:10.1016/S0140-6736(08)61239-8. PMID 18757090.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) Review in: Ann Intern Med. 2009 Jan 20;150(2):JC1-11

ProSavin ProSavin is an experimental drug believed to be of use in the treatment of Parkinson's Disease. It is administered to the striatum in the brain, inducing production of dopamine. It is manufactured by Oxford BioMedica, who plan to start European Phase I and Phase II clinical trials in 2007. Animal trials have been a success, with dopamine levels restored without the side effects associated with other current treatments for Parkinson's. # Mechanism of Action Prosavin uses Oxford BioMedica's Lentivector delivery system to transfer three genes, aromatic amino acid dopa decarboxylase, tyrosine hydroxylase and GTP-cyclohydrolase 1, to the striatum in the brain, reprogramming transduced cells to secrete dopamine.

HLA-B27 Human Leukocyte Antigen B*27 (subtypes B*2701-2724) is a class I surface antigen encoded by the B locus in the major histocompatibility complex (MHC) on chromosome 6 and presents microbial antigens to T-cells. HLA-B27 strongly associated with a certain set of autoimmune diseases referred to as the "seronegative spondyloarthropathies". In the general population, about 8% Caucasian, 4% African, 2-9% Chinese, and 0.1-0.5% Japanese have the HLA-B27 antigen. In Northern Scandinavia (Lapland), 24% of people are HLA-B27 positive while 1.8% have ankylosing spondylitis (AS). # Mystery The relationship between HLA-B27 and many diseases has not yet been fully elucidated. Though it is associated with a wide range of pathology, it does not appear to be the sole mediator in development of disease. For example, while nearly all people with ankylosing spondylitis (AS) are HLA-B27 positive, only a fraction of people with HLA-B27 ever develop AS. This raises two important questions: why don't all HLA-B27 positive people develop AS, and why do some (although rarely) people who are HLA-B27 negative develop it? The literature is inconclusive, though several theories have been suggested and research continues. # Associated pathology In addition to its connection with AS, HLA-B27 is implicated in Reiter's syndrome, certain eye disorders such as acute anterior uveitis and iritis, psoriatic arthritis and Crohn's disease. Reiter's syndrome then again, is statistically associated with AS.

Vertical direction In astronomy, geography, geometry and related sciences and contexts, a direction passing by a given point is said to be vertical if it is locally aligned with the gradient of the gravity field, i.e., with the direction of the gravitational force (per unit mass) at that point. # Discussion Although the word vertical is very commonly used in daily life and language (see below), it is subject to many misconceptions. The precise definition above and the following discussion points will hopefully clarify these issues. - The concept of verticality only makes sense in the context of a clearly measurable gravity field, i.e., in the 'neighborhood' of a planet, star, etc. When the gravity field becomes very weak (the masses are too small or too distant from the point of interest), the notion of being vertical loses its meaning. - In the presence of a simple, time-invariant, rotationally symmetric gravity field, the vertical directions passing by different points in space (and not belonging to the same vertical direction) intersect at the center of mass of that gravity field. This implies that no two different vertical directions are ever parallel to each other. - In general, a vertical direction will only be perpendicular to a horizontal plane if both are specifically defined with respect to the same point: a plane is only horizontal at the point of reference. Thus both verticality and horizontality are strictly speaking local concepts, and it is always necessary to state to which location the direction or the plane refers to. - In reality, the gravity field of a heterogeneous planet such as Earth is deformed due to the inhomogeneous spatial distribution of materials with different densities. Actual vertical directions are thus neither straight lines nor even convergent. - At any given location, the total gravitational force is a function of time, because the objects that generate the reference gravity field move relative to each other. For instance, on Earth, the local vertical direction at a given point (as materialized by a plumb line) changes with the relative position of the Moon (air, sea and land tides). - Furthermore, on a rotating planet such as Earth, there is a difference between the strictly gravitational pull of the planet (and possibly other celestial objects such as the Moon, the Sun, etc), and the apparent net force applied (e.g., on a free-falling object) that can be measured in the laboratory or in the field. This difference is due to the centrifugal force associated with the planet's rotation. This is a fictitious force: it only arises when calculations or experiments are conducted in non-inertial frames of reference. # Practical use in daily life The concept of a vertical line is thus anything but simple, although, in practice, most of these effects and variations are rather small: they are measurable and can be predicted with great accuracy, but they may not greatly affect our daily life. This dichotomy between the apparent simplicity of a usual concept and an actual complexity of defining (and measuring) it in scientific terms is because the typical linear scales and dimensions of relevance in daily life are 3 orders of magnitude (or more) smaller than the size of the Earth. Hence, the latter appears to be flat locally, and vertical directions in nearby locations appear to be parallel. Such statements are nevertheless approximations; whether they are acceptable in any particular context or application depends on the applicable requirements, in particular in terms of accuracy. In graphical contexts, such as drawing and drafting on rectangular paper, it is very common to associate one of the dimensions of the paper with a vertical, even though the entire sheet of paper is standing on a flat horizontal (or slanted) table. In this case, the vertical direction is typically from the side of the paper closest to the user to the opposite side (farthest away). This is purely conventional (although it is somehow 'natural' when drawing a natural scene as it is seen in reality), and may lead to misunderstandings or misconceptions, especially in an educational context.

Primula veris Primula veris (Cowslip; syn. Primula officinalis Hill) is a flowering plant in the genus Primula. The species is native throughout most of temperate Europe and Asia, and although absent from more northerly areas including much of north-westScotland, it reappears in northernmost Sutherland and Orkney. It is a low growing herbaceous perennial plant with a rosette of leaves 5-15 cm long and 2-6 cm broad. The deep yellow flowers are produced in the spring between April and May; they are in clusters of 10-30 together on a single stem 5-20 cm tall, each flower 9-15 mm broad. Red-flowered plants do occur, very rarely. It is frequently found on more open ground than Primula vulgaris (Primrose) including open fields, meadows, and coastal dunes and clifftops. It is often included in wild-flower seed mixes used to landscape motorway banks and similar civil engineering earth-works where it may be seen in dense stands. It may be confused with the closely related Primula elatior (Oxlip) which has a similar general appearance although the Oxlip has larger, pale yellow flowers more like a Primrose, and a corolla tube without folds. Cowslip is a favourite food of wild rabbits. # Folklore and herbalism It is used medicinally as a diuretic, an expectorant, and an antispasmodic, as well as for the treatment of headaches, whooping cough, tremors, and other conditions. However it can have irritant effects in people who are allergic to it Cowslips were made into wine, and also to flavour conventional wines. An ancient name for the plant is "paigle" (origin unknown). Another name, herb Peter, derives from the tale of St. Peter dropping the keys to the Gates of Heaven, with the cowslip springing from the spot. In the nineteenth century, cowslips were used as a garland on maypoles. The Cowslip is the county flower of four counties in England, these are Essex, Northamptonshire, Surrey, and Worcestershire.

Endometrial polyp An endometrial polyp or uterine polyp is a polyp or lesion in the lining of the uterus (endometrium) that takes up space within the uterine cavity. Commonly occurring, they are experienced by up to 10% of women. They may have a large flat base (sessile) or be attached to the uterus by an elongated pedicle (pedunculated). Pedunculated polyps are more common that sessile ones. They range in size from a few millimeters to several centimeters. If pedunculated, they can protrude through the cervix into the vagina. Small blood vessels may be present in polyps, particularly large ones. # Cause and symptoms No definitive cause of endometrial polyps is known, but they appear to be affected by hormone levels and grow in response to circulating estrogen. They often cause no symptoms. Where they occur, symptoms include irregular menstrual bleeding, bleeding between menstrual periods, excessively heavy menstrual bleeding (menorrhagia), and vaginal bleeding after menopause. Bleeding from the blood vessels of the polyp contributes to an increase of blood loss during menstruation and blood "spotting" between mentstrual periods, or after menopause. If the polyp protrudes through the cervix into the vagina, pain (dysmenorrhea) may result. # Diagnosis Endometrial polyps can be detected by vaginal ultrasound (sonohysterography), hysteroscopy and dilation and curettage. Detection by ultrasonography can be difficult, particularly when there is endometrial hyperplasia (excessive thickening of the endometrium). Larger polyps may be missied by curettage. Endometrial polyp with feeding vessel on power doppler image # Treatment Polyps can be surgically removed using curettage or hysterescopy. When curettage is performed, polyps may be missed. To reduce this risk, the uterues can be first explored using grasping forceps at the beginning of the curettage procedure. During hysterescopy, the polyp can be visualized and removed through the cervix. If it is a large polyp, it can be cut into sections before each section is removed. If cancerous cells are discovered, a hysterectomy may be performed. A hysterectomy would usually not be cconsidered if cancer has been ruled out. Whichever method is used, polyps are usually treated under general anesthetic. # Prognosis and complications Endometrial polyps are usually benign although some may be precancerous or cancerous. About 0.5% of endometrial polyps contain adenocarcinoma cells. Polyps can increase the risk of miscarriage in women undergoing IVF treatment. If they develop near the fallopian tubes, they may lead to difficulty in becoming pregnant. Although treatments such as hysterescopy usually cure the polyp concerned, recurrence of endometrial polyps is frequent. # Risk factors and epidemiology Endometrial polyps usually occur in women in their 40s and 50s. Risk factors include obesity, high blood pressure, a history of cervical polyps. Taking tamoxifen or hormone replacement therapy can also increase the risk of uterine polyps. Endometrial polyps occur in up to 10% of women. It is estimated that they are present in 25% of women with abnormal vaginal bleeding. # Structure Endometrial polyps can be solitary or occur with others. They are round or oval and measure between a few millimeters to several centimeters in diameter. They are usually the same red/brown color of the surrounding endometrium although large ones can appear to be a darker red. The polyps consist of dense, fibrous tissue (stroma), blood vessels and glandlike spaces lined with endometrial epithelium. If they are pedunculated, they are attached by a thin stalk (pedicle). If they are sessile, they are connected by a flat base to the uterine wall. Pedunculated polyps are more common than sessile ones.

Isocitrate dehydrogenase Isocitrate dehydrogenase (IDH) (EC 1.1.1.42) and (EC 1.1.1.41) is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. This is a two-step process, which involves oxidation of isocitrate (a secondary alcohol) to oxalosuccinate (a ketone), followed by the decarboxylation of the carboxyl group beta to the ketone, forming alpha-ketoglutarate. In humans, IDH exists in three isoforms: IDH3 catalyzes the third step of the citric acid cycle while converting NAD+ to NADH in the mitochondria. The isoforms IDH1 and IDH2 catalyze the same reaction outside the context of the citric acid cycle and use NADP+ as a cofactor instead of NAD+. They localize to the cytosol as well as the mitochondrion and peroxisome. # Isozymes The following is a list of human isocitrate dehydrogenase isozymes: ## NADP+ dependent Each NADP+-dependent isozyme functions as a homodimer: ## NAD+ dependent The isocitrate dehydrogenase 3 isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit: # Structure The NAD-IDH is composed of 3 subunits, is allosterically regulated, and requires an integrated Mg2+ or Mn2+ ion. The closest homologue that has a known structure is the E. coli NADP-dependent IDH, which has only 2 subunits and a 13% identity and 29% similarity based on the amino acid sequences, making it dissimilar to human IDH and not suitable for close comparison. All the known NADP-IDHs are homodimers. Most isocitrate dehydrogenases are dimers, to be specific, homodimers (two identical monomer subunits forming one dimeric unit). In comparing C. glutamicum and E. coli, monomer and dimer, respectively, both enzymes were found to "efficiently catalyze identical reactions." However, C. glutamicum was recorded as having ten times as much activity than E. coli and seven times more affinitive/specific for NADP. C. glutamicum favored NADP+ over NAD+. In terms of stability with response to temperature, both enzymes had a similar Tm or melting temperature at about 55 °C to 60 °C. However, the monomer C. glutamicum showed a more consistent stability at higher temperatures, which was expected. The dimer E. coli showed stability at a higher temperature than normal due to the interactions between the two monomeric subunits. The structure of Mycobacterium tuberculosis (Mtb) ICDH-1 bound with NADPH and Mn(2+) bound has been solved by X-ray crystallography. It is a homodimer in which each subunit has a Rossmann fold, and a common top domain of interlocking β sheets. Mtb ICDH-1 is most structurally similar to the R132H mutant human ICDH found in glioblastomas. Similar to human R132H ICDH, Mtb ICDH-1 also catalyzes the formation of α-hydroxyglutarate. # Regulation The IDH step of the citric acid cycle, due to its large negative free energy change, is one of the irreversible reactions in the citric acid cycle, and, therefore, must be carefully regulated to avoid unnecessary depletion of isocitrate (and therefore an accumulation of alpha-ketoglutarate). The reaction is stimulated by the simple mechanisms of substrate availability (isocitrate, NAD+ or NADP+, Mg2+ / Mn2+ ), product inhibition (by NADH (or NADPH outside the citric acid cycle) and alpha-ketoglutarate), and competitive feedback inhibition (by ATP). # Catalytic mechanisms Isocitrate dehydrogenase catalysis|catalyze the chemical reactions The overall free energy for this reaction is -8.4 kJ/mol. ## Steps Within the citric acid cycle, isocitrate, produced from the isomerization of citrate, undergoes both oxidation and decarboxylation. Using the enzyme isocitrate dehydrogenase (IDH), isocitrate is held within its active site by surrounding arginine, tyrosine, asparagine, serine, threonine, and aspartic acid amino acids. The first box shows the overall isocitrate dehydrogenase reaction. The reactants necessary for this enzyme mechanism to work are isocitrate, NAD+/NADP+, and Mn2+ or Mg2+. The products of the reaction are alpha-ketoglutarate, carbon dioxide, and NADH + H+/NADPH + H+. Water molecules are used to help deprotonate the oxygens (O3) of isocitrate. The second box is Step 1, which is the oxidation of the alpha-C (C#2). Oxidation is the first step that isocitrate goes through. In this process, the alcohol group off the alpha-carbon (C#2) is deprotonated and the electrons flow to the alpha-C forming a ketone group and removing a hydride off C#2 using NAD+/NADP+ as an electron accepting cofactor. The oxidation of the alpha-C allows for a position where electrons (in the next step) will be coming down from the carboxyl group and pushing the electrons (making the double bonded oxygen) back up on the oxygen or grabbing a nearby proton off a nearby Lysine amino acid. The third box is Step 2, which is the decarboxylation of oxalosuccinate. In this step, the carboxyl group oxygen is deprotonated by a nearby Tyrosine amino acid and those electrons flow down to carbon 2. Carbon dioxide leaves the beta carbon of isocitrate as a leaving group with the electrons flowing to the ketone oxygen off the alpha-C placing a negative charge on the oxygen of the alpha-C and forming an alpha-beta unsaturated double bond between carbons 2 and 3. The lone pair on the alpha-C oxygen picks up a proton from a nearby Lysine amino acid. The fourth box is Step 3, which is the saturation of the alpha-beta unsaturated double bond between carbons 2 and 3. In this step of the reaction, Lysine deprotonates the oxygen off the alpha carbon and the lone pair of electrons on the oxygen of the alpha carbon comes down reforming the ketone double bond and pushing the lone pair (forming the double bond between the alpha and beta carbon) off, picking up a proton from the nearby Tyrosine amino acid. This reaction results in the formation of alpha-ketoglutarate, NADH + H+/NADPH + H+, and CO2. ## Detailed mechanism Two aspartate amino acid residues (below left) are interacting with two adjacent water molecules (w6 and w8) in the Mn2+ isocitrate porcine IDH complex to deprotonate the alcohol off the alpha-carbon atom. The oxidation of the alpha-C also takes place in this picture where NAD+ accepts a hydride resulting in oxalosuccinate. Along with the sp3 to sp2 stereochemical change around the alpha-C, there is a ketone group that is formed form the alcohol group. The formation of this ketone double bond allows for resonance to take place as electrons coming down from the leaving carboxylate group move towards the ketone. The decarboxylation of oxalosuccinate (below center) is a key step in the formation of alpha-ketoglutarate. In this reaction, the lone pair on the adjacent Tyrosine hydroxyl abstracts the proton off the carboxyl group. This carboxyl group is also referred to as the beta subunit in the isocitrate molecule. The deprotonation of the carboxyl group causes the lone pair of electrons to move down making carbon dioxide and separating from oxalosuccinate. The electrons continue to move towards the alpha carbon pushing the double bond electrons (making the ketone) up to abstract a proton off an adjacent lysine residue. An alpha-beta unsaturated double bond results between carbon 2 and three. As you can see in the picture, the green ion represents either Mg2+ or Mn2+, which is a cofactor necessary for this reaction to occur. The metal-ion forms a little complex through ionic interactions with the oxygen atoms on the fourth and fifth carbons (also known as the gamma subunit of isocitrate). After the carbon dioxide is split from the oxalosuccinate in the decarboxylation step (below right), the enol will tautomerize to the keto from. The formation of the ketone double bond is started by the deprotonation of that oxygen off the alpha carbon (C#2) by the same lysine that protonated the oxygen in the first place. The lone pair of electrons moves down kicking off the lone pairs that were making the double bond. This lone pair of electrons abstracts a proton off the Tyrosine that deprotonated the carboxyl group in the decarboxylation step. The reason that we can say that the Lys and Tyr residues will be the same from the previous step is because they are helping in holding the isocitrate molecule in the active site of the enzyme. These two residues will be able to form hydrogen bonds back and forth as long as they are close enough to the substrate. The isocitrate dehydrogenase enzyme as stated above produces alpha-ketoglutarate, carbon dioxide, and NADH + H+/NADPH + H+. There are three changes that occurred throughout the reaction. The oxidation of Carbon 2, the decarboxylation (loss of carbon dioxide) off Carbon 3, and the formation of a ketone group with a stereochemical change from sp3 to sp2. ## Active site The Isocitrate Dehydrogenase (IDH) enzyme structure in Escherichia coli was the first structure to be elucidated and understood. Since then, the Escherichia coli IDH structure has been used by most researchers to make comparisons to other isocitrate dehydrogenase enzymes. There is much detailed knowledge about this bacterial enzyme, and it has been found that most isocitrate dehydrogenases are similar in structure and therefore also in function. This similarity of structure and function gives a reason to believe that the structures are conserved as well as the amino acids. Therefore, the active sites amongst most prokaryotic isocitrate dehydrogenase enzymes should be conserved as well, which is observed throughout many studies done on prokaryotic enzymes. Eukaryotic isocitrate dehydrogenase enzymes on the other hand, have not been fully discovered yet. Each dimer of IDH has two active sites. Each active site binds a NAD+/NADP+ molecule and a divalent metal ion (Mg2+,Mn2+). In general, each active site has a conserved sequence of amino acids for each specific binding site. In Desulfotalea psychrophila (DpIDH) and porcine (PcIDH) there are three substrates bound to the active site. - Isocitrate binds within the active site to a conserved sequence of about eight amino acids through hydrogen bonds. These acids include (may vary in residue but with similar properties) tyrosine, serine, asparagine, arginine, arginine, arginine, tyrosine, and lysine. Their positions on the backbone vary but they are all within a close range (i.e. Arg131 DpIDH and Arg133 PcIDH, Tyr138 DpIDH and Tyr140 PcIDH). - The metal ion (Mg2+, Mn2+) binds to three conserved amino acids through hydrogen bonds. These amino acids include three Aspartate residues. - NAD+ and NADP+ bind within the active site within four regions with similar properties amongst IDH enzymes. These regions vary but are around , , , and . Again regions vary but the proximity of regions are conserved. # Clinical significance Specific mutations in the isocitrate dehydrogenase gene IDH1 have been found in several brain tumors including astrocytoma, oligodendroglioma and glioblastoma multiforme, with mutations found in nearly all cases of secondary glioblastomas, which develop from lower-grade gliomas, but rarely in primary high-grade glioblastoma multiforme. Patients whose tumor had an IDH1 mutation had longer survival. Furthermore, mutations of IDH2 and IDH1 were found in up to 20% of cytogenetically normal acute myeloid leukemia (AML). These mutations are known to produce (D)-2-hydroxyglutarate from alpha-ketoglutarate. (D)-2-hydroxyglutarate accumulates to very high concentrations which inhibits the function of enzymes that are dependent on alpha-ketoglutarate. This leads to a hypermethylated state of DNA and histones, which results in different gene expression that can activate oncogenes and inactivate tumor-suppressor genes. Ultimately, this may lead to the types of cancer described above. Somatic mosaic mutations of this gene have also been found associated to Ollier disease and Maffucci syndrome. However, recent studies have also shown that (D)-2-hydroxyglutarate may be converted back into alpha-ketoglutarate either enzymatically or non-enzymatically. Further studies are required to fully understand the roles of IDH1 mutation (and (D)-2-hydroxyglutarate) in cancer.

Striae (patient information) For the WikiDoc page for this topic, click here # Overview Striae are irregular areas of skin that look like bands, stripes, or lines. Striae are seen when a person grows or gains weight rapidly or has certain diseases or conditions. Striae are commonly called stretch marks. # What are the symptoms of Striae? Stretch marks can appear when there is rapid stretching of the skin. They are often associated with the abdominal enlargement of pregnancy. They can be found in children who have become rapidly obese. They may also occur during the rapid growth of puberty in males and females. Striae are most commonly located on the breasts, hips, thighs, buttocks, abdomen, and flank. Stretch marks appear as parallel streaks of red, thinned, glossy skin that over time become whitish and scarlike in appearance. The stretch marks may be slightly depressed and have a different texture than normal skin. Striae may also occur as a result of abnormal collagen formation, or a result of medications or chemicals that interfere with collagen formation. They may also be associated with longtime use of cortisone compounds, diabetes, Cushing disease, and post-pregnancy. # What causes Striae? - Cushing syndrome - Ehlers-Danlos syndrome - Pregnancy - Puberty - Obesity - Overuse of cortisone skin creams # When to seek urgent medical care? If striae or stretch marks appear without obvious cause such as pregnancy or rapid weight gain, call your health care provider. # Treatment options There is no specific care for stretch marks. Marks often will disappear after the cause of the skin stretching is gone. Creams and ointments that claim to prevent stretch marks during pregnancy are of little value. Avoiding rapid weight gain helps reduce stretch marks caused by obesity. # Where to find medical care for Striae? Directions to Hospitals Treating Striae # What to expect (Outlook/Prognosis)? You health care provider will examine you and ask questions about your symptoms, including: - Is this the first time that you have developed striae? - When did you first notice the stretchmarks? - What medicines have you taken? - Have you used a cortisone skin cream? - What other symptoms do you have? If the striae are not caused by normal physical changes, tests may be done. # Sources

Sp1 gene transcriptions Specificity protein 1 is Sp1. Sp1 has been used as a control protein to compare with when studying the increase or decrease of the aryl hydrocarbon receptor and/or the estrogen receptor, since it binds to both and generally remains at a relatively constant level. Withaferin A, a sterodial lactone from Withania somnifera is known to inhibit Sp1 transcription factor. # Consensus sequences SP1 belongs to the Sp/KLF family of transcription factors. The protein is 785 amino acids long, with a molecular weight of 81 kDA. The SP1 transcription factor contains a zinc finger motif, by which it binds directly to DNA and enhances gene transcription. Its zinc fingers are of the Cys2/His2 type and bind the consensus sequence 5'-(G/T)GGGCGG(G/A)(G/A)(C/T)-3' (GC box). # Human genes GeneID: 6667 is SP1 Sp1 transcription factor. "The protein encoded by this gene is a zinc finger transcription factor that binds to GC-rich motifs of many promoters. The encoded protein is involved in many cellular processes, including cell differentiation, cell growth, apoptosis, immune responses, response to DNA damage, and chromatin remodeling. Post-translational modifications such as phosphorylation, acetylation, glycosylation, and proteolytic processing significantly affect the activity of this protein, which can be an activator or a repressor. Three transcript variants encoding different isoforms have been found for this gene." - NP_612482.2 transcription factor Sp1 isoform a. - NP_003100.1 transcription factor Sp1 isoform b. - NP_001238754.1 transcription factor Sp1 isoform c. - XP_011536998.1 transcription factor Sp1 isoform X1. GeneID: 6668 is SP2 Sp2 transcription factor. "This gene encodes a member of the Sp subfamily of Sp/XKLF transcription factors. Sp family proteins are sequence-specific DNA-binding proteins characterized by an amino-terminal trans-activation domain and three carboxy-terminal zinc finger motifs. This protein contains the least conserved DNA-binding domain within the Sp subfamily of proteins, and its DNA sequence specificity differs from the other Sp proteins. It localizes primarily within subnuclear foci associated with the nuclear matrix, and can activate or in some cases repress expression from different promoters." - NP_003101.3 transcription factor Sp2. - XP_011523438.1 transcription factor Sp2 isoform X1. - XP_011523439.1 transcription factor Sp2 isoform X2. - XP_011523440.1 transcription factor Sp2 isoform X3. - XP_011523441.1 transcription factor Sp2 isoform X4. - XP_011523442.1 transcription factor Sp2 isoform X5. - XP_006722086.1 transcription factor Sp2 isoform X6. - XP_006722088.1 transcription factor Sp2 isoform X7. - XP_006722089.1 transcription factor Sp2 isoform X7. - XP_006722090.1 transcription factor Sp2 isoform X7. - XP_011523444.1 transcription factor Sp2 isoform X7. - XP_011523445.1 transcription factor Sp2 isoform X7. - XP_016880457.1 transcription factor Sp2 isoform X7. - XP_024306660.1 transcription factor Sp2 isoform X8. Gene ID: 6670 is SP3 Sp3 transcription factor. "This gene belongs to a family of Sp1 related genes that encode transcription factors that regulate transcription by binding to consensus GC- and GT-box regulatory elements in target genes. This protein contains a zinc finger DNA-binding domain and several transactivation domains, and has been reported to function as a bifunctional transcription factor that either stimulates or represses the transcription of numerous genes. Transcript variants encoding different isoforms have been described for this gene, and one has been reported to initiate translation from a non-AUG (AUA) start codon. Additional isoforms, resulting from the use of alternate downstream translation initiation sites, have also been noted. A related pseudogene has been identified on chromosome 13." - NP_003102.1 transcription factor Sp3 isoform 1. - NP_001017371.3 transcription factor Sp3 isoform 2. - NP_001166183.1 transcription factor Sp3 isoform 3. GeneID: 6671 is SP4 Sp4 transcription factor. "The protein encoded by this gene is a transcription factor that can bind to the GC promoter region of a variety of genes, including those of the photoreceptor signal transduction system. The encoded protein binds to the same sites in promoter CpG islands as does the transcription factor SP1, although its expression is much more restricted compared to that of SP1. This gene may be involved in bipolar disorder and schizophrenia." - NP_003103.2 transcription factor Sp4 isoform 1. - NP_001313471.1 transcription factor Sp4 isoform 2. - NP_001313472.1 transcription factor Sp4 isoform 3. - NR_137166.1 RNA Sequence non-coding (variant 4). - XP_011513788.1 transcription factor Sp4 isoform X1. - XP_005249886.1 transcription factor Sp4 isoform X2. - XP_016868046.1 transcription factor Sp4 isoform X3. - XP_011513789.1 transcription factor Sp4 isoform X4. GeneID: 389058 is SP5 Sp5 transcription factor. - NP_001003845.1 transcription factor Sp5. - XP_011509461.1 transcription factor Sp5 isoform X1. - XP_005246599.1 transcription factor Sp5 isoform X2. GeneID: 80320 is SP6 Sp6 transcription factor (aka KLF14). "SP6 belongs to a family of transcription factors that contain 3 classical zinc finger DNA-binding domains consisting of a zinc atom tetrahedrally coordinated by 2 cysteines and 2 histidines (C2H2 motif). These transcription factors bind to GC-rich sequences and related GT and CACCC boxes." - NP_001245177.1 transcription factor Sp6 (variant 1). - NP_954871.1 transcription factor Sp6 (variant 2). - XP_006722178.1 transcription factor Sp6 isoform X1. GeneID: 121340 is SP7 Sp7 transcription factor. "This gene encodes a member of the Sp subfamily of Sp/XKLF transcription factors. Sp family proteins are sequence-specific DNA-binding proteins characterized by an amino-terminal trans-activation domain and three carboxy-terminal zinc finger motifs. This protein is a bone specific transcription factor and is required for osteoblast differentiation and bone formation." - NP_001166938.1 transcription factor Sp7 isoform a. - NP_690599.1 transcription factor Sp7 isoform a. - XP_011536202.1 transcription factor Sp7 isoform X1. - NP_001287766.1 transcription factor Sp7 isoform b. GeneID: 221833 is SP8 Sp8 transcription factor. "The protein encoded by this gene is an SP family transcription factor that in mouse has been shown to be essential for proper limb development. Two transcript variants encoding different isoforms have been found for this gene." - NP_874359.2 transcription factor Sp8 isoform 1. - NP_945194.1 transcription factor Sp8 isoform 2. GeneID: 100131390 is SP9 Sp9 transcription factor. # Sp/KLF family The Sp/KLF family (specificity protein/Krüppel-like factor) is a family of transcription factors, including the Kruppel-like factors as well as Sp1 transcription factor, Sp2 transcription factor, Sp3 transcription factor, Sp4 transcription factor, Sp8 transcription factor, Sp9; and possibly Sp5 and Sp7 transcription factor. KLF14 is also designated Sp6. # Specificity proteins Sp1-box 1 (GGGGCT) and Sp1-box 2 (CTGCCC). "Sp3 has been shown to repress transcriptional activity of Sp1 ." Sp-1 (CCGCCCC). Sp1 (GCGGC). SP1 (GGGGCGGGCC). An apparent consensus sequences for Sp1 (GGGGCT), (CTGCCC) or (CCGCCCC) is 5'-(C/G)(C/G/T)G(C/G)C(C/T)-3'. Or, each must be considered separately. Copying the apparent consensus sequences for Sp1 (GGGGCT), (CTGCCC) or (CCGCCCC) and putting each sequence in "⌘F" finds none located between ZSCAN22 and A1BG and four, two or none between ZNF497 and A1BG as can be found by the computer programs. # SP1 (Long 2020) samplings Copying a responsive elements consensus sequence GGGGCGGGCC and putting the sequence in "⌘F" finds none between ZNF497 and A1BG or none between ZSCAN22 and A1BG as can be found by the computer programs. For the Basic programs testing consensus sequence GGGGCGGGCC (starting with SuccessablesSP1L.bas) written to compare nucleotide sequences with the sequences on either the template strand (-), or coding strand (+), of the DNA, in the negative direction (-), or the positive direction (+), the programs are, are looking for, and found: - Negative strand, negative direction: 0. - Positive strand, negative direction: 0. - Negative strand, positive direction: 0. - Positive strand, positive direction: 0. - inverse complement, negative strand, negative direction: 0. - inverse complement, positive strand, negative direction: 0. - inverse complement, negative strand, positive direction: 0. - inverse complement, positive strand, positive direction: 0. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff. Initial content for this page in some instances came from Wikiversity. Initial content for this page in some instances incorporates text from the United States National Library of Medicine.

PRDX6 Peroxiredoxin-6 is a protein that in humans is encoded by the PRDX6 gene. It is a member of the peroxiredoxin family of antioxidant enzymes. # Function The protein encoded by this gene is a member of the thiol-specific antioxidant protein family. This protein is a bifunctional enzyme with two distinct active sites. It is involved in redox regulation of the cell; it can reduce H(2)O(2) and short chain organic, fatty acid, and phospholipid hydroperoxides. It may play a role in the regulation of phospholipid turnover as well as in protection against oxidative injury. ## Model organisms Model organisms have been used in the study of PRDX6 function. A conditional knockout mouse line, called Prdx6tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice but no significant abnormalities were observed.

Measles | Disease Directory | Travelers' Health | CDC ### What is measles? Measles is a disease caused by a highly contagious virus. People with measles spread the virus through the air when they cough, sneeze, or breathe.   [Symptoms](https://www.cdc.gov/measles/symptoms/signs-symptoms.html) of measles include high fever, cough, runny nose, red and watery eyes, and rash. Koplik spots (tiny white spots inside the mouth) can appear 2 to 3 days after symptoms begin. Some people who become sick with measles also get a serious lung infection, such as pneumonia. Although severe cases are rare, measles can cause swelling of the brain and even death. Measles can be especially severe in infants and in people who are malnourished or who have weakened immune systems. ### Who is at risk? Anyone who has not been fully vaccinated or had measles before can get measles. Measles remains a common disease in many parts of the world, including Europe, the Middle East, Asia, the Pacific, and Africa.  In the United States, most measles cases occur among unvaccinated travelers who get infected while traveling internationally and spread measles to people who are not fully vaccinated in the United States. Information by Destination  Where are you going? -- Select One --AfghanistanAlbaniaAlgeriaAmerican SamoaAndorraAnegadaAngolaAnguilla (U.K.)AntarcticaAntigua and BarbudaArgentinaArmeniaArubaAustral IslandsAustraliaAustriaAzerbaijanAzoresBahamas, TheBahrainBangladeshBarbadosBarbudaBelarusBelgiumBelizeBeninBermuda (U.K.)BhutanBoliviaBonaireBora-BoraBosnia and HerzegovinaBotswanaBrazilBritish Indian Ocean Territory (U.K.)BruneiBulgariaBurkina FasoBurma (Myanmar)BurundiCaicos IslandsCambodiaCameroonCanadaCanary Islands (Spain)Cape VerdeCayman Islands (U.K.)Central African RepublicChadChileChinaChristmas Island (Australia)Cocos (Keeling) Islands (Australia)ColombiaComorosCongo, Republic of theCook Islands (New Zealand)Costa RicaCôte d'IvoireCroatiaCubaCuraçaoCyprusCzech RepublicDemocratic Republic of the CongoDenmarkDjiboutiDominicaDominican RepublicDubaiEaster Island (Chile)EcuadorEgyptEl SalvadorEnglandEquatorial GuineaEritreaEstoniaEswatini (Swaziland)EthiopiaFalkland Islands (Islas Malvinas)Faroe Islands (Denmark)FijiFinlandFranceFrench Guiana (France)French Polynesia (France)GabonGalápagos IslandsGambia, TheGeorgiaGermanyGhanaGibraltar (U.K.)GreeceGreenland (Denmark)GrenadaGrenadinesGuadeloupeGuam (U.S.)GuatemalaGuernseyGuineaGuinea-BissauGuyanaHaitiHoly SeeHondurasHong Kong SAR (China)HungaryIcelandIndiaIndonesiaIranIraqIrelandIsle of ManIsrael, including the West Bank and GazaItalyIvory CoastJamaicaJapanJerseyJordanJost Van DykeKazakhstanKenyaKiribatiKosovoKuwaitKyrgyzstanLaosLatviaLebanonLesothoLiberiaLibyaLiechtensteinLithuaniaLuxembourgMacau SAR (China)MadagascarMadeira Islands (Portugal)MalawiMalaysiaMaldivesMaliMaltaMarquesas IslandsMarshall IslandsMartinique (France)MauritaniaMauritiusMayotte (France)MexicoMicronesia, Federated States ofMoldovaMonacoMongoliaMontenegroMontserrat (U.K.)MooreaMoroccoMozambiqueMyanmar (Burma)NamibiaNauruNepalNetherlands, TheNew Caledonia (France)New ZealandNicaraguaNigerNigeriaNiue (New Zealand)Norfolk Island (Australia)North KoreaNorth MacedoniaNorthern IrelandNorthern Mariana Islands (U.S.)NorwayOmanPakistanPalauPanamaPapua New GuineaParaguayPeruPhilippinesPitcairn Islands (U.K.)PolandPortugalPuerto Rico (U.S.)QatarRéunion (France)RomaniaRotaRurutuRussiaRwandaSabaSaint BarthelemySaint CroixSaint Helena (U.K.)Saint JohnSaint Kitts and NevisSaint LuciaSaint MartinSaint Pierre and Miquelon (France)Saint ThomasSaint Vincent and the GrenadinesSaipanSamoaSan MarinoSão Tomé and PríncipeSaudi ArabiaScotlandSenegalSerbiaSeychellesSierra LeoneSingaporeSint EustatiusSint MaartenSlovakiaSloveniaSociety IslandsSolomon IslandsSomaliaSouth AfricaSouth Georgia and the South Sandwich Islands (U.K.)South KoreaSouth Sandwich IslandsSouth SudanSpainSri LankaSudanSurinameSwaziland (Eswatini)SwedenSwitzerlandSyriaTahitiTaiwanTajikistanTanzaniaThailandTimor-Leste (East Timor)TinianTobagoTogoTokelau (New Zealand)TongaTortolaTrinidad and TobagoTubuaiTunisiaTurkeyTurkmenistanTurks and Caicos Islands (U.K.)TuvaluUgandaUkraineUnited Arab EmiratesUnited KingdomUnited StatesUruguayUzbekistanVanuatuVatican CityVenezuelaVietnamVirgin GordaVirgin Islands, BritishVirgin Islands, U.S.Wake IslandWalesYemenZambiaZanzibarZimbabweGo var e = document.getElementById("thlrdssl-traveler"); var value = e.options[e.selectedIndex].value; var url = "/travel/destinations/traveler/none/" - value; if (value == '0'){ window.location = "/travel/destinations/list"; window.location = url; ### What can travelers do to prevent measles? Getting vaccinated is the best way to protect yourself and others against measles. Measles vaccine is a routine vaccination given to children in the United States. Measles vaccine is usually given in two doses. It’s recommended that children get the first dose when they are 12 to 15 months old and the second dose when they are 4 to 6 years old. Measles vaccine is a combination vaccine that also protects against mumps and rubella (MMR vaccine) or mumps, rubella, and varicella (MMRV vaccine). If you were born in or after 1957 and have never had measles or have never been vaccinated against measles, you should get vaccinated with two doses of MMR vaccine before you travel. The second dose is given at least 28 days after the first dose. People born before 1957 were likely exposed to measles as children and do not need to be vaccinated with the MMR vaccine. Infants 6 to 11 months old traveling internationally should get one dose of MMR vaccine before travel. This dose does not count as part of the routine childhood vaccination series. CAUTION: Pregnant people should NOT get the MMR vaccine. Any unvaccinated person should get the MMR vaccine immediately after their pregnancy. Avoid getting pregnant for at least 4 weeks after receiving the MMR vaccine.

Vesicular monoamine transporter # Overview The vesicular monoamine transporter is a transport protein located within the presynaptic cell. # Isoforms It comprises the two isoforms: - VMAT1 - VMAT2 # Substrates Substrates for the transporter is mainly noradrenaline, adrenaline and isoprenaline. However, other substrates include dopamine, 5-HT, guanethidine and MPP+. # Clinicial significance It can be inhibited by reserpine and tetrabenazine. VMAT is the main target of methamphetamine. By acting as a competitive antagonist, methamphetamine blocks the presynaptic cell's ability to use VMAT to package the above mentioned neurotransmitters into vesicles. The result is increased neurotransimtter release that is not dependent on the phasic activity of the presynaptic cell.

Tobacco and health # Overview The effects of tobacco on health are significant, depending on the way the tobacco is used (smoked, snuffed or chewed) and the amount. Major health effects of smoking, the most common use of tobacco, include an increased risk in lung cancer and cardiovascular disease. The World Health Organization estimated in 2002 that in developed countries, 26% of male deaths and 9% of female deaths were attributable to smoking. Similarly, the United States Centers for Disease Control and Prevention describes tobacco use as "the single most important preventable risk to human health in developed countries and an important cause of premature death worldwide." # Primary risks Regular smokers are estimated to live to 2.5 to 10 years less than nonsmokers. About one-half of male smokers will die of illness due to smoking. Tobacco related illnesses kill approximately 438,000 USA citizens per year, about 1,205 per day, making it the leading cause of preventable death in the U.S. The World Health Organization has stated that tobacco is set to kill a billion people this century. The main health risks in tobacco pertain to diseases of the cardiovascular system, in particular smoking being a major risk factor for a myocardial infarction (heart attack), diseases of the respiratory tract such as Chronic Obstructive Pulmonary Disease (COPD) and emphysema, and cancer, particularly lung cancer and cancers of the larynx and mouth. It also increases the risk of developing pancreatic cancer by 75%. Prior to World War I, lung cancer was considered to be a rare disease, which most physicians would never see during their career. With the postwar rise in popularity of cigarette smoking came a virtual epidemic of lung cancer. Currently, among people who have ever smoked any kind of tobacco, almost one in ten will develop lung cancer. One in six men who continue to smoke tobacco will develop lung cancer. This compares to only one case of lung cancer in seventy-five lifelong non-smokers. Incidence of impotence is approximately 85 percent higher in male smokers compared to non-smokers, and it is a key cause of erectile dysfunction (ED). Smoking causes impotence because it promotes arterial narrowing. A person's increased risk of contracting disease is directly proportional to the length of time that a person continues to smoke as well as the amount smoked. However, if someone stops smoking, then these chances gradually decrease as the damage to their body is repaired. Diseases linked to smoking tobacco cigarettes include: - Many forms of cancer, particularly lung cancer, cancer of the kidney, cancer of the larynx and head and neck, breast cancer , bladder, esophagus, pancreas, and stomach. There is some evidence suggesting an increased risk of myeloid leukemia, squamous cell sinonasal cancer, liver cancer, cervical cancer, colorectal cancer after an extended latency, childhood cancers and cancers of the gall bladder, adrenal gland and small intestine. - Cardiovascular disease stroke peripheral vascular disease - stroke - peripheral vascular disease - Respiratory ailments common cold and bronchitis Chronic obstructive pulmonary disease, emphysema and chronic bronchitis in particular - common cold and bronchitis - Chronic obstructive pulmonary disease, emphysema and chronic bronchitis in particular - Birth defects of pregnant smokers' offspring - Buerger's disease (thromboangiitis obliterans) - Cataracts that may cause blindness - Cognitive dysfunction Increased risk of Alzheimer's disease and decline in cognitive abilities Reduced memory and cognitive abilities in adolescent smokers Brain shrinkage (cerebral atrophy) - Increased risk of Alzheimer's disease and decline in cognitive abilities - Reduced memory and cognitive abilities in adolescent smokers - Brain shrinkage (cerebral atrophy) - Impotence Cigar and pipe smokers tend to inhale less smoke than cigarette smokers, so their risk of lung cancer is lower but is still several times higher than the risk for nonsmokers. Pipe and cigar smokers are also at risk for cancers of the oral cavity, larynx (voice box), or esophagus, a risk which was widely hypothesized before any link between smoking and cancer was scientifically proved as seen in the news coverage of the tobacco-related cancers of two American presidents; Ulysses S. Grant died in 1885 at age sixty-three after a long and painful public battle with throat cancer which was widely assumed at the time to be the result of his lifelong cigar habit, and Grover Cleveland was diagnosed in 1893 with cancer of the left jaw, which was frequently remarked upon by the press and public as the side where he usually had a cigar clamped. Similarly, cancer of the mouth and jaw is also a risk for chewing tobacco. The benefits of smoking cessation are immediate: blood pressure, heart rate, and temperature return to normal range; heart attack risk decreases; ability to smell and taste is enhanced; circulation improves. It is generally assumed that the major motivational factor behind smoking is the nicotine it contains. However, the practice of ingesting the smoke from a smoldering leaf generates an enormous number of active chemical compounds, loosely lumped together as 'tar', many of which are biologically reactive and potential health dangers. (Chewing tobacco is also carcinogenic, likely because similar compounds are generated in the practice of curing it; the Nordic snus, which is steam cured and therefore does not generate these compounds, is much less carcinogenic.) There are around 3000 chemicals found in tobacco smoke. Long term exposure to other compounds in the smoke, such as carbon monoxide, cyanide, and other compounds that damage lung and arterial tissue, are believed to be responsible for cardiovascular damage and for loss of elasticity in the alveoli, leading to emphysema and COPD. ## Radioactive components of tobacco In addition to chemical, nonradioactive carcinogens, tobacco and tobacco smoke contain small amounts of lead-210 (210Pb) and polonium-210 (210Po) both of which are radioactive carcinogens. Lead 210 is a product of the decay of radium-226 and, in turn, its decay product, radon-222; lead 210 then decays to bismuth-210 and then to polonium 210, emitting beta particles in both steps. Tarry particles containing these elements lodge in the smokers' lungs where airflow is disturbed; the concentration found where bronchioles bifurcate is 100 times higher than that in the lungs overall. This gives smokers much more intense exposure than would otherwise be encountered. Polonium 210, for instance, emits high energy alpha particles which, because of their large mass, are considered to be incapable of penetrating the skin more than 40 micrometres deep, but do considerable damage (estimated at 100 times as much chromosome damage as a corresponding amount of other radiation) when a process such as smoking causes them to be emitted within the body, where all their energy is absorbed by surrounding tissue. (Lead 210 also emits gamma rays). The radioactive elements in tobacco are accumulated from the minerals in the soil, as with any plant, but are also captured on the sticky surface of the tobacco leaves in excess of what would be seen with plants not having this property. As might be expected, the radioactivity measured in tobacco varies widely depending on where and how it is grown. One study found that tobacco grown in India averaged only 0.09 pCi per gram of polonium-210, whereas tobacco grown in the United States averaged 0.516 pCi per gram. Another study of Indian tobacco, however, measured an average of 0.4 pCi of polonium 210 per cigarette, which also would be approximately a gram of tobacco. One factor in the difference between India and the United States may be the extensive use of apatite as fertilizer for tobacco in the United States, because it starves the plant for nitrogen, thereby producing more flavorful tobacco; apatite is known to contain radium, lead 210, and polonium 210. This would also account for increased concentration of these elements compared to other crops, which do not use this mineral as fertilizer. The presence of polonium-210 in mainstream cigarette smoke has been experimentally measured at levels of 0.0263 - 0.036 pCi, which is equivalent to about 0.1 pCi per milligram of smoke; or about 0.81 pCi of lead 210 per gram of dry condensed smoke. The amount of polonium 210 inhaled from a pack of 20 cigarettes is therefore about 0.72 pCi. This seems to be independent of any form of filtering or 'low tar' cigarette. This concentration results in a highly significant increase in the body burden of these compounds. Compared to nonsmokers, heavy smokers have four times greater radioisotope density throughout their lungs. The polonium 210 content of blood in smokers averages 1.72 pCi per kilogram, compared to 0.76 pCi per kilogram in nonsmokers. Higher concentrations of polonium 210 are also found in the livers of smokers than nonsmokers. Polonium 210 is also known to be incorporated into bone tissue, where the continued irradiation of bone marrow may be a cause of leukemia, although this has not been proved as yet. Research by NCAR radiochemist Ed Martell determined that radioactive compounds in cigarette smoke are deposited in "hot spots" where bronchial tubes branch. Since tar from cigarette smoke is resistant to dissolving in lung fluid, the radioactive compounds have a great deal of time to undergo radioactive decay before being cleared by natural processes. Indoors, these radioactive compounds linger in secondhand smoke, and therefore greater exposure occurs when these radioactive compounds are inhaled during normal breathing, which is deeper and longer than when inhaling cigarettes. Damage to the protective epithelial tissue from smoking only increases the prolonged retention of insoluble polonium 210 compounds produced from burning tobacco. Martell estimated that a carcinogenic radiation dose of 80-100 rads is delivered the lung tissue of most smokers who die of lung cancer. In other experiments, the alpha particle dosage from polonium 210 received by smokers of two packs a day was measured at 82.5 millirads per day, which would total 752.5 rads per 25 years, 150 times higher than the approximately 5 rem received from natural background radiation over 25 years. Other estimates of the dosage absorbed over 25 years of heavy smoking range from 165 to 1,000 rem, all significantly higher than natural background. In the case of the less radioactive Indian tobacco referred to above, the dosage received from polonium 210 is about 24 millirads a day, totalling 219 rads over 25 years or still about 40 times the natural background radiation exposure. In fact, all these numbers of total body burden are misleadingly low, because the dosage rate in the immediate vicinity of the deposited polonium 210 in the lungs can be from 100 to 10,000 times greater than natural background radiation. Lung cancer is seen in laboratory animals exposed to approximately one fifth of this total dosage of polonium 210. Whether the quantities of these elements are sufficient to cause cancer is still a matter of debate. Most studies of carcinogenicity of tobacco smoke involve painting tar condensed from smoke onto the skin of mice and monitoring for development of tumors of the skin, a relatively simple process. However, the specific properties of polonium 210 and lead 210 and the model for their action, as described above, do not permit such a simple assay and require more difficult studies, requiring dosage of the mice in a manner mimicking smoking behavior of humans and monitoring for lung cancer, more difficult to observe as it is internal to the mouse. Some researchers suggest that the degree of carcinogenicity of these radioactive elements is sufficient to account for most, if not all, cases of lung cancer related to smoking. In support of this hypothetical link between radioactive elements in tobacco and cancer is the observation that bladder cancer incidence is also proportional to the amount of tobacco smoked, even though nonradioactive carcinogens have not been detected in the urine of even heavy smokers; however, urine of smokers contains about six times more polonium 210 than that of nonsmokers, suggesting strongly that the polonium 210 is the cause of the bladder carcinogenicity, and would be expected to act similarly in the lungs and other tissue. Furthermore, many of the lung cancers contracted by cigarette smokers are adenocarcinomas, which are characteristic of the type of damage produced by alpha particle radiation such as that of polonium 210. It has also been suggested that the radioactive and chemical carcinogens in tobacco smoke act synergistically to cause a higher incidence of cancer than each alone. However, the view that polonium 210 is responsible for many cases of cancer in tobacco smokers is disputed by at least one researcher. ## Other carcinogens There are over 19 known carcinogens in cigarettes. The following are some of the most potent carcinogens: - Polynuclear aromatic hydrocarbons are produced by pyrolysis in smoldering organic matter and emitted into smoke. Many of them are highly carcinogenic and mutagenic, because they are toxicated to mutagenic epoxides. The first PAH to be identified as a carcinogen in tobacco smoke was benzopyrene, which been shown to toxicate into a diol epoxide and then permanently attach to nuclear DNA, which may either kill the cell or cause a genetic mutation. If the mutation inhibits programmed cell death, the cell can survive to become a cancer cell. Tobacco manufacturers have experimented with combustionless vaporizer technology to allow cigarettes to be consumed without the formation of carcinogenic benzopyrenes. - Nitrosamines are a group of carcinogenic compounds found in cigarette smoke but not in uncured tobacco leaves. Nitrosamines form on flue-cured tobacco leaves during the curing process through a chemical reaction between nicotine and other compounds contained in the uncured leaf and various oxides of nitrogen found in all combustion gases. Switching to indirect-fire curing has been shown to reduce nitrosamine levels to less than 0.1 parts per million. - The carcinogenity of tobacco smoke is not explained by nicotine per se, which is not carcinogenic or mutagenic. It can be a synergistic carcinogen, however. ## Nicotine Addiction and Genetic Factors According to three separate studies commissioned by governments in the US and Europe scientists have identified a genetic link that makes people more likely to become addicted to tobacco. This genetic variation causes individuals to smoke more cigarettes, makes it harder for them to quit and increases their likelihood of developing lung cancer by up to 80%. Genetic markers of more than 35,000 people (mostly smokers and ex-smokers) were surveyed by scientists in three separate studies and all three zoned in on the same set of genetic differences. The genetic variations of note encode nicotine receptors on cells and was identified on a region of chromosome 15. Possessing a single copy of the mutation raises an individuals risk of lung cancer by approximately 30%, while possessing two copies can raise that figure to about 80%. ## Nicotine and addiction Nicotine is a stimulant and is one of the main factors leading to continued tobacco smoking. Although the amount of nicotine inhaled with tobacco smoke is quite small (most of the substance is destroyed by the heat) it is still sufficient to cause physical and/or psychological dependence. The amount of nicotine absorbed by the body from smoking depends on many factors, including the type of tobacco, whether the smoke is inhaled, and whether a filter is used. Despite the design of various cigarettes advertised and even tested on machines to deliver less of the toxic tar, studies show that when smoked by humans instead of machines, they deliver the same net amount of smoke. Ingesting a compound by smoking is one of the most rapid and efficient methods of introducing it into the bloodstream, second only to injection, which allows for the rapid feedback which supports the smokers' ability to titrate their dosage. On average it takes about ten seconds for the substance to reach the brain. As a result of the efficiency of this delivery system, many smokers feel as though they are unable to cease. Of those who attempt cessation and last three months without succumbing to nicotine, most are able to remain smoke free for the rest of their lives. There exists a possibility of depression in some who attempt cessation, as with other psychoactive substances. Depression is also common in teenage smokers; teens who smoke are four times as likely to develop depressive symptoms as their nonsmoking peers . Although nicotine does play a role in acute episodes of some diseases (including stroke, impotence, and heart disease) by its stimulation of adrenaline release, which raises blood pressure, heart rate, and free fatty acids, the most serious longer term effects are more the result of the products of the smouldering combustion process. This has enabled development of various nicotine delivery systems, such as the nicotine patch or nicotine gum, that can satisfy the addictive craving by delivering nicotine without the harmful combustion by-products. This can help the heavily dependent smoker to quit gradually, while discontinuing further damage to health. ## Smoking and cardiovascular disease Smoking also increases the chance of heart disease. Several ingredients of tobacco lead to the narrowing of blood vessels, increasing the likelihood of a blockage, and thus a heart attack or stroke. According to a study by an international team of researchers, people under 40 are five times more likely to have a heart attack if they smoke. ## Oral health Perhaps the most serious oral condition that can arise from tobacco smoking is that of oral cancer. However, smoking also increases the risk for various other oral diseases, some almost completely exclusive to smokers. Roughly half of periodontitis cases are attributed to current or former smoking. Smokers experience widespread periodontal destruction and have significantly greater loss of bone height. Smokeless tobacco causes gingival recession and white mucosal lesions. Up to 90% of periodontitis patients who are not helped by common modes of treatment are smokers. Smoking has been proven to be an important factor in the staining of teeth. Halitosis is common among tobacco smokers. Other oral diseases that are known to have strong links to smoking are leukoplakia, Snuff Dipper's lesions and smoker's palate. In addition, many smokers report a loss of taste sensation and/or salivary changes. Tooth loss has been shown to be 2 to 3 times higher in smokers than in non-smokers. ## Physical and psychological effects on smokers Smokers report a variety of physical and psychological effects from smoking tobacco. Those new to smoking will experience nausea, dizziness, and rapid heart beat. The unpleasant symptoms will eventually vanish over time, with repeated use, as the body builds a tolerance to the chemicals in the cigarettes, such as nicotine. In many respects, nicotine acts on the nervous system in a similar way to caffeine. Some writings have stated that smoking can also increase mental concentration; one study documents a significantly better IQ on the normed Advanced Raven Progressive Matrices test after smoking. Most smokers say they enjoy smoking, which is part of the reason why many continue to do so even though they are aware of the health risks. Taste, smell, and visual enjoyment are also major contributions to the enjoyment of smoking, in addition to camaraderie with other smokers. Ironically, chronic exposure to tobacco smoke may inhibit one's sense of taste and smell, rendering him or her less able to enjoy these aspects of tobacco smoking. Most smokers, when denied access to nicotine, exhibit symptoms such as irritability, jitteriness, dry mouth, and rapid heart beat. Longer abstinence may lead to insomnia and even mild depression. The onset of these symptoms is very fast, nicotine's half-life being only 1 hour. Withdrawal symptoms can appear even if the smoker's consumption is very limited or irregular, appearing after only 4-5 cigarettes in most adolescents. An ex-smoker's chemical dependence to nicotine will cease after approximately ten to twenty days, although the brain's number of nicotine receptors is permanently altered, and the psychological dependence may linger for months or even many years. Unlike illicit recreational drugs and alcohol, nicotine does not measurably alter a smoker's motor skills, cognition, judgement, or language abilities while under the influence of the drug, but nicotine withdrawal symptoms such as irritability and incapacity to concentrate can have an influence on these aspects. Tobacco withdrawal has been shown to cause clinically significant distress. The majority of these effects are due to nicotine withdrawal, and so smokers who are not addicted to nicotine will not suffer from them. Some studies suggest that a link exists between smoking and mental illness, citing the high incidence of smoking amongst those suffering from schizophrenia and the possibility that smoking may alleviate some of the symptoms of mental illness, but these have not been conclusive. ## Epidemiology of smoking A team of British scientists headed by Richard Doll carried out a longitudinal study of 34,439 medical specialists from 1951 to 2001, generally called the "British doctors study." The study demonstrated that smoking decreased life expectancy by up to 10 years and that almost half of the smokers died from diseases possibly caused by smoking (cancer, heart disease, and stroke). In the UK, the impact of smoking is felt most keenly by the lower social classes, which are known to have lower life expectancy than those in wealthier classes. Half the difference in survival to age 70 between social classes I and V is estimated to be due to the higher smoking prevalence in the lower class group. # Tobacco and reproduction ## Effects of smoking on sperm cells There is increasing evidence that the harmful products of tobacco smoking kill sperm cells. Therefore, some governments require manufacturers to put warnings on packets. Smoking tobacco increases intake of cadmium, because the tobacco plant absorbs the metal. Cadmium, being chemically similar to zinc, may replace zinc in the DNA polymerase, which plays a critical role in sperm production. Zinc replaced by cadmium in DNA polymerase can be particularly damaging to the testes. ### Spontaneous abortion A number of studies have shown that tobacco use is a significant factor in spontaneous abortions among pregnant smokers, and that it contributes to a number of other threats to the health of the fetus. Second-hand smoke appears to present an equal danger to the fetus, as one study noted that "heavy paternal smoking increased the risk of early pregnancy loss." ### SIDS Secondhand smoke is connected to Sudden Infant Death Syndrome (SIDS). Infants who die from Sudden Infant Death Syndrome tend to have higher concentrations of nicotine and cotinine (a biological marker for secondhand smoke exposure) in their lungs than those who die from other causes. While smoking during pregnancy increases the risk of Sudden Infant Death Syndrome, infants exposed to secondhand smoke after birth are also at a greater risk of Sudden Infant Death Syndrome whether or not the parent(s) smoked during pregnancy. The nicotine obtained from smoking travels through a women into her breast milk, thus giving nicotine to her child, # Risks by kind of tobacco ## Low tar/light cigarettes There is no credible evidence that "Low Tar," "Light," or "Ultra Light" cigarettes are safer than regular cigarettes. Most of these terms refer to the type of filter that is used, and can vary depending on the brand. In some countries, the use of the word "Light" to refer to cigarettes has been banned. According to the United States' Federal Government’s National Cancer Institute (NCI), light cigarettes provide no benefit to smoker's health. ## Cigar vs cigarette smoking Although cigarette smoking causes a greater increase of the risk of cancer than cigar smoking, cigar smokers still have an increased risk for many health problems, including cancer, when compared to non-smokers. The National Institutes of Health, through the National Cancer Institute, determined in 1998 that "cigar smoking causes a variety of cancers including cancers of the oral cavity (lip, tongue, mouth, throat), esophagus, larynx, and lung." Relative risk for cigar-only smokers of all-cause mortality is 1.02 for 1-2 cigars/day, 1.08 for 3-4 cigars/day, and 1.17 for 5+ cigars/day. The NIH study concerned those who smoked at least one cigar per day, and stated "The health risks associated with less than daily smoking (occasional smokers) are not known." Though most cigar smokers do not inhale, those that do have risks of lung cancer similar to cigarette smokers. Increased risk for heart attack is less for cigar smokers, but still present. As for Environmental Tobacco Smoke (ETS, or "Second-hand Smoking"), the NIH study points to the large amount of smoke generated by one cigar, saying "cigars can contribute substantial amounts of tobacco smoke to the indoor environment; and, when large numbers of cigar smokers congregate together in a cigar smoking event, the amount of ETS produced is sufficient to be a health concern for those regularly required to work in those environments." ## Pipe smoking Pipe smoking involves significant health risks, particularly oral cancer. # Beneficial effects of smoking Tobacco has sometimes been reported to have isolated positive effects on certain medical conditions, presumably due to the biological effects of nicotine. Most notably, some studies have found that patients with Alzheimer's disease are more likely not to have smoked than the general population, which has been interpreted to suggest that smoking offers some protection against Alzheimer's. However, the research in this area is limited and the results are conflicting; some studies show that smoking increases the risk of Alzheimer's disease. A recent review of the available scientific literature concluded that the apparent decrease in Alzheimer risk may be simply due to the fact that smokers tend to die before reaching the age at which Alzheimer normally occurs. "Differential mortality is always likely to be a problem where there is a need to investigate the effects of smoking in a disorder with very low incidence rates before age 75 years, which is the case of Alzheimer's disease," it stated, noting that smokers are only half as likely as non-smokers to survive to the age of 80. Other findings include: - Former and current smokers have a lower incidence of Parkinson's disease compared to people who have never smoked, although the authors stated that it was more likely that the movement disorders which are part of Parkinson's disease prevented people from being able to smoke than that smoking itself was protective. Another study considered a possible role of nicotine in reducing Parkinson's risk: nicotine stimulates the dopaminergic system of the brain, which is damaged in Parkinson's disease. - A protective effect of current smoking against ulcerative colitis, although smoking increases the risk of Crohn's disease, the other form of inflammatory bowel disease. - Smoking reduces the risk of Kaposi's sarcoma in people without HIV infection. - There is some evidence for decreased rates of endometriosis in infertile smoking women, although other studies have found that smoking increases the risk in infertile women. There is little or no evidence of a protective effect in fertile women. - Some preliminary data from 1996 suggested a reduced incidence of uterine fibroids, but overall the evidence is unconvincing. - There is limited evidence that smoking reduces the incidence of pregnancy-induced hypertension, but not when the pregnancy is with more than one baby (i.e. it has no effect on twins etc.). Smoking does, however, increase the likelihood of almost every other pregnancy-related health risk to both mother and child, and is the single most preventable cause of illness and death among mothers and infants in the developed world. - A very large percentage of schizophrenics smoke tobacco as a form of self medication. The high rate of tobacco use by the mentally ill is a major factor in their decreased life expectancy, which is about 25 years shorter than the general population. Following the observation that smoking improves condition of people with schizophrenia, in particular working memory deficit, nicotine patches had been proposed as a way to treat schizophrenia. - Preliminary reports suggest that smoking can decrease the incidence of acne prophylactically. This was seen by a decreased percentage ratio of patients needing acne medication versus the percentage of entire population of smokers. (A smaller percentage of patients who smoked needed medication than found in the population as a whole). # Incidental problems An indirect public health problem posed by cigarettes is that of accidental fires, usually linked with consumption of alcohol. Numerous cigarette designs have been proposed, some by tobacco companies themselves, which would extinguish a cigarette left unattended for more than a minute or two, thereby reducing the risk of fire. However the tobacco companies have historically resisted this idea, on the grounds that the nuisance involved in having to relight a cigarette left untouched for too long would reduce their sales. In fact, untreated tobacco formed into a cigarette will extinguish itself relatively quickly if left alone, and as a result cigarette tobacco is treated chemically to allow it to smolder indefinitely.

Pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy for untreated advanced oesophageal and gastro-oesophageal junction cancer Evidence-based recommendations on pembrolizumab (Keytruda) with platinum- and fluoropyrimidine-based chemotherapy for untreated advanced oesophageal and gastro-oesophageal junction cancer in adults. # Recommendations Pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy is recommended, within its marketing authorisation, as an option for untreated locally advanced unresectable or metastatic carcinoma of the oesophagus or HER2‑negative gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD‑L1 with a combined positive score (CPS) of 10 or more. Pembrolizumab is only recommended if the company provides it according to the commercial arrangement. Why the committee made these recommendations Treatment for advanced oesophageal cancer or HER2‑negative gastro-oesophageal junction adenocarcinoma includes platinum- and fluoropyrimidine-based chemotherapy. Clinical trial evidence shows that for people whose tumours express PD‑L1 with a CPS of 10 or more, adding pembrolizumab increases how long they live. It also increases the time before their disease gets worse. Pembrolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates are likely to be within what NICE considers an acceptable use of NHS resources. Therefore, it is recommended.# Information about pembrolizumab # Marketing authorisation indication Pembrolizumab (Keytruda, MSD) has a marketing authorisation in the UK 'in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the oesophagus or HER2‑negative gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD‑L1 with a CPS equal to or greater than 10'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics. # Price The list price is £2,630 for a 100‑mg vial (excluding VAT; BNF online accessed July 2021). The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by MSD, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Oesophageal and HER2‑negative gastro-oesophageal junction cancer have a poor prognosis and a large impact on quality of life The patient experts explained that advanced oesophageal cancer (squamous or adenocarcinoma) or HER2‑negative gastro-oesophageal junction adenocarcinoma have a significant impact on quality of life. They explained that major symptoms include difficulty swallowing and malnutrition, which can lead to severe fatigue, weight loss and the need to use a feeding tube. These symptoms can be both painful and distressing, limiting people's ability to experience and participate in normal activities and social events. Around 40% of all new cases are in people aged 75 years and over, although the patient experts noted that increasing numbers of younger people are being diagnosed. The patient experts also explained that oesophageal and gastro-oesophageal junction cancer is more common in men than women but increasing numbers of women are being diagnosed. Diagnosis is often at an advanced stage. The committee concluded that oesophageal and HER2‑negative gastro-oesophageal junction cancer have a poor prognosis and a large impact on quality of life. # Treatment pathway ## People would welcome a new treatment option The patient and clinical experts explained that people with advanced oesophageal and HER2‑negative gastro-oesophageal junction cancer have a poor prognosis and no curative treatment options. Palliative combination chemotherapy regimens are standard first-line treatment for people with a performance status of 0 to 2 and no significant comorbidities. The NICE guideline on oesophago-gastric cancer: assessment and management in adults recommends dual therapy with fluorouracil or capecitabine in combination with cisplatin or oxaliplatin, or triple therapy with the addition of epirubicin. The clinical experts stated that triple therapy is no longer standard of care as it does not provide additional efficacy and increases toxicity. The clinical experts explained that dual therapy regimens are preferred and that most people would have capecitabine and oxaliplatin (XELOX). This is because oxaliplatin is preferred to cisplatin as it is better tolerated and has a shorter infusion time; however, there is no evidence that any one dual therapy combination is more effective than others. They suggested that dual therapy would be the appropriate comparator in this appraisal (see section 3.10). Pembrolizumab is an immunotherapy that has a different mechanism of action to chemotherapy and would be given as an additional treatment alongside chemotherapy. Therefore, it would not significantly add to the treatment administration burden. The patient experts explained that most people with advanced oesophageal or HER2‑negative gastro-oesophageal junction cancer would be willing to accept the additional side effects and treatment burden of pembrolizumab, because of its potential to improve quality of life and help people live longer. The committee concluded that there is an unmet clinical need in this population and people would welcome a new effective treatment option. ## It is preferable to give treatment with a PD-1 inhibitor early in the treatment pathway The NICE technology appraisal on nivolumab for previously treated unresectable advanced or recurrent oesophageal cancer recommends nivolumab as treatment for oesophageal squamous cell carcinoma (but not adenocarcinoma) after chemotherapy. The clinical experts explained that because pembrolizumab and nivolumab are both PD-1 inhibitors, it would not be suitable to give nivolumab as second-line treatment after pembrolizumab with chemotherapy. They explained that it would be preferable to give pembrolizumab as first-line treatment rather than nivolumab as second-line treatment for people with squamous carcinoma. This is because approximately 60% of people are unable to have second-line treatment and it is likely that immunotherapy is more effective when used earlier. The patient experts agreed that immunotherapy would be welcomed sooner in the treatment pathway. The committee concluded that pembrolizumab would potentially offer a first-line immunotherapy treatment option for people with advanced oesophageal cancer or HER2 gastro-oesophageal junction adenocarcinoma. # Marketing authorisation ## The population included in the marketing authorisation is narrower than the population in the scope The marketing authorisation specifies that pembrolizumab is indicated only for adults whose tumours express PD‑L1 with a combined positive score (CPS) of 10 or more and is restricted to treatment of gastro-oesophageal junction adenocarcinoma for tumours that are HER2 negative (see section 2.1). This is narrower than the population included in the scope, which did not specify HER2 or CPS status. The committee agreed that the appropriate population to consider for decision making was adults with unresectable locally advanced or metastatic oesophageal cancer or HER2‑negative gastro-oesophageal junction adenocarcinoma who had not had previous chemotherapy. The adults in the population should also have tumours that express PD‑L1 with a CPS of 10 or more, in line with the marketing authorisation. # PD-L1 testing ## PD-L1 testing is not routinely carried out in people with oesophageal cancer and HER2‑negative gastro-oesophageal junction adenocarcinoma Currently PD‑L1 testing is not part of routine clinical practice in gastrointestinal cancers. However, it is routinely carried out for people with other types of cancer such as head and neck cancer. The clinical experts and the Cancer Drugs Fund clinical lead explained that, ideally, PD‑L1 testing should be done early and before chemotherapy is started, so as to prevent delays in accessing appropriate treatment. They explained that PD‑L1 testing for people with oesophageal cancer and HER2‑negative gastro-oesophageal junction adenocarcinoma should not be problematic, and that current diagnostic tests could be used. The committee concluded that PD‑L1 testing is not currently routine for oesophageal and gastro-oesophageal junction cancers, but that this could be adopted easily in the NHS. # Clinical evidence ## KEYNOTE-590 data for the subgroup of tumours with CPS of 10 or more is appropriate for decision making KEYNOTE‑590 is a randomised, double-blind, placebo-controlled trial (n=749). It compared cisplatin and fluorouracil, with or without pembrolizumab, as first-line treatment for locally advanced unresectable or metastatic oesophageal adenocarcinoma, squamous cell carcinoma or advanced gastro-oesophageal junction adenocarcinoma. It excluded people with known HER2 positive gastro-oesophageal junction cancer. The marketing authorisation restricts pembrolizumab to a subgroup whose tumours are PD‑L1 positive with a CPS of 10 or more (see section 3.4). The proportion of people whose tumours had a CPS of 10 or more in the intention-to-treat population was similar in the pembrolizumab plus chemotherapy arm (49.9%) and the placebo plus chemotherapy arm (52.4%). The clinical experts explained that this proportion is comparable to UK clinical practice. The committee concluded that the data from the subgroup with a CPS of 10 or more is appropriate for decision making. ## KEYNOTE-590 data is generalisable to people in NHS clinical practice KEYNOTE‑590 recruited people from 26 countries including the UK. 54.8% of the CPS of 10 or more subgroup were from Asia. The ERG suggested that KEYNOTE‑590 may not be generalisable if disease prognosis or treatment pathways used in Asia differ from clinical practice in the NHS. However, the clinical experts explained that treatment regimens used in Asia and the NHS are similar, and common international guidelines are used. They also explained that there is no reason, based on molecular biology, that the effect of pembrolizumab on oesophageal cancer or gastro-oesophageal junction adenocarcinoma would differ between the trial population and the population treated in the NHS. The ERG also suggested that the proportion of people with squamous cell carcinoma and adenocarcinoma in KEYNOTE‑590 is different to the distribution seen in UK clinical practice. The clinical experts explained that PD‑L1 status and CPS was a more important biomarker than carcinoma type for predicting treatment effect. They explained that it is possible that people with squamous cell carcinoma (who appear to be more sensitive to immunotherapies) would benefit more from pembrolizumab than people with adenocarcinoma. However, the magnitude of benefit is smaller between the 2 cancer types when CPS is 10 or more. The clinical experts explained that although there is a difference in the proportion of people with squamous cell carcinoma and adenocarcinoma in KEYNOTE‑590 and UK clinical practice, the results are generalisable to people with oesophageal cancer or HER2 gastro-oesophageal junction adenocarcinoma with a CPS of 10 or more. The committee concluded that although this is an area of uncertainty, for the subgroup of interest, KEYNOTE‑590 is generalisable to clinical practice in the NHS. # Clinical effectiveness ## Pembrolizumab improves progression-free survival and overall survival compared with chemotherapy alone Median progression-free survival in KEYNOTE‑590 for people with a tumour with a CPS of 10 or more was 7.5 months in the pembrolizumab plus chemotherapy arm and 5.5 months in the placebo plus chemotherapy arm. The difference in median progression-free survival was 2 months (hazard ratio 0.51, 95% confidence interval 0.41 to 0.65; p<0.001). The corresponding median overall survival for the pembrolizumab plus chemotherapy arm was 13.5 months and 9.4 months in the placebo plus chemotherapy arm. The difference in median overall survival was 4.1 months (hazard ratio 0.62, 95% CI 0.49 to 0.78; p<0.001). The committee concluded that adding pembrolizumab to chemotherapy improves both progression-free survival and overall survival for people with locally advanced unresectable or metastatic oesophageal cancer or HER2‑negative gastro-oesophageal junction adenocarcinoma whose tumours express PD‑L1 with a CPS of 10 or more. # Company's economic model ## The company's economic model is appropriate for decision making The company presented a 3‑state partitioned survival model to estimate the cost effectiveness of pembrolizumab plus chemotherapy compared with chemotherapy alone. The 3 health states were progression-free, progressive disease and death. The ERG agreed that the company's model structure captured all relevant health states and partitioned survival models are widely used in cancer modelling. The committee concluded that the company's model structure was acceptable for decision making. # Assumptions in the economic model ## A dual chemotherapy regimen is the most appropriate comparator The scope included dual and triple chemotherapy regimens. The company assumed equivalent efficacy between dual and triple regimens and used a dual therapy regimen in its economic model. The ERG stated that all relevant scope comparators, including triple therapy, should be considered. The clinical experts reiterated that dual chemotherapy regimens are more commonly used in UK clinical practice (see section 3.2). The Cancer Drugs Fund clinical lead also confirmed that the use of triple regimens is rapidly diminishing. The committee concluded that a dual chemotherapy regimen would be the appropriate comparator for this appraisal. ## The dual chemotherapy regimen used by the company in its model is acceptable for decision making The company base case included the dual regimen of cisplatin and fluorouracil as used in KEYNOTE‑590, both in the comparator arm and in combination with pembrolizumab in the intervention arm. The clinical experts explained that dual therapy is the standard of care. However, they explained that several combinations are available, and oxaliplatin is more commonly used than cisplatin in the NHS (see section 3.2). The ERG provided a scenario analysis exploring an alternative dual regimen of oxaliplatin and capecitabine in both the pembrolizumab and comparator arms. This scenario included differences in costs but assumed equal efficacy to cisplatin and fluorouracil used in the company's model. The company also presented a scenario analysis using a blended comparator arm, which applied the costs of chemotherapy based on UK market share data. The company stated that they agreed with the ERG's approach to exploring an additional scenario but that both the ERG's and the company's scenarios have a negligible effect on the cost-effectiveness estimate. The committee agreed that the ERG's scenario using oxaliplatin and capecitabine was most reflective of current clinical practice, and that it was likely that this regimen would also be used in combination with pembrolizumab. However, it noted that there was comparable efficacy between the different dual regimens and that which combination the model used had little effect on the cost-effectiveness estimate. It therefore concluded that, although it was not reflective of clinical practice, it was appropriate to use the dual regimen included in the company's model for decision making. ## Multiple models for estimating overall survival are plausible The company modelled overall survival in both treatment arms using Kaplan–Meier data from KEYNOTE‑590, with a log-logistic extrapolation from 40 weeks. The ERG considered this approach to be broadly acceptable but focused on 3 alternative scenarios to explore uncertainty associated with overall survival extrapolation: a log-logistic piecewise model plus treatment waning (presented by the company as a scenario analysis); a generalised gamma piecewise model; and a log-logistic fully parametric model. The ERG stated that, according to clinical expert opinion, all the scenarios, including the company's base case, are plausible. The ERG's preferred scenario was the log-logistic piecewise model plus treatment waning, which is the same as the company's preferred model for overall survival but also includes a treatment waning effect between 5 and 7 years. The ERG preferred this scenario as it results in survival estimates in the middle of the range of the 4 plausible scenarios and addressed the uncertainty around pembrolizumab having a lifetime treatment effect. The company suggested that the generalised gamma piecewise model had a poor statistical fit, and the log-logistic fully parametric model did not have as good a visual fit to the observed overall survival data as the piecewise model. The company also commented that clinical evidence indicates a sustained treatment benefit with pembrolizumab and therefore including a treatment waning effect was conservative. The clinical experts agreed that a small proportion of people receiving pembrolizumab could be cured or enter long-term remission. The Cancer Drugs Fund clinical lead also stated that it is very likely there will be long-term survivors but there will also be people who relapse after 2 years, and stated that, although it is unclear if there is a treatment waning effect, it is a reasonable assumption. The committee acknowledged the long-term uncertainty in overall survival and concluded that all 4 scenarios presented provided plausible estimates of overall survival and resulted in a range of cost-effectiveness estimates. However, the scenarios preferred by the company and ERG were not widely different. ## Progression-based utilities are preferred for use in the model because the values are more plausible Utility values were calculated using EQ‑5D data from KEYNOTE‑590. The company used a time-to-death approach to calculate utility values in its base case, which produced utility values using groupings of utility observations based on how close the values were reported to the patient's overall survival time. The ERG explained that the time-to-death approach was a reasonable method but that it produced utility values that were higher than expected when compared with the general population, especially for the group who were more than 1 year from death. The company responded to this at technical engagement by capping the utility values for the group who were more than 1 year from death to the general population utility values. The ERG suggested that it was not plausible that the quality of life for a person with advanced oesophageal or HER2 gastro-oesophageal junction adenocarcinoma would be equal to or similar to the general population. It preferred to use a progression-based approach to calculate utility values, as the values from this approach appeared more plausible. The company suggested that the time-to-death approach was more appropriate as it captures more health states than the progression-based approach. It stated that this was more important for a condition that has a short life expectancy, as quality of life decreases rapidly as people approach the end of life. The company also explained that EQ‑5D scores were collected once from people who had progressed disease, which may not have fully captured quality of life for the progressed health state. At technical engagement, the company also presented an interaction utility model that combined progression status and time-to-death categories, to aim to address the ERG's concerns around the plausibility of the values produced. The ERG commented that this approach could not be fully evaluated based on the information provided, and that the same issue persisted: the utility values for the group furthest from death were higher than the general population. The committee discussed that any of the time-to-death, progression-based and interaction approaches could be appropriate for capturing quality of life as direct trial data was used for them all. However, it noted that progression-based utilities are more common in cancer appraisals and the values were more plausible. It also noted that the ERG had not been able to fully critique the interaction approach. The committee concluded that it preferred the progression-based utilities for decision making because the values were more plausible. ## It is appropriate to include the cost of subsequent treatment with nivolumab in the model The NICE technology appraisal on nivolumab for previously treated unresectable advanced or recurrent oesophageal cancer was published before technical engagement. It recommends nivolumab for treating unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma in adults after fluoropyrimidine and platinum-based therapy (see section 3.3). At technical engagement, the company updated its base case to include costs associated with nivolumab. The updated model included costs for nivolumab based on the number of people in the KEYNOTE‑590 CPS of 10 or more subgroup who received an anti‑PD‑1 or anti‑PD‑L1 treatment after pembrolizumab with chemotherapy or placebo with chemotherapy. The ERG agreed that the company's approach is the most suitable method to include nivolumab within the treatment pathway without having to make assumptions about efficacy, because this is captured in the outcomes of people in KEYNOTE‑590 who received a subsequent anti‑PD‑1 or anti‑PD‑L1 treatment. However, the ERG noted that in KEYNOTE‑590 some people received an anti‑PD‑1 or anti‑PD‑L1 treatment after pembrolizumab with chemotherapy, which is not what would happen in UK clinical practice (see section 3.3). The ERG also noted that the proportion of people in KEYNOTE‑590 who received an anti‑PD‑1 or anti‑PD‑L1 treatment was likely to be lower than the number of people who receive nivolumab after first-line chemotherapy without pembrolizumab in UK clinical practice. To address this, it provided a scenario to reflect how nivolumab is likely to be used in clinical practice that estimated the costs and efficacy of nivolumab. This scenario assumed that all participants who had received a subsequent treatment in the placebo with chemotherapy arm in the KEYNOTE‑590 CPS of 10 or more subgroup, received nivolumab as second-line treatment. However, the ERG explained that there were several limitations to this scenario analysis, including uncertainty around the impact nivolumab would have on overall survival, and unconventional adjustments being made to the survival curves as needed by the partitioned survival model framework. Therefore, it did not include this analysis in its base case. The committee was aware that both the company's and the ERG's approaches had limitations but concluded that it was appropriate to include the costs of nivolumab as a subsequent treatment in the model. ## The company and the ERG have appropriately incorporated PD-L1 testing into the model PD‑L1 testing is currently not routinely funded for oesophageal or gastro-oesophageal junction cancer (see section 3.5). The company and the ERG included the costs of PD‑L1 testing in their models, as this is an additional cost to current care for oesophageal and gastro-oesophageal junction cancer. The committee concluded that introducing PD‑L1 testing for oesophageal and gastro-oesophageal junction cancer would be unlikely to add a significant burden to the NHS and that it was appropriate to include the costs of testing in the model. # End of life ## Pembrolizumab meets the end of life criteria The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Data from KEYNOTE‑590 showed that, for the subgroup of people whose tumours express PD‑L1 with a CPS of 10 or more, median overall survival was 9.4 months for people receiving placebo with chemotherapy (see section 3.8). The clinical and patient experts also agreed that the average life expectancy of people with advanced oesophageal cancer or HER2‑negative gastro-oesophageal junction adenocarcinoma was less than 2 years. In the subgroup of interest (people whose tumours express PD‑L1 with a CPS of 10 or more), KEYNOTE‑590 showed an increase in median overall survival with the addition of pembrolizumab to chemotherapy of 4.1 months (see section 3.8). The company's model also indicated that pembrolizumab increased mean overall survival by 13.9 months. The ERG agreed that, in the subgroup of people whose tumours express PD‑L1 with a CPS of 10 or more, there is an improvement in overall survival of at least 3 months with pembrolizumab. The committee concluded that pembrolizumab meets the end of life criteria for this population. # Cost-effectiveness estimate ## Pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy is likely to be cost effective The company's base case included the following assumptions: Using the dual chemotherapy regimen from KEYNOTE‑590 in the model, both alone as the comparator and in combination with pembrolizumab as the intervention (see section 3.11). Using a log-logistic extrapolation for modelling overall survival (see section 3.12). Using utilities obtained using time-to-death methodology (see section 3.13). Adding the costs of nivolumab as a subsequent treatment into the model (see section 3.14). Adding the costs of PD‑L1 testing to the model (see section 3.15).The ERG's base case included the same assumptions as the company in its model on the choice of dual chemotherapy (see section 3.11), the costs of nivolumab (see section 3.14), and the costs of PD‑L1 testing (see section 3.15). It included different assumptions to the company on overall survival modelling (using a log-logistic extrapolation plus a treatment waning effect between 5 and 7 years ) and used the committee's preferred assumption of progression-based utilities (see section 3.13). The incremental cost-effectiveness ratios (ICERs) cannot be reported here because of confidential commercial arrangements for pembrolizumab and subsequent treatments. Although including the ERG's assumptions increased the ICER compared with the company's base case, both the company's and the ERG's cost-effectiveness estimates are below £50,000 per quality-adjusted life year gained. As end of life criteria have been met (see section 3.16) the committee concluded that it was likely that pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy is likely to be a cost-effective use of NHS resources. # Conclusion ## Pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy is recommended The committee noted that both the company's and the ERG's base cases show that pembrolizumab with platinum-based chemotherapy is likely to be cost effective compared with chemotherapy alone, when considering a life-extending treatment for people with short life expectancy (see section 3.17). The committee was aware of continuing uncertainty related to the generalisability of the population in KEYNOTE‑590 to clinical practice in the NHS (see section 3.7) and the most appropriate method to extrapolate overall survival (see section 3.12). However, despite the remaining areas of uncertainty, it was agreed that the cost-effectiveness estimates are likely to be within the range usually considered a cost-effective use of NHS resources for a life-extending treatment for people with short life expectancy. Therefore, pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy is recommended for use in the NHS as an option for treating locally advanced unresectable or metastatic carcinoma of the oesophagus or HER2‑negative gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD‑L1 with a CPS of 10 or more.

W box gene transcriptions "Consistent with its role as a transcriptional repressor, OsWRKY71 binds specifically to functionally defined TGAC-containing W boxes of the Amy32b promoter in electrophoretic mobility shift assays (Zhang et al. 2004)." "Details of auto-regulation or cross-regulation by WRKY factors were provided for the parsley group I member PcWRKY1 and its ortholog AtWRKY33 . In response to PAMP treatment PcWRKY1 transcripts accumulate rapidly and transiently . AtWRKY33 is activated with similar kinetics by defense-related stimuli . This rapid response is mediated by a conserved arrangement of three synergistically acting W boxes (WABC). Chromatin immunoprecipitation (ChIP) revealed that in vivo these orthologous W boxes are constitutively occupied by WRKY proteins ." "The synthesis of SA and the expression of NPR1, a key regulator of some PAMP-triggered responses, appear to be partly controlled by WRKY factors. NPR1 is regulated by WRKY TFs interacting with two W box elements in its 50UTR . Defense-associated SA production is strongly dependent on pathogen-inducible expression of ICS1 . This gene is a likely target of WRKY TFs, as its promoter is enriched for W boxes." A "missense mutation within its WRKY domain results in conditional activation of defense responses and loss of in vitro binding to W boxes suggesting a negative role of this factor in defense signaling ." Functionality and conservation of the W-box element across plant species shown by gel shift experiments, random binding site selection, yeast one-hybrid screens and co-transfection assays performed with many different WRKY proteins and In silico-based studies have identified clusters of W-boxes in stress-inducible promoters, where the binding of WRKY proteins to W-boxes is a feature of both biotic and abiotic stress responses, together with other plant processes such as germination. It has also been shown that multiple W-boxes have a synergistic effect on transcription. Almost all WRKY transcription factors bind preferentially to W-boxes, and since their discovery, this has raised the question as to how they show specificity for the promoters of their target genes. Although the W-box core is required, adjacent sequences also play a role in determining binding-site preference. Recent evidence suggests that the TGAC core is more degenerate, composed of a guanine adenine cytosine (GAC) core, and the upstream thymine and downstream pyrimidine flanking sequences help dictate recognition by specific WRKY factors. Basic residues of the WRKY protein domain also are believed to recognize the phosphate backbone of the cis-element. The solution structure of the C-terminal WRKY domain of Arabidopsis WRKY4 in complex with the W-box DNA has been determined by NMR. A four-stranded β-sheet enters the major groove of DNA in a structure called the β-wedge, where the sheet is nearly perpendicular to the DNA helical ais: as predicted amino acids in the conserved WRKYGQK signature motif contact the W-box DNA. # WRKY WRKY family of genes contain the common degenerate nucleotide sequence: WRKY, or W = A or T (U) , R = A or G , K = G or T (U) , Y = C or T (U) . "Plant immune responses are associated with the concerted modulation of a large number of different WRKY transcripts and proteins . Upon triggering of SA-dependent defenses, at least 49 AtWRKY genes exhibited differential regulation representing separate waves of transcript accumulation or repression . Their promoters are statistically enriched for W boxes, suggesting that they are autoregulated or controlled by other WRKY proteins ." "Some architectural features of the WRKY web are emerging. As motif D containing group I WRKY TFs can be phosphorylated by MAP-kinases, they are likely to serve as the first WRKY proteins activated in response to PAMP-triggered MAPK signaling. Their targets may include the IIe WRKY genes AtWRKY22 and AtWRKY29, which are upregulated by a PAMP-induced MAPK cascade and contain multiple W boxes within their respective promoters ." # Consensus sequences The "presence of WRKY TF binding sites (C/TTGACC/T, W boxes) in numerous co-regulated Arabidopsis defense gene promoters provided circumstantial evidence that zinc-finger-type WRKY factors play a broad and pivotal role in regulating defenses ." The W box is a DNA cis-regulatory element sequence, (T)TGAC(C/T), which is recognized by the family of WRKY transcription factors. # W box samplings For the Basic programs (starting with SuccessablesWbox.bas) written to compare nucleotide sequences with the sequences on either the template strand (-), or coding strand (+), of the DNA, in the negative direction (-), or the positive direction (+), including extending the number of nts from 958 to 4445, the programs are, are looking for, and found: - negative strand in the negative direction (from ZSCAN22 to A1BG) is SuccessablesWbox--.bas, looking for 3'-(C/T)TGAC(C/T)-5', 5, 3'-CTGACT-5', 17, 3'-TTGACT-5', 130, 3'-TTGACT-5', 307, 3'-CTGACT-5', 1935, 3'-CTGACC-5', 3749, - positive strand in the negative direction is SuccessablesWbox+-.bas, looking for 3'-(C/T)TGAC(C/T)-5', 1, 3'-CTGACC-5', 734, - negative strand in the positive direction (from ZNF497 to A1BG) is SuccessablesWbox-+.bas, looking for 3'-(C/T)TGAC(C/T)-5', 6, 3'-CTGACC-5', 1662, 3'-CTGACC-5', 2213, 3'-TTGACC-5', 2873, 3'-CTGACT-5', 2945, 3'-TTGACC-5', 4018, 3'-CTGACC-5', 4216, - positive strand in the positive direction is SuccessablesWbox++.bas, looking for 3'-(C/T)TGAC(C/T)-5', 3, 3'-TTGACC-5', 1953, 3'-CTGACT-5', 2674, 3'-TTGACT-5', 3735, - complement, negative strand, negative direction is SuccessablesWboxc--.bas, looking for 3'-(A/G)ACTG(A/G)-5', 1, 3'-GACTGG-5', 734, - complement, negative strand, positive direction is SuccessablesWboxc-+.bas, looking for 3'-(A/G)ACTG(A/G)-5', 3, 3'-AACTGG-5', 1953, 3'-GACTGA-5', 2674, 3'-AACTGA-5', 3735, - complement, positive strand, negative direction is SuccessablesWboxc+-.bas, looking for 3'-(A/G)ACTG(A/G)-5', 5, 3'-GACTGA-5', 17, 3'-AACTGA-5', 130, 3'-AACTGA-5', 307, 3'-GACTGA-5', 1935, 3'-GACTGG-5', 3749, - complement, positive strand, positive direction is SuccessablesWboxc++.bas, looking for 3'-(A/G)ACTG(A/G)-5', 6, 3'-GACTGG-5', 1662, 3'-GACTGG-5', 2213, 3'-AACTGG-5', 2873, 3'-GACTGA-5', 2945, 3'-AACTGG-5', 4018, 3'-GACTGG-5', 4216, - inverse complement, negative strand, negative direction is SuccessablesWboxci--.bas, looking for 3'-(A/G)GTCA(A/G)-5', 2, 3'-GGTCAG-5', 1353, 3'-GGTCAA-5', 4416, - inverse complement, negative strand, positive direction is SuccessablesWboxci-+.bas, looking for 3'-(A/G)GTCA(A/G)-5', 6, 3'-AGTCAG-5', 2101, 3'-GGTCAG-5', 2221, 3'-AGTCAG-5', 2608, 3'-AGTCAA-5', 2614, 3'-AGTCAG-5', 2619, 3'-GGTCAG-5', 4270, - inverse complement, positive strand, negative direction is SuccessablesWboxci+-.bas, looking for 3'-(A/G)GTCA(A/G)-5', 6, 3'-GGTCAG-5', 440, 3'-GGTCAG-5', 577, 3'-GGTCAG-5', 713, 3'-GGTCAG-5', 2249, 3'-GGTCAG-5', 2586, 3'-GGTCAA-5', 4308, - inverse complement, positive strand, positive direction is SuccessablesWboxci++.bas, looking for 3'-(A/G)GTCA(A/G)-5', 6, 3'-GGTCAG-5', 2025, 3'-AGTCAG-5', 2099, 3'-GGTCAG-5', 2606, 3'-GGTCAG-5', 2997, 3'-GGTCAG-5', 3083, 3'-GGTCAA-5', 3380, - inverse, negative strand, negative direction, is SuccessablesWboxi--.bas, looking for 3'-(C/T)CAGT(C/T)-5', 6, 3'-CCAGTC-5', 440, 3'-CCAGTC-5', 577, 3'-CCAGTC-5', 713, 3'-CCAGTC-5', 2249, 3'-CCAGTC-5', 2586, 3'-CCAGTT-5', 4308, - inverse, negative strand, positive direction, is SuccessablesWboxi-+.bas, looking for 3'-(C/T)CAGT(C/T)-5', 6, 3'-CCAGTC-5', 2025, 3'-TCAGTC-5', 2099, 3'-CCAGTC-5', 2606, 3'-CCAGTC-5', 2997, 3'-CCAGTC-5', 3083, 3'-CCAGTT-5', 3380, - inverse, positive strand, negative direction, is SuccessablesWboxi+-.bas, looking for 3'-(C/T)CAGT(C/T)-5', 2, 3'-CCAGTC-5', 1353, 3'-CCAGTT-5', 4416, - inverse, positive strand, positive direction, is SuccessablesWboxi++.bas, looking for 3'-(C/T)CAGT(C/T)-5', 6, 3'-TCAGTC-5', 2101, 3'-CCAGTC-5', 2221, 3'-TCAGTC-5', 2608, 3'-TCAGTT-5', 2614, 3'-TCAGTC-5', 2619, 3'-CCAGTC-5', 4270. ## Wbox (4560-2846) UTRs - Negative strand, negative direction: CTGACC at 3749. - Negative strand, negative direction: GGTCAA at 4416. - Positive strand, negative direction: GGTCAA at 4308. ## Wbox positive direction (4445-4265) core promoters - Negative strand, positive direction: GGTCAG at 4270. ## Wbox positive direction (4265-4050) proximal promoters - Negative strand, positive direction: CTGACC at 4216. ## Wbox negative direction (2596-1) distal promoters - Negative strand, negative direction: CTGACT at 1935, TTGACT at 307, TTGACT at 130, CTGACT at 17. - Negative strand, negative direction: GGTCAG at 1353. - Positive strand, negative direction: CTGACC at 734. - Positive strand, negative direction: GGTCAG at 2586, GGTCAG at 2249, GGTCAG at 713, GGTCAG at 577, GGTCAG at 440. ## Wbox positive direction (4050-1) distal promoters - Negative strand, positive direction: TTGACC at 4018, CTGACT at 2945, TTGACC at 2873, CTGACC at 2213, CTGACC at 1662. - Negative strand, positive direction: AGTCAG at 2619, AGTCAA at 2614, AGTCAG at 2608, GGTCAG at 2221, AGTCAG at 2101. - Positive strand, positive direction: TTGACT at 3735, CTGACT at 2674, TTGACC at 1953. - Positive strand, positive direction: GGTCAA at 3380, GGTCAG at 3083, GGTCAG at 2997, GGTCAG at 2606, AGTCAG at 2099, GGTCAG at 2025. # W box random dataset samplings - Wboxr0: 6, TTGACC at 4380, TTGACT at 4031, CTGACT at 3270, CTGACC at 1834, CTGACC at 1659, TTGACT at 231. - Wboxr1: 5, TTGACT at 4021, TTGACC at 3051, TTGACT at 2937, CTGACC at 1160, CTGACC at 154. - Wboxr2: 4, CTGACC at 3755, CTGACC at 3580, TTGACT at 1736, TTGACC at 853. - Wboxr3: 4, TTGACT at 4479, CTGACC at 4438, TTGACC at 3102, CTGACT at 1141. - Wboxr4: 7, TTGACT at 2961, TTGACC at 2892, TTGACT at 2539, TTGACC at 2131, CTGACT at 1980, CTGACT at 1922, TTGACC at 344. - Wboxr5: 1, TTGACT at 1914. - Wboxr6: 3, CTGACT at 4233, TTGACC at 2398, TTGACT at 2043. - Wboxr7: 2, CTGACC at 3140, TTGACC at 898. - Wboxr8: 2, TTGACC at 1241, TTGACC at 776. - Wboxr9: 3, CTGACC at 4209, TTGACT at 4205, CTGACT at 3521. - Wboxr0ci: 3, AGTCAA at 4044, GGTCAA at 1985, GGTCAG at 846. - Wboxr1ci: 4, GGTCAA at 4484, AGTCAA at 3855, GGTCAA at 2778, GGTCAG at 1751. - Wboxr2ci: 9, AGTCAA at 4375, GGTCAG at 3906, AGTCAA at 3850, GGTCAA at 3164, AGTCAG at 2900, GGTCAA at 2186, GGTCAG at 468, GGTCAA at 142, GGTCAG at 24. - Wboxr3ci: 4, GGTCAG at 3506, GGTCAG at 2239, GGTCAA at 1052, GGTCAA at 601. - Wboxr4ci: 3, AGTCAA at 3240, AGTCAA at 3119, AGTCAA at 986. - Wboxr5ci: 3, AGTCAA at 3608, AGTCAG at 1920, AGTCAG at 1355. - Wboxr6ci: 6, AGTCAA at 4504, AGTCAA at 4450, GGTCAA at 2737, AGTCAG at 2125, GGTCAA at 1833, AGTCAG at 394. - Wboxr7ci: 1, GGTCAA at 4458. - Wboxr8ci: 4, AGTCAA at 4172, GGTCAA at 3494, GGTCAA at 3434, GGTCAA at 2695. - Wboxr9ci: 7, GGTCAA at 4380, AGTCAA at 3950, AGTCAG at 3359, GGTCAA at 3056, AGTCAA at 2475, GGTCAG at 2057, AGTCAG at 107. ## Wboxr arbitrary (evens) (4560-2846) UTRs - Wboxr0: TTGACC at 4380, TTGACT at 4031, CTGACT at 3270. - Wboxr2: CTGACC at 3755, CTGACC at 3580. - Wboxr6: CTGACT at 4233. - Wboxr4: TTGACT at 2961, TTGACC at 2892. - Wboxr0ci: AGTCAA at 4044. - Wboxr2ci: AGTCAA at 4375, GGTCAG at 3906, AGTCAA at 3850, GGTCAA at 3164, AGTCAG at 2900. - Wboxr4ci: AGTCAA at 3240, AGTCAA at 3119. - Wboxr6ci: AGTCAA at 4504, AGTCAA at 4450. - Wboxr8ci: AGTCAA at 4172, GGTCAA at 3494, GGTCAA at 3434. ## Wboxr alternate (odds) (4560-2846) UTRs - Wboxr1: TTGACT at 4021, TTGACC at 3051, TTGACT at 2937. - Wboxr3: TTGACT at 4479, CTGACC at 4438, TTGACC at 3102. - Wboxr7: CTGACC at 3140. - Wboxr9: CTGACC at 4209, TTGACT at 4205, CTGACT at 3521. - Wboxr1ci: GGTCAA at 4484, AGTCAA at 3855. - Wboxr3ci: GGTCAG at 3506. - Wboxr5ci: AGTCAA at 3608. - Wboxr7ci: GGTCAA at 4458. - Wboxr9ci: GGTCAA at 4380, AGTCAA at 3950, AGTCAG at 3359, GGTCAA at 3056. ## Wboxr arbitrary positive direction (odds) (4445-4265) core promoters - Wboxr3: CTGACC at 4438. - Wboxr9ci: GGTCAA at 4380. ## Wboxr alternate positive direction (evens) (4445-4265) core promoters - Wboxr0: TTGACC at 4380. - Wboxr2ci: AGTCAA at 4375. ## Wboxr arbitrary negative direction (evens) (2811-2596) proximal promoters - Wboxr6ci: GGTCAA at 2737. - Wboxr8ci: GGTCAA at 2695. ## Wboxr alternate negative direction (odds) (2811-2596) proximal promoters - Wboxr1ci: GGTCAA at 2778. ## Wboxr arbitrary positive direction (odds) (4265-4050) proximal promoters - Wboxr9: CTGACC at 4209, TTGACT at 4205. ## Wboxr alternate positive direction (evens) (4265-4050) proximal promoters - Wboxr6: CTGACT at 4233. - Wboxr8ci: AGTCAA at 4172. ## Wboxr arbitrary negative direction (evens) (2596-1) distal promoters - Wboxr0: CTGACC at 1834, CTGACC at 1659, TTGACT at 231. - Wboxr2: TTGACT at 1736, TTGACC at 853. - Wboxr4: TTGACT at 2539, TTGACC at 2131, CTGACT at 1980, CTGACT at 1922, TTGACC at 344. - Wboxr6: TTGACC at 2398, TTGACT at 2043. - Wboxr8: TTGACC at 1241, TTGACC at 776. - Wboxr0ci: GGTCAA at 1985, GGTCAG at 846. - Wboxr2ci: GGTCAA at 2186, GGTCAG at 468, GGTCAA at 142, GGTCAG at 24. - Wboxr4ci: AGTCAA at 986. - Wboxr6ci: AGTCAG at 2125, GGTCAA at 1833, AGTCAG at 394. ## Wboxr alternate negative direction (odds) (2596-1) distal promoters - Wboxr1: CTGACC at 1160, CTGACC at 154. - Wboxr3: CTGACT at 1141. - Wboxr5: TTGACT at 1914. - Wboxr7: TTGACC at 898. - Wboxr1ci: GGTCAG at 1751. - Wboxr3ci: GGTCAG at 2239, GGTCAA at 1052, GGTCAA at 601. - Wboxr5ci: AGTCAG at 1920, AGTCAG at 1355. - Wboxr9ci: AGTCAA at 2475, GGTCAG at 2057, AGTCAG at 107. ## Wboxr arbitrary positive direction (odds) (4050-1) distal promoters - Wboxr1: TTGACT at 4021, TTGACC at 3051, TTGACT at 2937, CTGACC at 1160, CTGACC at 154. - Wboxr3: TTGACC at 3102, CTGACT at 1141. - Wboxr5: TTGACT at 1914. - Wboxr7: CTGACC at 3140, TTGACC at 898. - Wboxr9: CTGACT at 3521. - Wboxr1ci: AGTCAA at 3855, GGTCAA at 2778, GGTCAG at 1751. - Wboxr3ci: GGTCAG at 3506, GGTCAG at 2239, GGTCAA at 1052, GGTCAA at 601. - Wboxr5ci: AGTCAA at 3608, AGTCAG at 1920, AGTCAG at 1355. - Wboxr9ci: AGTCAA at 3950, AGTCAG at 3359, GGTCAA at 3056, AGTCAA at 2475, GGTCAG at 2057, AGTCAG at 107. ## Wboxr alternate positive direction (evens) (4050-1) distal promoters - Wboxr0: TTGACT at 4031, CTGACT at 3270, CTGACC at 1834, CTGACC at 1659, TTGACT at 231. - Wboxr2: CTGACC at 3755, CTGACC at 3580, TTGACT at 1736, TTGACC at 853. - Wboxr4: TTGACT at 2961, TTGACC at 2892, TTGACT at 2539, TTGACC at 2131, CTGACT at 1980, CTGACT at 1922, TTGACC at 344. - Wboxr6: TTGACC at 2398, TTGACT at 2043. - Wboxr8: TTGACC at 1241, TTGACC at 776. - Wboxr0ci: AGTCAA at 4044, GGTCAA at 1985, GGTCAG at 846. - Wboxr2ci: GGTCAG at 3906, AGTCAA at 3850, GGTCAA at 3164, AGTCAG at 2900, GGTCAA at 2186, GGTCAG at 468, GGTCAA at 142, GGTCAG at 24. - Wboxr4ci: AGTCAA at 3240, AGTCAA at 3119, AGTCAA at 986. - Wboxr6ci: GGTCAA at 2737, AGTCAG at 2125, GGTCAA at 1833, AGTCAG at 394. - Wboxr8ci: GGTCAA at 3494, GGTCAA at 3434, GGTCAA at 2695. # Wbox analysis and results The "presence of WRKY TF binding sites (C/TTGACC/T, W boxes) in numerous co-regulated Arabidopsis defense gene promoters provided circumstantial evidence that zinc-finger-type WRKY factors play a broad and pivotal role in regulating defenses ." Comparison: The occurrences of real W-box UTRs are ≤ randoms, cores, proximals and distals are greater than the randoms. This suggests that the real W boxes are likely active or activable. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff. Initial content for this page in some instances came from Wikiversity.

Telaprevir drug interactions # Drug Interactions ## Potential for INCIVEK to Affect Other Drugs INCIVEK is a strong inhibitor of CYP3A. Co-administration of INCIVEK with drugs that are primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase adverse reactions (see Table 5). INCIVEK is also an inhibitor of P-gp, OATP1B1, and OATP2B1. Co-administration of INCIVEK with drugs that are substrates for P-gp, OATP1B1, and OATP2B1 transport may result in increased plasma concentrations of such drugs, which could increase adverse reactions (see Table 5). If dose adjustments of concomitant medications are made during INCIVEK treatment, they should be re-adjusted after administration of INCIVEK is completed. ## Potential for Other Drugs to Affect INCIVEK INCIVEK is a substrate of CYP3A and P-gp; therefore, drugs that induce CYP3A and/or P-gp may decrease INCIVEK plasma concentrations and reduce the therapeutic effect of INCIVEK. Co-administration of INCIVEK with drugs that inhibit CYP3A and/or P-gp may increase INCIVEK plasma concentrations. ## Established and Other Potentially Significant Drug Interactions Table 5 provides effect on concentration of INCIVEK or concomitant drug with INCIVEK. These recommendations are based on either drug interaction trials (indicated with *) or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. Most drug interaction studies have been performed with a dose of 750 mg q8h of INCIVEK. The 1125 mg twice-daily regimen provides similar total daily exposures of telaprevir; thus drug interactions are expected to be similar between the two regimens when evaluated after multiple doses . In addition to the drugs included in Table 5, the interaction between INCIVEK and the following drugs was evaluated in clinical trials and no dose adjustment is needed for any drug : esomeprazole, raltegravir, or buprenorphine.

2C-T-15 2C-T-15 or 2,5-dimethoxy-4-(β-cyclopropylthio)phenethylamine is a psychedelic phenethylamine of the 2C family. It was presumably first synthesized by Alexander Shulgin and reported in his book PIHKAL. # Chemistry 2C-T-15 is the 2 carbon homologue of Aleph-15, which has not been synthesized. The full chemical name is 2-ethanamine. The drug has structural properties similar to 2C-T-2 and other drugs in the 2C-T series. # General Information The dosage range of 2C-T-15 is typically 30 mg or more. Its duration is unspecified by Shulgin, and its entry in PiHKAL says it lasts for "several hours." The effects are not prominent, and 2C-T-15 is not very potent. # Pharmacology The mechanism that produces 2C-T-15’s hallucinogenic and entheogenic effects has not been specifically established, however it is most likely to result from action as a 5-HT2A serotonin receptor agonist in the brain, a mechanism of action shared by all of the hallucinogenic tryptamines and phenethylamines for which the mechanism of action is known. # Dangers The toxicity of 2C-T-15 is not well documented. 2C-T-15 is much less potent than 2C-T-7, but it may be expected that at very high doses it would display similar toxicity to that of other phenethylamines of the 2C-T family. Other phenethylamine derivatives substituted with an alkylthio group at the 4 position such as 2C-T-7 and 4-MTA are known to act as selective monoamine oxidase A inhibitors, a side effect which can lead to lethal serotonin syndrome when they are combined with stimulant drugs. Most confirmed fatalities involving 2C-T drugs involve their combination with other hard drugs such as alcohol, ecstasy or cocaine. # Legality 2C-T-15 is not illegal, but possession and sales of 2C-T-15 could be prosecuted under the Federal Analog Act because of its structural similarities to 2C-T-7. # Reference - ↑ Template:CitePiHKAL # Categorization

Fluconazole dosage and administration # Dosage and Administration ### Dosage in Adults Single Dose - Vaginal candidiasis The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg as a single oral dose. Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient's response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse. - Oropharyngeal candidiasis The recommended dosage of DIFLUCAN for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse. - Esophageal candidiasis The recommended dosage of DIFLUCAN for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient's response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms. - Systemic Candida infections For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used. - Urinary tract infections and peritonitis For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50–200 mg have been used in open, noncomparative studies of small numbers of patients. - Cryptococcal meningitis The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient's response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10–12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. - Prophylaxis in patients undergoing bone marrow transplantation The recommended DIFLUCAN daily dosage for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm. ### Dosage in Children The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding DIFLUCAN pharmacokinetics in full-term newborns is available. - Oropharyngeal candidiasis The recommended dosage of DIFLUCAN for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse. - Esophageal candidiasis For the treatment of esophageal candidiasis, the recommended dosage of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used, based on medical judgment of the patient's response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms. - Systemic Candida infections For the treatment of candidemia and disseminated Candida infections, daily doses of 6–12 mg/kg/day have been used in an open, noncomparative study of a small number of children. - Cryptococcal meningitis For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient's response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10–12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily. ### Dosage In Patients With Impaired Renal Function Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table: ### Administration DIFLUCAN is administered orally. DIFLUCAN can be taken with or without food. Directions for Mixing the Oral Suspension Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows:

Recovery, Inc. # Processes Recovery's method is essentially cognitive therapy; helping a person to be aware of possible errors or misconceptions in their perception of reality. Because its methods do not conflict with other therapies, it can be used in conjunction with twelve-step programs and is often recommended to patients by mental health professionals as an adjunct to their therapy. At the meetings, members share examples from their lives that caused nervous symptoms (e.g. physical sensations, racing thoughts) and try to "spot" the thoughts that occurred just beforehand. Other members offer alternative ways of looking at the situation and suggest how to better handle similar symptoms in the future. For example, a person may experience depression (or "lowered feelings" in Recovery language) because they are aiming for a perfect performance. Trying to be perfect or trying to appear perfect leads one to feel down if one makes even the slightest mistake. Members are encouraged to "endorse" (to give themselves credit) for their efforts—not for their successes. All improvements are acknowledged, no matter how small. Members are are taught only to compare themselves to themselves, not to other people. Longstanding members are encouraged to share their success with the Recovery methods to help newcomers. # Effectiveness Following participation in Recovery, Inc., former mental patients reported no more anxiety about their mental health than the general public. Members rated their life satisfaction levels as high, or higher, than the general public. Members who had participated two years or more reported the highest levels of satisfaction with their health. Conversely, members who had participated less than two years tended to be still taking medication, living below the poverty level and having smaller social networks. Participation in Recovery, Inc. decreased members' symptoms of mental illness and the amount of psychiatric treatment needed. About half of the members had been hospitalized before joining. Following participation less than 8% had been hospitalized. Members' scores of neurotic distress decreased, and scores of psychological well-being for longstanding members were no different from members of a control group in the same community. Long-term members were being treated with less psychiatric medication and psychotherapy than newer members.

Mpemba effect The Mpemba effect is the observation that, in certain specific circumstances, warmer water freezes faster than colder water. New Scientist recommends starting the experiment with containers at 35°C and 5°C to maximise the effect. # Origin The effect is named for the Tanzanian high-school student Erasto B. Mpemba. Mpemba first encountered the phenomenon in 1963 in Form 3 of Magamba Secondary School, Tanzania when freezing hot ice cream mix in cookery classes and noticing that they froze before cold mixes. After passing his O-level examinations, he became a student at Mkwawa Secondary (formerly High) School, Iringa, Tanzania. The headmaster invited Dr. Denis G. Osborne from the University College in Dar Es Salaam to give a lecture on physics. After the lecture, Erasto Mpemba asked him the question "If you take two similar containers with equal volumes of water, one at 35°C and the other at 100°C, and put them into a refrigerator, the one that started at 100°C freezes first. Why?" only to be ridiculed by his classmates. After initial consternation, Dr. Osborne confirmed Erasto's finding and they published the results together in 1969. Erasto Mpemba currently works for the African Forestry and Wildlife Commission. # Causes At first sight, the behaviour seems contrary to thermodynamics. However, the Mpemba effect can be explained with standard physical theory. Many effects can contribute to the observation, depending on the experimental set-up: - Definition of frozen: Is it the physical definition of the point at which water forms a visible surface layer of ice, or the point at which the entire volume of water becomes a solid block of ice? - Evaporation: Reducing the volume to be frozen. Evaporation is endothermic. - Convection: Accelerating heat transfers. Reduction of water density below 4°C tends to suppress the convection currents cooling the lower part of the liquid mass; the lower density of hot water would reduce this effect, perhaps sustaining the more rapid initial cooling. - Frost: Has insulating effects. The lower temperature water will tend to freeze from the top, reducing further heat loss by radiation and air convection, while the warmer water will tend to freeze from the bottom and sides because of water convection. This is disputed as there are experiments which account for this factor. - Supercooling: It is hypothesized that cold water, when placed in a freezing environment, supercools more than hot water in the same environment, thus solidifying slower than hot water. However, supercooling tends to be less significant where there are particles that act as nuclei for ice crystals, thus precipitating rapid freezing. - Solutes: The effects of calcium, magnesium carbonate among others. - The effect of heating on dissolved gases. ## Scalar functionality According to an article by Monwhea Jeng: "Analysis of the situation is now quite complex, since we are no longer considering a single parameter, but a scalar function, and computational fluid dynamics (CFD) is notoriously difficult." This effect is a heat transfer problem, and therefore well suited to be studied from a transport phenomena viewpoint, based on continuum mechanics. When heat transfer is analyzed in terms of partial differential equations, whose solutions depend on a number of conditions, it becomes clear that measuring only a few lumped parameters, such as the water average temperature is generally insufficient to define the system behaviour, since conditions such as geometry, fluid properties and temperature and flow fields play an important role. The counterintuitiveness of the effect, if analyzed only in terms of simplified thermodynamics illustrates the need to include all the relevant variables and use the best available theoretical tools when approaching a physical problem. # Recent view of the Mpemba effect A reviewer for Physics World writes, "Even if the Mpemba effect is real - if hot water can sometimes freeze more quickly than cold - it is not clear whether the explanation would be trivial or illuminating." # Historical observations Similar behavior may have been observed by ancient scientists such as Aristotle, and Early Modern scientists such as Francis Bacon and René Descartes. Aristotle's explanation involved an erroneous property he called antiperistasis, defined as "the supposed increase in the intensity of a quality as a result of being surrounded by its contrary quality".

AHA 2015 Schedule Here is the page we will use to coordinate the TV events at AHA 2015. Open time slots are indicated below in red. Filming Location: Hyatt Regency Orlando, 9801 International Dr, Orlando, FL 32819, U.S.A. # Click on Date for Detailed Schedule Sunday, November 8, 2015 Monday, November 9, 2015 Tuesday, November 10, 2015 Wednesday, November 11, 2015 # Sunday, November 8, 2015 ## 8:00 AM OPEN TIME SLOT ## 8:30 AM OPEN TIME SLOT ## 9:00 AM OPEN TIME SLOT ## 9:30 AM OPEN TIME SLOT ## 10:00 AM OPEN TIME SLOT ## 10:30 AM OPEN TIME SLOT ## 11:00 AM - Interviewee: Dr. Karen Alexander - Topic: Angina and Quality of Life Following PCI With Incomplete Revascularization: Results From the Ranolazine for Incomplete Vessel Revascularization (RIVER-PCI) Trial - Embargo Lift: Tuesday, November 10, 2015 at 11:45 AM ## 11:30 AM OPEN TIME SLOT ## 12:00 PM - Interviewee: Dr. Mihai Gheorghiade - Topic: Oral sGC Stimulator Vericiguat in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction - The SOluble guanylate Cyclase stimulatoR in heArT failurE patientS With REDUCED EF (SOCRATES-REDUCED) Study - Embargo Lift: Sunday, November 8, 2015 at 4:13 PM ## 12:30 PM OPEN TIME SLOT ## 1:00 PM - Interviewee: Dr. Henning Bundgaard - Topic: The-First-in-Man Randomized Trial of a β3-adrenoceptor Agonist in Chronic Heart Failure - the BEAT-HF Trial - Embargo Lift: Wednesday, November 11, 2015 at 10:57 AM ## 1:30 PM - Interviewee: Dr. Margaret Redfield - Topic: Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction (NEAT-HFpEF) - Embargo Lift: Sunday, November 8, 2015 at 4:04 PM ## 2:00 PM - Interviewee: Dr. Michael Ong - Topic: Remote Patient Management After Discharge of Hospitalized Heart Failure Patients: The Better Effectiveness After Transition - Heart Failure Study - Embargo Lift: Sunday, November 8, 2015 at 4:22 PM ## 2:30 PM - Interviewee: Dr. Bonnie Spring - Topic: Clinical Trial of a Mobile Health Intervention for Simultaneous versus Sequential Diet and Activity Change - Embargo Lift: Monday, November 9, 2015 at 11:13 AM ## 3:00 PM - Interviewee: Dr. Iftikhar Kullo - Topic: The Effect of Disclosing Genomic Risk of Coronary Heart Disease on Low-density Lipoprotein Cholesterol Levels: The Myocardial Infarction Genes (MI-GENES) Study - Embargo Lift: Monday, November 9, 2015 at 11:22 AM ## 3:30 PM OPEN TIME SLOT ## 4:00 PM OPEN TIME SLOT ## 4:30 PM OPEN TIME SLOT # Monday, November 9, 2015 ## 8:00 AM OPEN TIME SLOT ## 8:30 AM OPEN TIME SLOT ## 9:00 AM - Interviewee: Dr. Noel Bairey-Merz - Topic: A Randomized, Placebo Controlled Trial of Late Na Channel Inhibition (ranolazine) in Coronary Microvascular Dysfunction (CMD): Impact on Angina and Myocardial Ischemia - Embargo Lift: Wednesday, November 11, 2015 at 11:45 AM ## 9:30 AM OPEN TIME SLOT ## 10:00 AM - Interviewee: Dr. Robert Yeh - Topic: Individualizing Treatment Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention: An Analysis of the DAPT Study - Embargo Lift: Tuesday, November 10, 2015 at 11:30 AM ## 10:30 AM - Interviewee: Dr. Myeong-ki Hong - Topic: Clinical Outcomes of Intravascular Ultrasound Guided Everolimus-Eluting Stents Implantation in Long Coronary Lesions - Embargo Lift: Tuesday, November 10, 2015 at 11:00 AM​ ## 11:00 AM OPEN TIME SLOT ## 11:30 AM - Interviewee: Dr. Geeta Gulati, Dr. Siri Heck and Dr. Torbjørn Omland - Topic: Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Primary Results of a Randomized, 2 x 2 Factorial, Placebo-Controlled, Double-Blind Clinical Trial - Embargo Lift: Wednesday, November 11, 2015 at 11:09 AM ## 12:00 PM - Interviewee: Dr. Basil Lewis - Topic: AHA 2015 Wrap-Up in Hebrew ## 12:30 PM - Interviewee: Dr. Douglas Mann - Topic: One Year Follow-up Results From AUGMENT-HF: A Multicenter Randomized Controlled Clinical Trial of the Efficacy of Left Ventricular Augmentation With Algisyl-LVR in the Treatment of Heart Failure - Embargo Lift: Wednesday, November 11, 2015 at 10:45 AM ## 1:00 PM - Interviewee: Dr. Valentin Fuster - Topic: Impact of a Comprehensive Lifestyle Peer-group-based Intervention on Cardiovascular Risk Factors: A Randomized Controlled Trial - Embargo Lift: Monday, November 9, 2015 at 11:04 AM ## 1:30 PM - Interviewee: Dr. Justin Ezekowitz and Dr. Robert Welsh - Topic: Providing Rapid Out of Hospital Acute Cardiovascular Treatment (PROACT-4) - Embargo Lift: Tuesday, November 10, 2015 at 10:45 AM ## 2:00 PM - Interviewee: Dr. Mark Eisenberg - Topic: The Efficacy and Safety of Varenicline, a Selective Alpha4beta2 Nicotinic Receptor Partial Agonist, for Smoking Cessation in Patients Hospitalized With Acute Coronary Syndrome: A Randomized Controlled Trial - Embargo Lift: Monday, November 9, 2015 at 10:55 AM ## 2:30 PM - Interviewee: Dr. Lars Wallentin - Topic: AHA 2015 Wrap-Up from a Scandinavian Perspective ## 3:00 PM OPEN TIME SLOT ## 3:30 PM OPEN TIME SLOT ## 4:00 PM OPEN TIME SLOT ## 4:30 PM OPEN TIME SLOT # Tuesday, November 10, 2015 ## 8:00 AM OPEN TIME SLOT ## 8:30 AM OPEN TIME SLOT ## 9:00 AM OPEN TIME SLOT ## 9:30 AM OPEN TIME SLOT ## 10:00 AM - Interviewee: Dr. Paul Whelton - Topic: Systolic Blood Pressure Intervention Trial (SPRINT) - Embargo Lift: Monday, November 9, 2015 at 2:05 PM ## 10:30 AM OPEN TIME SLOT ## 11:00 AM OPEN TIME SLOT ## 11:30 AM OPEN TIME SLOT ## 12:00 PM OPEN TIME SLOT ## 12:30 PM OPEN TIME SLOT ## 1:00 PM - Interviewee: Dr. Marc Bonaca - Topic: Long-Term Tolerability of Ticagrelor in the PEGASUS-TIMI 54 Trial - Embargo Lift: Tuesday, November 10, 2015 at 11:15 AM ## 1:30 PM - Interviewee: Dr. Freek Verheugt - Topic: AHA 2015 Wrap-Up from a Perspective of the Netherlands ## 2:00 PM - Interviewee: Dr. Renato Lopes - Topic: AHA 2015 Wrap-Up in Portuguese ## 2:30 PM - Interviewee: Dr. Myeong-ki Hong - Topic: Clinical Outcomes of Intravascular Ultrasound Guided Everolimus-Eluting Stents Implantation in Long Coronary Lesions - Embargo Lift: Tuesday, November 10, 2015 at 11:00 AM​ ## 3:00 PM - Interviewee: Dr. Kenneth Margulies - Topic: A Randomized Trial of Liraglutide for High-Risk Heart Failure Patients With Reduced Ejection Fraction - Embargo Lift: Sunday, November 8, 2015 at 3:55 PM ## 3:30 PM OPEN TIME SLOT ## 4:00 PM OPEN TIME SLOT ## 4:30 PM - Interviewee: Dr. Kevin Fitzgerald - Topic: ALN-PCSsc, an RNAi Investigational Agent That Inhibits PCSK9 With Potential for Effective Quarterly or Possibly Bi-Annual Dosing: Results of Single-Blind, Placebo-Controlled, Phase 1 Single-Ascending Dose (SAD), and Multi-Dose (MD) Trial in Adults With Elevated LDL-C, on and off Statins - Embargo Lift: Wednesday, November 11, 2015 at 11:57 AM ## 4:45 PM - Interviewee: Prof. Dr. Sigmund Silber - Topic: AHA 2015 Wrap-Up in German # Wednesday, November 11, 2015 ## 8:00 AM OPEN TIME SLOT ## 8:30 AM OPEN TIME SLOT ## 9:00 AM OPEN TIME SLOT ## 9:30 AM - Interviewee: Pr. Harvey White - Topic: AHA 2015 Wrap-Up from a Pacific Rim Perspective ## 10:00 AM - Interviewee: Dr. Hisao Ogawa - Topic: AHA 2015 Wrap-Up in Japanese ## 10:30 AM OPEN TIME SLOT ## 11:00 AM OPEN TIME SLOT ## 11:30 AM OPEN TIME SLOT ## 12:00 PM OPEN TIME SLOT ## 12:30 PM OPEN TIME SLOT ## 1:00 PM OPEN TIME SLOT ## 1:30 PM OPEN TIME SLOT ## 2:00 PM OPEN TIME SLOT ## 2:30 PM OPEN TIME SLOT ## 3:00 PM OPEN TIME SLOT ## 3:30 PM OPEN TIME SLOT ## 4:00 PM OPEN TIME SLOT ## 4:30 PM OPEN TIME SLOT

Amantadine drug interactions # Drug Interactions Careful observation is required when amantadine hydrochloride is administered concurrently with central nervous system stimulants. Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with Parkinson's disease, however, it is not known if other phenothiazines produce a similar response. Coadministration of Dyazide® (triamterene/hydrochlorothiazide) resulted in a higher plasma amantadine concentration in a 61-year-old man receiving amantadine hydrochloride 100 mg TID for Parkinson's disease.1 It is not known which of the components of Dyazide® contributed to the observation or if related drugs produce a similar response. Coadministration of quinine or quinidine with amantadine was shown to reduce the renal clearance of amantadine by about 30%. The concurrent use of amantadine hydrochloride with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of amantadine hydrochloride, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of amantadine hydrochloride.

Interest (emotion) # Overview Interest (emotion) is a feeling or emotion that causes attention to focus on an object or an event or a process. In contemporary psychology of interest it is used as a general concept which encompasses other more specific emotion terms, such as curiosity and to a certain degree surprise, in a similar way the general term anger encompasses other terms for the emotion such as rage (intense anger). The facial expression of emotion of interest shares most of the features with surprise: - Eyebrows that are raised so they become curved and high. - Stretched skin below the eyebrows. - Horizontal wrinkles across the forehead. - Open eyelids -- the upper lid is raised and the lower lid is drawn down, often exposing the white sclera above and below the iris. - Dropped jaw so that the lips and teeth are parted, with no tension around the mouth. However, the facial expression of interest encompasses additional features which are not characteristic for surprise, such as: - Dilated pupils. - Widened nostriles. - Visible tongue -- in slightly upward position (while, for example, in disgust the tongue is visible in more or less downward position)

Summary of the Standards, Options and Recommendations for the management of patients with carcinoma of unknown primary site (2002) Carcinomas of unknown primary site are metastatic malignant epithelial tumours whose primary site cannot be identified during pretreatment assessment. They are characterised by their slow local development and their high metastatic potential. The primary site remains unknown in 20 -50% of the patients, but the results from autopsies show that the primary tumours are most often located in the pancreas, lung, gut or kidney.In France, the incidence of carcinomas of unknown primary site is eight out of 100 000 per year, corresponding to between 5 and 7% of the solid tumours in adults. The average age at detection is 60 years old, with slightly more men being affected. The median survival time is only a few months.The heterogeneity of carcinoma of unknown primary site is due to the different histopathological types and anatomical localisations, making this a difficult topic to cover. In this document, we present the diagnostic strategy based on these two parameters, with the first entry point being the histopathological type. The therapeutic strategies to be used depend on the prognostic factors: specific anatomoclinical entities (neuroendocrine tumours, cervical lymph node metastases from squamous cell carcinoma, axillary lymph node metastases from an adenocarcinoma in women, undifferentiated carcinoma of the mediastinum in young men) and other nonspecific situations. Although primary papillary serous carcinoma is no longer included in the classification of peritoneum carcinomas of unknown primary site, we covered the management in women here in an attempt to be exhaustive. Carcinomas of unknown primary site are metastatic malignant epithelial tumours whose primary site cannot be identified during pretreatment assessment. They are characterised by their slow local development and their high metastatic potential. The primary site remains unknown in 20 -50% of the patients, but the results from autopsies show that the primary tumours are most often located in the pancreas, lung, gut or kidney. In France, the incidence of carcinomas of unknown primary site is eight out of 100 000 per year, corresponding to between 5 and 7% of the solid tumours in adults. The average age at detection is 60 years old, with slightly more men being affected. The median survival time is only a few months. The heterogeneity of carcinoma of unknown primary site is due to the different histopathological types and anatomical localisations, making this a difficult topic to cover. In this document, we present the diagnostic strategy based on these two parameters, with the first entry point being the histopathological type. The therapeutic strategies to be used depend on the prognostic factors: specific anatomoclinical entities (neuroendocrine tumours, cervical lymph node metastases from squamous cell carcinoma, axillary lymph node metastases from an adenocarcinoma in women, undifferentiated carcinoma of the mediastinum in young men) and other nonspecific situations. Although primary papillary serous carcinoma is no longer included in the classification of peritoneum carcinomas of unknown primary site, we covered the management in women here in an attempt to be exhaustive. ## Objectives The objective was to define guidelines for the management of adult patients with carcinomas of unknown primary site. These guidelines are aimed at health professionals treating these patients with the goal of helping to homogenising clinical practice. The principal questions addressed in this document are: What pathological diagnostic strategies should be used for each localisation? To what extent should the primary site be searched for, and what are the limits for this strategy? What are the prognostic factors? What treatment strategies should be used for each anatomoclinical type? # Methods The details of the full methodology have been previously published [bib_ref] SOR: project methodology, Fervers [/bib_ref]. In summary, a multidisciplinary working group was set up by the French National Federation of Cancer Centres (Fédération Nationale des Centres de Lutte Contre le Cancer -FNCLCC) to review the literature on the management of patients with carcinomas of unknown primary site. Medline s was searched between 1980 and 2001 using keywords pertinent for each topic covered and this was completed with references provided by the members of the working group. The majority of the articles were in English and French. After selection and critical appraisal of this literature, the working group defined the 'Standards', for the management of patients with carcinomas of unknown primary site, based on a synthesis of the best available evidence and expert agreement. These guidelines were then reviewed by a group of independent experts (see the Appendix) and finalised after taking into consideration their comments. SORs are considered as being validated when the members of the working group give their agreement for publication. When all the members of the working group agree, based on the best available evidence, that a procedure or intervention is beneficial, inappropriate, or harmful, it is classified as a 'Standard', and when the majority agree, it is classified as an 'Option' [fig_ref] Table 1: Definition of Standards, Options and Recommendations Standards Procedures or treatments that are... [/fig_ref]. In the SORs, there can be several 'Options' for a given clinical situation. 'Recommendations' provide additional information that enable the available options to be ranked using explicit criteria (e.g. survival, toxicity) with an indication of the level of evidence. These recommendations thus help clinicians to select an appropriate option. Thus, clinicians can make choices for the management of patients using this information and taking into consideration local circumstances, skills, equipment, resources and/or patient preferences. The adaptation of the SOR to the local situation is allowable if the reason for the choice is sufficiently transparent and this is crucial for successful implementation. Inclusion of patients in clinical trials is an appropriate form of patient management in oncology and is recommended frequently within the SORs, particularly in situations where only weak evidence exists to support a procedure or an intervention. The type of evidence underlying any 'Standard', 'Option' or 'Recommendation' is indicated using a classification developed by the FNCLCC based on previously published methods. The level of evidence depends not only on the type and quality of the studies reviewed, but also on the concordance of the results [fig_ref] Table 2: Definition of level of evidence [/fig_ref]. When no clear scientific evidence exists, judgement is made according to professional experience and consensus of the expert group ('expert agreement'), and this is then validated by the peerreview process. This is a translation of the French version of the summary rapport [bib_ref] ) Standards, Options and Recommendations for the management of patient with carcinoma..., Bugat [/bib_ref] , which was based on the full-text version in French, available on internet at the following address: http://www.fnclcc.fr. The document will be updated as new evidence becomes available or there is a change in expert agreement. The list of abbreviations used in this article and their meaning is given in [fig_ref] Table 3: Abbreviations and their meanings [/fig_ref]. ## Pathological examination ## Treatment of samples prior to pathological examination Samples should be fixed using buffered formalin or AFA (acetic acid, formaldehyde, alcohol) (standard, level of evidence: B2). The standard staining technique is haematoxylin and eosin (standard, level of evidence: B2). Immunohistochemical investigations should be performed using a panel of antibodies (standard, level of evidence: B2). Samples can be frozen directly in liquid nitrogen and then stored in a freezer at À801C or lower, or stored in liquid nitrogen (option, expert agreement). ## Strategies for specific histopathological types (figures 1 -3) Undifferentiated malignant tumour An immunohistochemical investigation should be performed to eliminate the diagnosis of lymphoma, melanoma or germ cell tumour. This should involve the use of a panel of reference antibodies against epithelial antigens (pan-cytokeratins), lymphoid antigens (CD45, CD20, CD3), melanotic antigens (PS100 et HMB45) and germ cell tumour antigens (aFP, bHCG, PLAP) depending on the clinical presentation (standard, level of evidence: B2). Undifferentiated carcinoma or adenocarcinoma Neuroendocrine tumour markers should be used in the immunohistochemical investigation (e.g. chromogranin, synaptophysin), as well as carcinoma markers (cytokeratins: CK5/6, CK7, CK19, CK20, ACE) and other antibodies depending on the anatomoclinical presentation (e.g. thyroglobulin, prostate specific antigen (PSA), hormonal receptors) (standard, level of evidence: B2). Level A There exists a high-standard meta-analysis or several high-quality randomised clinical trials that give consistent results ## Level b There exist good quality evidence from randomised trials (B1) or prospective or retrospective studies (B2). The results are consistent when considered together Level C The methodology of the available studies is weak or their results are not consistent when considered together Level D Either the scientific data do not exist or there is only a series of cases ## Expert agreement The data do not exist for the method concerned, but the experts are unanimous in their judgement ## Diagnostic strategy systematic diagnostic assessment Diagnostic strategy should aim to identify anatomoclinical entities of carcinomas of unknown primary site for which there is a specific treatment (standard, level of evidence: B2). For other anatomoclinical entities, identification of the primary tumour has no impact on the prognostic or therapeutic consequences, thus a systematic complete assessment is unnecessary (standard, level of evidence: B2). The systematic diagnostic assessment is summarised in step 1 in . Specific work-up to eliminate diagnosis of extragonadal germ cell tumour The main differential diagnoses for patients with carcinomas of unknown primary site are extragonadal germ cell tumour and lymphoma, because they are potentially curable. The specific work-up for eliminating the diagnosis of extragonadal germ cell tumour, includes a systematic diagnostic work-up and a specific work-up for adenocarcinomas and undifferentiated carcinomas (standard). Diagnostic work-up depending on histopathological and anatomic localisation [fig_ref] Figure 4: Second diagnostic step for adenocarcinoma and undifferentiated carcinoma [/fig_ref] The diagnostic steps (steps 2 and 3), performed depending on the histopathological and anatomic localisation, are shown in . [formula] + + + - CK - CD45 - PS100 + − − - CK - CD45 - PS100 − + − - CK - CD45 - PS100 − − + - CK - CD45 - PS100 − − − [/formula] ## Prognostic factors for carcinoma of unknown primary site No prospective studies or meta-analyses for prognostic factors have been published, but there are several retrospective studies with coherent results, which suggest that the following are the best prognostic factors: general good health status; women; lymph node metastases; neuroendocrine or squamous cell carcinoma; and few metastatic sites (level of evidence: B2). It is recommended to include patients with carcinomas of unknown primary site in good-quality studies assessing prognostic factors (recommendation). ## Treatment strategy ## Treatment of specific anatomoclinical entities Treatment of neuroendocrine carcinoma The treatment of metastases from a neuroendocrine carcinoma is not modified by the identification of the primary site (expert agreement). The management of patients with neuroendocrine carcinoma of unknown primary site should take into consideration the cellular differentiation (standard, expert agreement). Poorly differentiated forms are considered to be chemosensitive (level of evidence: C). The usual treatment is based on a combination of a platinum salt and etoposide (level of evidence: C). Although the results from clinical trials do not provide evidence for efficacy in terms of increased survival, clinicians should prescribe this treatment (standard, expert agreement). There is no standard for the forms that are well differentiated. The treatment decision should be based on a multidisciplinary decision taking into consideration the patient's symptoms and the progression of the carcinoma, particularly for those with welldifferentiated forms (recommendation). Treatment of cervical lymph node metastases in patients with squamous cell carcinoma Patients with cervical lymph node metastases from squamous cell carcinoma should be offered lymph node dissection and complementary radiotherapy (standard, level of evidence: C). If surgery is not possible, radiotherapy should be performed (standard). Chemotherapy can be proposed to patients with tumours that are not suitable for resection or surgery (option). Diagnostic work-up for carcinoma of unknown primary site as a function of their histopathological and anatomic localisation Step 1 Step 2 Step 3 ## Diagnostic step 3 standards ## Diagnostic step 3 standards (women) ## Diagnostic step 3 standards ## Diagnostic step 3 options ## Diagnostic step 3 option ## Diagnostic step 3 Options ( Locoregional treatment (axilla): Axillary dissection should be offered (standard, expert agreement). Axillary and/or supraclavicular irradiation can be undertaken (option, expert agreement). Systemic treatment: The management of these patients should be identical to that for patients with breast cancer with lymph node metastases (recommendation). Treatment of primary papillary serous carcinoma in women By analogy with ovarian cancer, the standard treatment is tumour reduction by surgery (level of evidence: D) followed by poly-chemotherapy containing a platinum salt (standard, expert agreement). About six cycles of treatment should be undertaken (recommendation). Treatment for carcinomas of unknown primary site not belonging to a specific anatomoclinical entity [fig_ref] Figure 1: First diagnostic step for carcinoma of unknown primary site [/fig_ref] treatment only, or a treatment based on bisphosphonates in patients with bone metastases. If chemotherapy is prescribed, it is recommended to administer a combination therapy with two drugs, containing cisplatin (recommendation, expert agreement) for patients with a good general health status (WHO performance status of 1 or less). The treatment response should be evaluated early (after two cycles) to avoid treatment in patients with known progressive disease (recommendation). [fig_ref] Figure 9, Figures: Figure 9 [/fig_ref] Treatment of axillary lymph node metastases in patients with adenocarcinoma. General treatment for carcinoma of unknown primary site not belonging to a specific anatomoclinical entity [fig_ref] Figure 1: First diagnostic step for carcinoma of unknown primary site [/fig_ref] General treatment of carcinoma of unknown primary site not belonging to a specific anatomoclinical entity. [fig] Figure 1: First diagnostic step for carcinoma of unknown primary site. [/fig] [fig] Figure 2: Histopathological diagnosis for carcinoma of unknown primary site. [/fig] [fig] Figure 3: Histopathological diagnosis of undifferentiated carcinoma and adenocarcinoma. [/fig] [fig] Figure 4: Second diagnostic step for adenocarcinoma and undifferentiated carcinoma. [/fig] [fig] Figure 9, Figures: Figure 9 [/fig] [fig] Figure 5: Third diagnostic step for adenocarcinoma and undifferentiated carcinoma. of Cancer (2003) 89(Suppl 1), S59 -S66 & 2003 FNCLCC Treatment of axillary lymph node metastases in women with adenocarcinoma (Figure 9) Locoregional treatment (breast): If the results from the breast MRI are negative, surgery and breast radiotherapy should not be offered (standard, expert agreement). [/fig] [fig] Figure 6, Figure 7, Figure 8: Complementary examinations for squamous cell carcinoma. Treatment of neuroendocrine carcinoma. Treatment of cervical lymph node metastases in patients with squamous cell carcinoma. [/fig] [table] Table 2: Definition of level of evidence [/table] [table] Table 3: Abbreviations and their meanings [/table] [table] Table 1: Definition of Standards, Options and Recommendations Standards Procedures or treatments that are considered to be of benefit inappropriate or harmful by unanimous decision, based on the best available evidence Options Procedures or treatments that are considered to be of benefit, inappropriate or harmful by a majority, based on the best available evidenceRecommendations Additional information to enable the available options to be ranked using explicit criteria (e.g. survival, toxicity) with an indication of the level of evidence An immunohistochemical investigation for the diagnosis should be performed using an appropriate panel of specific antibodies (standard). This should enable the diagnosis of lymphoma, melanoma, germ cell tumour and sarcoma to be eliminated and the diagnosis of prostate, breast, ovary, thyroid or neuroendocrine tumours to be positively identified. A sample can be frozen to enable typing, cytogenetic and, particularly, molecular biological studies to be performed later (option). The clinician and pathologist should compare their opinions before and after the pathological diagnosis (recommendation, expert agreement). [/table]

ADAMTS7 A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7) is an enzyme that in humans is encoded by the ADAMTS7 gene on chromosome 15. It is ubiquitously expressed in many tissues and cell types. This enzyme catalyzes the degradation of cartilage oligomeric matrix protein (COMP) degradation. ADAMTS7 has been associated with cancer and arthritis in multiple tissue types. The ADAMTS7 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. # Structure ## Gene The ADAMTS7 gene resides on chromosome 15 at the band 15q24.2 and contains 25 exons. ## Protein This 1686-amino acid protein belongs to the ADAMTS family and is one of 19 members known in humans. As an ADAMTS protein, ADAMTS7 contains a shared proteinase domain and an ancillary domain. The proteinase domain can be further divided into a signal peptide, a prodomain, a metalloproteinase domain, and a disintegrin-like domain. In particular, the metalloproteinase domain contains a cysteine-switch motif in its binding site for binding the catalytic zinc ion (Zn2+). A pharmacophore model consisting of four hydrogen bond donor sites and three hydrogen bond acceptor sites was proposed for this domain. Unlike the proteinase domain, the ancillary domain varies by ADAMTS protein and includes any number of thrombospondin (TSP) type 1 motifs, one cysteine-rich and spacer domain, and other domains specific to certain ADAMTS proteins. ADAMTS7 in particular possesses 8 TSP type 1 motifs which, together with its spacer domain, participate in the protein’s tight interaction with the extracellular matrix. # Function ADAMTS7 was identified in a yeast two-hybrid screen using epidermal growth factor (EGF) domain of COMP as the bait. As a metalloproteinase, ADAMTS7 utilizes Zn2+ to catalyze its proteolytic function for COMP degradation. In vascular smooth muscle cell (VSMC), ADAMTS7 mediates VSMC migration, which plays an essential role during the development of atherosclerosis and restenosis. Adamts7 deficiency in both the Ldlr−/− and Apoe−/− hyperlipidemic mouse models markedly attenuates formation of atherosclerotic lesions; furthermore, wire-injury experiments in the Adamts7−/− mouse show reduced neointima formation. The association of ADAMTS7 with atherosclerosis suggests that inhibition of ADAMTS7 should be atheroprotective in humans. # Clinical Significance A negative correlation between the expression levels of specific miRNAs and ADAMTS7 is observed in normal tissues but not in disease tissues, implying an altered miRNA-target interaction in the disease state. Accordingly, expression profiles of these miRNAs and ADAMTS7 may be useful diagnostic tools to differentiate cancer and lichen planus from normal tissues. ADAMTS7 has also been identified as a putative oncogene and reported to be mutated exclusively in Asians, which may have implications for the prevention and treatment of hepatocellular carcinoma. In addition, ADAMTS7 plays a crucial role in the pathogenesis of arthritis. For example, the FGF2/p65/miR-105/Runx2/ADAMTS axis is reportedly involved in osteoarthritis (OA) pathogenesis. Specifically, ADAMTS7 forms a positive feedback loop with tumour necrosis factor (TNF)-α in the pathogenesis of OA. ## Clinical Marker Genome-wide association studies identified ADAMTS7 as a risk locus for coronary artery disease. Studies have been carried on classification of ADAMTS7 binding site, which may serve as the first step toward developing a new therapeutic target for coronary artery disease. Significant associations for coronary artery calcification with SNPs in ADAMTS7 has also been found in Hispanics. Additionally, a multi-locus genetic risk score study based on a combination of 27 loci, including the ADAMTS7 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).

Amphetamine psychosis # Overview Amphetamine psychosis is a form of psychosis which can result from amphetamine or methamphetamine use. Typically it appears after large doses or chronic use, although in rare cases some people may become psychotic after relatively small doses. Other chemicals or drugs which similarly increase dopamine function (such as cocaine and L-DOPA) can produce similar psychotic states. Because of this, the term stimulant psychosis is sometimes preferred. Amphetamine psychosis can include delusions, hallucinations and thought disorder. This is thought to be largely due to the increase in dopamine and perhaps serotonin activity in the mesolimbic pathway of the brain caused by amphetamine-like drugs, although other factors such as chronic sleep deprivation may also play a part. The link between amphetamine and psychosis is one of the major sources of evidence for the dopamine hypothesis of psychosis. The link between amphetamine and psychosis was first made by Young and Scoville in 19381 and was originally considered to be a rare condition. As amphetamine use increased after World War II, largely due to the widespread use of amphetamine compounds in nasal decongestant and dieting preparations, it became clear that chronic amphetamine use often led to psychotic symptoms. Hallucinations are frequently reported in chronic amphetamine users, with over 80% of users reporting the presence of hallucinatory experiences2, typically as visual or auditory experiences. Delusions, paranoia, fears about persecution, hyperactivity and panic are also reported as the most common features3 Concurrent to having delusions and hallucinations, chronic amphetamine users may also display stereotyped, repetitive and seemingly purposeless movements, known as 'motor stereotypies' or more commonly as 'knick knacking', 'tweaking' or being 'hung-up'. These may include examining, sorting, disassembling, and cleaning. The article on punding gives a more complete description of this behavior. This behavior may be similar to the symptoms of OCD. One particular manifestation of psychosis associated with amphetamine use is delusional parasitosis or Ekbom's syndrome, where a person falsely believes themselves to be infested with parasites. However, related behaviour may occur in non-psychotic conditions, where users will realise they are not infested by parasites but will pick at their skin anyway. This more closely resembles obsessive-compulsive disorder. # Amphetamine psychosis in popular culture There is a chapter in Hunter S. Thompson's Fear and Loathing in Las Vegas entitled 'Aaawww, Mama, Can This Really Be the End?... Down and Out in Vegas, with Amphetamine Psychosis Again?', a reference to Bob Dylan's Stuck Inside of Mobile with the Memphis Blues Again. In the film Requiem for a Dream, Sara Goldfarb, one of the four main characters clearly suffers from amphetamine psychosis after having been prescribed amphetamines as a weight loss drug, specifically, hallucinations of her refrigerator trying to devour her. The meth song is a drug awareness public service announcement that has become part of popular culture. The film A Scanner Darkly (as well as the novel of the same name) contains a scene where the character Charles Freck suffers from formication. The anti-drug advertising of the Montana Meth Project often focuses on the dangers of amphetamine psychosis.

Enterocolitis Enterocolitis (or "coloenteritis") is an inflammation of the colon and small intestine. However, most conditions are categorfized as one or the other of the following: - Enteritis is the inflammation of the small intestine - Colitis is inflammation of the large intestine, especially the colon # Types Specific types of enterocolitis include: - necrotizing enterocolitis (most common in premature infants) - autistic enterocolitis (a controversial entity of bowel disease in autistic children) - pseudomembranous enterocolitis (also called "Pseudomembranous colitis") ## Causes - Ipilimumab - Ixabepilone - Tetracyclines (Idarubicin hydrochloride)

Transcutaneous electrical stimulation of the trigeminal nerve for ADHD Evidence-based recommendations on transcutaneous electrical stimulation of the trigeminal nerve for ADHD. This involves a single-use electrode patch stuck to the forehead, which sends small electrical pulses through the skin during sleep. # Recommendations Evidence on the safety and efficacy of transcutaneous electrical stimulation of the trigeminal nerve for attention deficit hyperactivity disorder (ADHD) is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. Further research could be in the form of multicentre, sham‑controlled (or other suitable comparator) trials and should include details of patient selection, treatment protocols, adherence and long-term outcomes.# The condition, current treatments and procedure # The condition Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder characterised by the core symptoms of hyperactivity, impulsivity and inattention, which are judged excessive for the person's age or level of overall development. Symptoms are usually evident in childhood and may persist into adulthood. # Current treatments Treatment for ADHD may be non-pharmacological, pharmacological or a combination of both. Non-pharmacological treatment includes cognitive behavioural therapy and parent‑training programmes (for parents of children and young people with ADHD). Pharmacological treatment includes central nervous system stimulants such as methylphenidate and amphetamines, and non-stimulants such as atomoxetine. # The procedure In this procedure, an external trigeminal nerve stimulation device is worn on the clothes and attached by wires to a single-use adhesive patch which is worn overnight. The patch contains 2 electrodes placed over the left and right V1 branches of the trigeminal nerve on the forehead. The stimulator bilaterally stimulates the trigeminal nerve for approximately 8 hours. For children, parents or carers attach the device. In a typical treatment course, stimulation is given nightly for approximately 4 weeks. Treatment duration may vary; a clinical response may take longer, and continued therapy may be needed. The mechanism of action is not completely understood. The trigeminal nerve connects to regions of the brain that may be associated with selective maintenance of attention and arousal, and it is thought that its stimulation improves the symptoms of ADHD.

Tildrakizumab for treating moderate to severe plaque psoriasis Evidence-based recommendations on tildrakizumab (Ilumetri) for treating moderate to severe plaque psoriasis in adults. # Recommendations Tildrakizumab is recommended as an option for treating plaque psoriasis in adults, only if: the disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10 and the disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and the company provides the drug according to the commercial arrangement. Consider stopping tildrakizumab between 12 weeks and 28 weeks if there has not been at least a 50% reduction in the PASI score from when treatment started. Stop tildrakizumab at 28 weeks if the psoriasis has not responded adequately. An adequate response is defined as: a 75% reduction in the PASI score (PASI 75) from when treatment started or a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in DLQI from when treatment started. If patients and their clinicians consider tildrakizumab to be one of a range of suitable treatments, the least expensive should be chosen (taking into account administration costs, dosage, price per dose and commercial arrangements). When using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. When using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any adjustments they consider appropriate. These recommendations are not intended to affect treatment with tildrakizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Treatment for moderate to severe plaque psoriasis includes systemic biological treatments for disease that does not respond to systemic non-biological treatments. Tildrakizumab is proposed as an alternative to other systemic biological treatments already recommended by NICE. Clinical trial results show that tildrakizumab improves severe plaque psoriasis compared with placebo or etanercept. More improvement is usually seen at 28 weeks compared with 12 weeks of treatment. When compared indirectly, tildrakizumab appears to be as effective as adalimumab and ustekinumab but not as effective as other biological treatments. The most plausible cost-effectiveness estimates for tildrakizumab compared with most other available biological treatments show that it is generally cost effective. Therefore, tildrakizumab is recommended as an option for use in the NHS for severe psoriasis that has not responded to systemic non-biological treatments, or if these are contraindicated or not tolerated.# Information about tildrakizumab Marketing authorisation indication Tildrakizumab (Ilumetri, Almirall) has a marketing authorisation 'for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy.' Dosage in the marketing authorisation Tildrakizumab is administered by subcutaneous injection at a dose of 100 mg at weeks 0 and 4 and every 12 weeks thereafter. In patients with certain characteristics (for example, high disease burden, body weight of 90 kg or more), a 200 mg dose may provide greater efficacy. Consideration should be given to stopping treatment in patients whose psoriasis has shown no response after 28 weeks of treatment. An initial partial response may subsequently improve with continued treatment beyond 28 weeks. Price The list price of tildrakizumab is £3,241 for both the 100 mg (single-dose pack of 1 prefilled syringe) and the 200 mg (single-dose pack of 2×100 mg prefilled syringes) doses (excluding VAT; price as quoted in company's submission). The company has a commercial arrangement. This makes tildrakizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee (section 6) considered evidence submitted by Almirall and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence. # Experience of people with psoriasis ## Psoriasis is a lifelong condition that affects all aspects of a person's life Psoriasis at any level of severity can be distressing and debilitating, affecting all aspects of life (physical, psychological, social and financial), and it is a lifelong condition. The committee noted that having treatments with few or manageable side effects, and which are effective for psoriasis on the face, hands, feet and genitals, is especially important to people with psoriasis, as is having a choice of treatments. # Clinical management ## Psoriasis can be treated with topical therapies, phototherapy, and systemic non-biological and biological treatments People with plaque psoriasis may have topical therapies first line, followed by phototherapy second line. If these do not control the psoriasis, people may have systemic conventional non-biological treatments third line (such as methotrexate, ciclosporin or acitretin). If the disease does not respond to these, people may have fourth-line treatment including systemic biological treatments (such as adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, infliximab, secukinumab or ustekinumab), or apremilast or dimethyl fumarate. Biosimilar versions of some biologicals are also available. The drugs are used for as long as they continue to work. If the disease no longer responds to 1 biological, people will be offered another biological. This pattern is likely to be repeated over their lifetime. However, 1 clinical expert explained that previous biological treatments may affect the effectiveness of subsequent treatments, although there is uncertainty about the degree to which this occurs. Also, switching treatments can have a negative psychological effect on people with psoriasis. The clinical expert also stated that a variety of treatments are needed because patients can respond very differently to treatments with the same biological method of action. For people whose disease does not respond to multiple biological treatments, apremilast or dimethyl fumarate, the only remaining treatment option is best supportive care, which usually consists of topical agents and bandaging. # Treatment pathway ## Tildrakizumab is most likely to be used as an alternative to other systemic biological treatments The marketing authorisation for tildrakizumab is for 'adults who are candidates for systemic therapy'. However, in the company submission, tildrakizumab was positioned as an alternative only to systemic biological treatments, which are used after systemic non-biological treatments in current NHS practice. The positioning therefore captures a narrower population than the marketing authorisation. However, the clinical expert confirmed that this is the most likely stage in the treatment pathway at which NHS clinicians would consider using tildrakizumab. The committee concluded that this position in the treatment pathway was appropriate and that it would appraise tildrakizumab compared with other biological treatments. ## Infliximab is a relevant comparator to tildrakizumab The company suggested that infliximab was not a relevant comparator because it was recommended only for people with very severe plaque psoriasis. The ERG explained that a large proportion of the population in the tildrakizumab trials (see section 3.7) had very severe plaque psoriasis. Also, infliximab was included as a comparator in previous appraisals at the same position in the treatment pathway as tildrakizumab. The committee concluded that infliximab was a relevant comparator to tildrakizumab. ## The most relevant comparators to tildrakizumab are other biological treatments The company suggested that the systemic non-biological treatments apremilast and dimethyl fumarate, used in NHS clinical practice at the same position as systemic biological treatments, were not relevant comparators. The clinical expert explained that these options were rarely used in practice because they are perceived to be less effective than biological treatments. They would only be considered for use for people for whom a biological treatment was unsuitable or who were unwilling to have a biological treatment. The committee concluded that although apremilast and dimethyl fumarate were used in the NHS for some people with psoriasis, the most relevant comparators to tildrakizumab were other biological treatments. # Clinical evidence ## The reSURFACE trials provide the key clinical evidence for tildrakizumab The main evidence for tildrakizumab came from the reSURFACE trials (reSURFACE 1 and reSURFACE 2). These were double-blind randomised controlled trials that included a total of 1,862 patients with plaque psoriasis. They compared 2 doses of tildrakizumab (100 mg and 200 mg) with placebo, and reSURFACE 2 also included an etanercept arm. The primary outcomes were the Psoriasis Area and Severity Index (PASI) and the Physician Global Assessment (PGA). Both PASI and PGA were assessed at 12 weeks and 28 weeks, as follows: PASI 75: a 75% reduction in the PASI score from when treatment started and PGA: a PGA rating of 'clear' (score of 0) or 'almost clear' (score of 1).Patients in reSURFACE 1 and reSURFACE 2 were followed up for longer-term outcomes, for 64 weeks and 52 weeks respectively. ## The populations in the reSURFACE trials are similar to patients in the NHS who may have tildrakizumab The committee considered whether patients in the reSURFACE trials were similar to those in NHS clinical practice for: Severity of disease: the reSURFACE trials included patients with moderate to severe psoriasis with a PASI score of 12 or more. No minimum Dermatology Life Quality Index (DLQI) score was included. Previous NICE technology appraisals have defined severe and very severe psoriasis based on the PASI and DLQI; the PASI threshold for severe psoriasis is 10 or more. Previous systemic non-biological treatment: the committee noted that 24% of patients in reSURFACE 1 and 40% of patients in reSURFACE 2 had previous systemic non-biological treatment. The clinical expert stated that these proportions were lower than in the relevant population in NHS clinical practice. The committee was aware that subgroup analyses did not provide any evidence of a clinically relevant effect of previous systemic non-biological treatments on subsequent response to tildrakizumab. Previous systemic biologicals: the committee noted that 23% of patients in reSURFACE 1 and 13% of patients in reSURFACE 2 had previous systemic biological treatment. The ERG suggested that this might not represent NHS clinical practice at the proposed positioning of tildrakizumab. The committee recalled the clinical expert's advice that previous biological treatments may influence the effectiveness of subsequent treatments (see section 3.2). However, the committee was also aware that there was uncertainty as to the extent that this may occur, and that subgroup analyses did not provide any evidence of a clinically relevant effect of previous biological treatments on subsequent response to tildrakizumab.The committee noted that the results of the reSURFACE trials may have overestimated the clinical effectiveness of tildrakizumab because of the proportions of patients who had not had previous non-biological and biological systemic treatment. The clinical expert advised that this would not be expected to have a large effect on the relative efficacy results. The committee concluded that the patients in the trials generally reflected those who would have treatment with tildrakizumab in NHS clinical practice. ## Both 100 mg and 200 mg doses of tildrakizumab are appropriate The company presented results for both licensed doses of tildrakizumab (100 mg and 200 mg). The company representative explained that the higher dose is intended for use from treatment induction in people with a higher body weight or disease burden, determined by the clinician. The committee noted that there was no difference in efficacy between the 2 doses in the reSURFACE trials. The clinical expert explained that clinicians would welcome flexibility in available doses of the same treatment. The committee concluded that it was appropriate to consider both licensed doses in its decision making. ## Clinical outcomes assessed at 12 weeks and 28 weeks should be considered The committee was aware that tildrakizumab's marketing authorisation states that, if there is no response after 28 weeks of treatment, stopping tildrakizumab should be considered. It recalled that the PASI 75 response rate for tildrakizumab at 28 weeks was statistically significantly higher than at 12 weeks in the reSURFACE trials, and other biological treatments also had higher response rates at later assessments. The committee considered that tildrakizumab's less frequent dosing schedule meant that this late treatment effect was more noticeable because only 2 doses had been given before assessment of response at 12 weeks. The clinical expert advised that assessment at 12 weeks would be premature, and they would prefer to minimise the risk of a patient switching from a potentially effective treatment (see section 3.2). The committee concluded that the clinical outcomes from the reSURFACE trials at weeks 12 and 28 should be considered in its decision making. ## Tildrakizumab is more clinically effective than placebo or etanercept The committee noted that: At week 12, patients randomised to tildrakizumab were more likely to have a PASI 75 and PGA clear or minimal response than patients randomised to placebo or etanercept. At week 28, patients randomised to tildrakizumab were more likely to have a PASI 75 and PGA clear or minimal response than those randomised to etanercept, but no information compared with placebo was available.The committee concluded that tildrakizumab was more clinically effective than placebo and etanercept. ## Assess response to tildrakizumab before and at 28 weeks, and consider stopping treatment if there is no response Based on consultation comments, the committee understood that clinicians may find it unreasonable to continue tildrakizumab for 28 weeks for patients whose psoriasis is not responding to treatment. The committee recalled that, in the reSURFACE trials, patients whose disease had not had at least a 50% reduction in the PASI score at 12 weeks were less likely to have a PASI 75 response at 28 weeks than patients whose disease had partially responded at 12 weeks (PASI 50). The committee also recalled that most patients whose psoriasis had a PASI 75 response reached this outcome by week 22, after taking the third dose in week 16. It was aware that no similar data were presented for other outcomes such as DLQI. The committee considered that although stopping treatment from 14 weeks was considered in the economic modelling (see section 3.17), it was more appropriate to consider stopping treatment from 12 weeks. This was because this reflected the trial data and was in line with previous NICE technology appraisal guidance, such as NICE's technology appraisal guidance for etanercept efalizumab for the treatment of adults with psoriasis, brodalumab for treating moderate to severe plaque psoriasis, ixekizumab for treating moderate to severe plaque psoriasis and secukinumab for treating moderate to severe plaque psoriasis. The committee concluded that if there was no adequate response at 28 weeks (either a PASI 75 response, or a PASI 50 response and a 5‑point reduction in DLQI), tildrakizumab should be stopped (see section 3.9). Also, if there has not been at least a 50% reduction in the PASI score from when treatment started to between 12 weeks and 28 weeks, stopping tildrakizumab should be considered. # Network meta-analysis ## The network meta-analysis including infliximab is appropriate for decision making The company did a network meta-analysis to indirectly compare tildrakizumab with other biological treatments (adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, secukinumab and ustekinumab) using data from 45 trials. The included trials assessed PASI 75 response at various time points, which the company grouped into separate stages for its analysis: Response measured at 12 weeks to 16 weeks (stage I). Response measured at 16 weeks to 24 weeks (stage II). Stage II was a separate planned analysis that excluded the placebo arms, resulting in an incomplete network, therefore it was not considered in this appraisal. Response measured at 24 weeks to 28 weeks (stage III).No trials reported placebo outcomes at stage III. To include placebo in its stage III network, the company used placebo response rates from the same trials at stage I. The ERG noted that this made the stage III analysis weaker than the stage I analysis. This was because there were no direct placebo data at 24 weeks to 28 weeks, and because most trials were open label at this point, although a stage III etanercept control group was included. The ERG also advised that excluding infliximab from the network was inconsistent with previous appraisals, and that including it would strengthen the network. The ERG therefore included 6 additional trials in an exploratory analysis. The committee concluded that the network meta-analysis, including infliximab, was appropriate for decision making. The company accepted the committee's preference and the ERG's exploratory analysis. ## Tildrakizumab is more effective at 28 weeks than at 12 weeks For the stage I (12 weeks to 16 weeks) analysis, the committee noted that the PASI 75 response rates for tildrakizumab were higher than those for etanercept, similar to adalimumab and ustekinumab, and lower than for other targeted biological treatments, including guselkumab (an interleukin‑23 inhibitor, as is tildrakizumab). For the stage III (24 weeks to 28 weeks) analysis the committee noted that the network meta-analysis suggested that the PASI 75 response rates for tildrakizumab were statistically significantly higher than at stage I. It also noted that tildrakizumab at stage III had a higher PASI 75 response rate than etanercept and adalimumab at stage III, and similar efficacy to other targeted biological treatments at stage I, which reflected the stopping rules used in NHS practice for those treatments. The committee concluded that tildrakizumab was more effective at stage III than at stage I. It also concluded that the efficacy of tildrakizumab at stage I was closest to adalimumab at stage I, and the efficacy of tildrakizumab at stage III was closest to guselkumab at stage I. # Company's economic model ## The model has a Markov state transition structure A Markov state transition model was used to assess the cost effectiveness of tildrakizumab. It assumed that treatments improved quality of life but did not extend length of life. The model contained 4 health states: induction treatment, maintenance treatment, best supportive care and death. All patients entered the model in the induction state and had the first treatment in a given sequence (see section 3.15). They moved from the induction state to the maintenance state if there was at least a PASI 75 response measured at the end of induction. From there, some patients could stop treatment for any reason and move to the next treatment in the sequence. If there was not a PASI 75 response, patients moved to the induction phase of the next treatment in the sequence. Patients moved to the best supportive care state if their psoriasis did not respond to the last active treatment in a sequence. All patients could move to the death state at any time. ## The company's model compares treatment sequences The company's decision problem compared a sequence of treatments including tildrakizumab with 7 other sequences excluding tildrakizumab. Each sequence comprised 4 treatments: The first treatment was either tildrakizumab or another biological treatment (adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, secukinumab or ustekinumab). The second treatment was ustekinumab, except in the sequence in which ustekinumab was used as the first treatment; in that sequence, adalimumab was used as the second treatment. The third treatment was secukinumab, except in the sequence in which secukinumab was used as the first treatment; in that sequence, adalimumab was used as the third treatment. The fourth treatment in all sequences was best supportive care.The company chose these sequences based on expert advice. The committee was aware that, over time, a sequence of biologicals would be used to treat severe psoriasis in current NHS practice because people switch from 1 option to another. It was also aware that additional factors should be considered when comparing treatment sequences, such as the best ordering of treatments and the effect of including treatments that may not be cost effective. The committee agreed that, in principle, it was appropriate to compare treatment sequences in this appraisal. # Assumptions in the economic model ## A common 14‑week induction period is inappropriate The company included a common 14‑week induction period for tildrakizumab and all comparators in its economic model. The company explained that this was to simplify the model, and that a 14‑week induction period was chosen to represent the midpoint of the range of typical induction periods (stage I from the network meta-analysis; 12 weeks to 16 weeks). The ERG explained that this method would create bias in the costs of the induction period. So, it explored a scenario of modelling treatment-specific induction period costs to reflect the recommended induction duration of each one. The committee recognised that a common 14‑week induction period was particularly inconsistent with a potential 28‑week induction period for tildrakizumab (see section 3.11). The committee concluded that assuming a common induction period could apply to treatments with different induction durations was inappropriate. It therefore preferred the ERG's modelling of treatment-specific induction period costs. The company subsequently provided a revised base case in which treatment-specific induction costs were used. ## Tildrakizumab is compared with the induction periods used in current practice for other biological treatments The company included a scenario analysis in its submission comparing the cost effectiveness of tildrakizumab with a 28‑week induction period with all other treatments at 28 weeks. The ERG noted that no other treatments had a recommended assessment time in the stage III time range, and so the appropriate comparison would be with treatments at their recommended assessment times. The ERG therefore included tildrakizumab with 14‑week and 28‑week induction periods as separate interventions in its exploratory analysis. The committee recalled that the network meta-analyses showed a statistically significant improvement in the PASI 75 response rate for tildrakizumab between the 2 assessment points (see section 3.13). The committee concluded that it preferred the ERG's approach; namely, that tildrakizumab with a 14‑week and a 28‑week induction period should be compared with other biological treatments at their recommended 12‑week to 16‑week induction periods, to reflect the stopping rules used in NHS practice for those treatments. The company subsequently provided a revised base case in which tildrakizumab with a 14‑week and a 28‑week induction period was compared with other biological treatments at their recommended 12‑week to 16‑week induction periods. # Utility values in the economic model ## The company's utility values are appropriate, without adjustment for age The company used EQ‑5D data collected in the reSURFACE 1 trial to inform utility values in its economic model. Utility values were stratified by the level of PASI response. The company implemented its utility values in the economic model by assuming a percentage change from general age-related population values. The ERG suggested that adjusting utility values for age in this way may be inappropriate because it assumes a constant relationship between age and PASI score. It also noted that, because no extension of life for any treatment had been modelled, adjusting for age added a complexity to the model that was not needed. The committee concluded that the ERG's scenario analysis using the company's absolute utility values without adjusting for age was more appropriate. The company subsequently provided a revised base case in which absolute utility values without adjusting for age were used. ## Best supportive care utility values should return to baseline The company assumed, in its model, that the utility value for patients having best supportive care was equal to the utility value associated with the lowest PASI reduction (less than 50%). The clinical expert considered this to be inappropriate, advising that a patient who switched from an active treatment to best supportive care would revert to their baseline quality of life shortly after switching. The ERG noted limitations in stratifying utility value by PASI response; namely, a person with a PASI response below 50% might still have some improvement in their PASI that has a positive effect on quality of life, and that PASI response may not fully capture improvements in the psoriasis from treatment. This may explain why the utility value for the 'PASI response less than 50%' group was notably higher than the baseline value. The ERG did an exploratory analysis using the baseline utility value for those having best supportive care. The committee concluded that the baseline utility value was more appropriate for representing health-related quality of life than the utility value for patients whose psoriasis had the lowest response to treatment. The company subsequently provided a revised base case in which baseline utility values were used for patients having best supportive care. # Costs in the economic model ## The ERG's drug costs and resource use estimates are appropriate for decision making The company presented drug costs adjusted for a 14‑week induction period and annual maintenance costs adjusted for a 14‑week cycle length. The ERG revised these costs for each treatment-specific induction period (see section 3.16) and corrected maintenance costs. Biosimilar price reductions for etanercept were considered by the company. The ERG included additional healthcare costs for those whose psoriasis did not respond to biological treatments, increasing the company's one-off switching costs to reflect a 14‑week cycle cost. The committee concluded that the ERG's amendments to costs and resource use were appropriate for decision making. The company subsequently provided a revised base case using the ERG's amendments to costs and resource use. ## The costs of best supportive care are uncertain In its model, the company included the costs of best supportive care from NICE's guideline on psoriasis: assessment and management, which includes drug treatment, day centre care and inpatient care. Previous psoriasis appraisals obtained direct costs from an observational study (Fonia et al. 2010). The ERG advised that the costs of best supportive care from this source, used in previous appraisals, were considerably lower than the company's estimate from the psoriasis guideline. The ERG advised that, despite being lower than the company's estimates, the costs in Fonia et al. may still have overestimated the true costs of best supportive care in NHS practice because the secondary care resource use in the study appeared to be high. The committee concluded that the costs of best supportive care for people whose psoriasis does not respond to treatment is uncertain because of a lack of recent studies to quantify the true costs in clinical practice. It concluded that, for this appraisal, the Fonia et al. costs should be used because they are more likely to reflect current clinical practice than the costs used in the company's model, and this is consistent with previous appraisals. The company subsequently provided a revised base case using the Fonia et al. best supportive care costs. The committee further concluded that defining costs associated with psoriasis that reflect current clinical practice was an important area for research. # Cost-effectiveness estimates ## Treatment sequences may result in misleading cost-effectiveness estimates The committee was aware that treatment sequences, although more likely to reflect the treatment switching seen in clinical practice, may have provided misleading cost-effectiveness estimates for tildrakizumab. It noted that some of the treatments were not cost effective in the model. Therefore, the cost effectiveness of any new treatment included early in these sequences would likely be driven by avoiding potentially cost-ineffective subsequent treatments or by choosing treatments with lower response rates, resulting in an earlier transition to best supportive care. The committee was also aware that the company's model compared a limited number of all potential treatment sequences. The ERG compared individual treatments with best supportive care in its own base case, setting the second and third options in all sequences to best supportive care. The committee concluded that it would consider these comparisons of individual treatments with best supportive care in its decision making to account for potential bias caused by analysing treatment sequences. The company subsequently provided a revised base case with pairwise comparisons of individual treatments with best supportive care. ## Considering incremental net monetary benefit in addition to ICERs is appropriate for decision making The company did a fully incremental analysis of treatment sequences, using the cheapest biological treatment (etanercept) as a baseline. The committee noted that several treatments had only small differences in total costs and quality-adjusted life year (QALY) gains, and that these small differences could be difficult to see using incremental cost-effectiveness ratios (ICERs) from fully incremental or pairwise analyses. The ERG therefore presented the cost-effectiveness results in a net monetary benefit framework. The incremental net monetary benefit of each comparator was compared with best supportive care at opportunity costs of £20,000 and £30,000 per QALY gained. The committee concluded that incremental net monetary benefit was useful in determining the relative cost effectiveness of the interventions with similar costs and QALYs, and that it should be considered alongside the company's and the ERG's ICERs. The company subsequently provided a revised base case, which included results presented in a net monetary benefit framework. ## Tildrakizumab is more cost effective than other biological treatments The committee considered whether tildrakizumab would be a cost-effective use of NHS resources for people with severe psoriasis for whom biological treatments are an option, taking into account a revised patient access scheme for tildrakizumab and the patient access schemes for the other biological treatments. The committee considered deterministic results from the company's revised analyses as adjusted by the ERG to take into account the patient access schemes for brodalumab, guselkumab, ixekizumab and secukinumab. The revised analyses included results of comparisons between treatment sequences (see section 3.15) as well as results of pairwise comparisons of individual treatments with best supportive care (see section 3.22). The revised analyses used the committee's preferred utility values (see section 3.18 and section 3.19), cost estimates (see section 3.20 and section 3.21) and induction period durations (see section 3.16 and section 3.17). For tildrakizumab assessed at 28 weeks, its QALY gain compared with best supportive care was closer to the QALY gains of other targeted treatments that are usually assessed between 12 weeks to 16 weeks (such as brodalumab, guselkumab, ixekizumab, infliximab and secukinumab). The committee agreed that this meant that tildrakizumab, when assessed at 28 weeks, could potentially displace these treatments. The committee therefore considered the cost-effectiveness estimates for tildrakizumab assessed at 28 weeks compared with these comparators. It noted that, although other biological treatments were more expensive and more effective, tildrakizumab provided one of the highest net benefits compared with best supportive care (more than £7,000 at an opportunity cost of £20,000 per QALY gained, compared with less than £6,000 for the comparators) and was therefore considered cost effective. The committee concluded that tildrakizumab assessed at 28 weeks was likely to be a cost-effective use of NHS resources. The committee then considered whether tildrakizumab would be cost effective with a shorter induction period (14 weeks). The QALY gain compared with best supportive care was lower than when assessed at 28 weeks and lower than the QALY gain of most other biological treatments. However, tildrakizumab had a higher net benefit compared with best supportive care (around £7,000) than many other NICE approved biological treatments, such as ixekizumab, guselkumab and secukinumab compared with best supportive care (less than £6,000). The committee, therefore, concluded that tildrakizumab assessed at 14 weeks was likely to be a cost-effective use of NHS resources.The committee concluded that tildrakizumab was likely to be a cost-effective use of NHS resources when response was assessed either at 14 or 28 weeks. However, tildrakizumab with a 28‑week stopping rule produced a higher QALY gain than with a 14‑week stopping rule and had a higher net benefit. The committee, taking into account the considerations mentioned in section 3.9, concluded that if there was no adequate response at 28 weeks (either a PASI 75 response, or a PASI 50 response and a 5‑point reduction in DLQI) tildrakizumab should be stopped. The committee also concluded that, if there had not been at least a 50% reduction in the PASI score from when treatment started to between 12 and 28 weeks, stopping tildrakizumab should be considered (see section 3.11). # Other factors ## The PASI and DLQI may not be appropriate for all people with psoriasis The committee noted, as in previous NICE technology appraisal guidance on psoriasis, potential equality issues: the PASI might underestimate disease severity in people with darker skin the DLQI has limited validity in some people, and may miss anxiety and depressionThe committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate. ## Tildrakizumab is not innovative The committee understood that tildrakizumab is an interleukin‑23 inhibitor with a 12‑week dosing schedule. The committee was aware that the 12‑week interval between doses is longer than for most other biological treatments currently available in NHS practice. The clinical expert advised that this would be welcomed by patients as a less burdensome treatment option. The committee concluded that, although less frequent dosing may reduce the burden to people with psoriasis, it was unlikely that there were additional gains in health-related quality of life over those already included in the QALY calculations.# Recommendations for research The committee noted that the costs of best supportive care are derived from a study published in 2010 and that clinical practice has changed substantially since then. It therefore considered that it would be valuable to have studies investigating: the costs associated with best supportive care resource use, including frequency and length of hospitalisation, and associated costs.

Interleukin 7 Interleukin 7 (IL-7) is a protein that in humans is encoded by the IL7 gene. IL-7 is a hematopoietic growth factor secreted by stromal cells in the bone marrow and thymus. It is also produced by keratinocytes, dendritic cells, hepatocytes, neurons, and epithelial cells, but is not produced by normal lymphocytes. # Structure The three-dimensional structure of IL-7 in complex with the ectodomain of IL7R has been determined using X-ray diffraction. # Function ## Lymphocyte maturation IL-7 stimulates the differentiation of multipotent (pluripotent) hematopoietic stem cells into lymphoid progenitor cells (as opposed to myeloid progenitor cells where differentiation is stimulated by IL-3). It also stimulates proliferation of all cells in the lymphoid lineage (B cells, T cells and NK cells). It is important for proliferation during certain stages of B-cell maturation, T and NK cell survival, development and homeostasis. IL-7 is a cytokine important for B and T cell development. This cytokine and the hepatocyte growth factor (HGF) form a heterodimer that functions as a pre-pro-B cell growth-stimulating factor. This cytokine is found to be a cofactor for V(D)J rearrangement of the T cell receptor beta (TCRß) during early T cell development. This cytokine can be produced locally by intestinal epithelial and epithelial goblet cells, and may serve as a regulatory factor for intestinal mucosal lymphocytes. Knockout studies in mice suggested that this cytokine plays an essential role in lymphoid cell survival. ## IL-7 signaling IL-7 binds to the IL-7 receptor, a heterodimer consisting of Interleukin-7 receptor alpha and common gamma chain receptor. Binding results in a cascade of signals important for T-cell development within the thymus and survival within the periphery. Knockout mice which genetically lack IL-7 receptor exhibit thymic atrophy, arrest of T-cell development at the double positive stage, and severe lymphopenia. Administration of IL-7 to mice results in an increase in recent thymic emigrants, increases in B and T cells, and increased recovery of T cells after cyclophosphamide administration or after bone marrow transplantation. # Disease ## Cancer IL-7 promotes hematological malignancies (acute lymphoblastic leukemia, T cell lymphoma). ## Viral Infections Elevated levels of IL-7 have also been detected in the plasma of HIV-infected patients. # Clinical application IL-7 as an immunotherapy agent has been examined in many pre-clinical animal studies and more recently in human clinical trials for various malignancies and during HIV infection. ## Cancer Recombinant IL-7 has been safely administered to patients in several phase I and II clinical trials. A human study of IL-7 in patients with cancer demonstrated that administration of this cytokine can transiently disrupt the homeostasis of both CD8+ and CD4+ T cells with a commensurate decrease in the percentage of CD4+CD25+Foxp3+ T regulatory cells. No objective cancer regression was observed, however a dose limiting toxicity (DLT) was not reached in this study due to the development of neutralizing antibodies against the recombinant cytokine. ## HIV infection Associated with antiretroviral therapy, IL-7 administration decreased local and systemic inflammations in patients that had incomplete T-cell reconstitution. These results suggest that IL-7 therapy can possibly improve the quality of life of those patients. ## Transplantation IL-7 could also be beneficial in improving immune recovery after allogenic stem cell transplant.

2-Hydroxyglutaric aciduria 2-hydroxyglutaric aciduria is a rare, autosomal recessive neurometabolic disorder characterized by the significant elevation of urinary levels of hydroxyglutaric acid. # Forms 2-hydroxyglutaric aciduria is an organic aciduria, and has two distinct isometric variants: ## L-2-hydroxyglutaric aciduria The L-2 form is more common, severe, and mainly affects the central nervous system. The basal ganglia are affected, and cystic cavitations in the white matter of the brain are common, beginning in infancy. This form is chronic, with early symptoms such as hypotonia, tremors, and epilepsy declining into spongiform leukoencephalopathy, muscular choreodystonia, mental retardation, and psychomotor regression. It is associated with L2HGDH. ## D-2-hydroxyglutaric aciduria The D2 form is rare, with symptoms including macrocephaly, cardiomyopathy, mental retardation, hypotonia, and cortical blindness.

Anatomy Anatomy (from the Greek Template:Polytonic anatomia, from Template:Polytonic ana: separate, apart from, and temnein, to cut up, cut open) is a branch of biology that is the consideration of the structure of living things. It is a general term that includes human anatomy, animal anatomy (zootomy) and plant anatomy (phytotomy). In some of its facets anatomy is closely related to embryology, comparative anatomy and comparative embryology, through common roots in evolution. Anatomy is subdivided into gross anatomy (or macroscopic anatomy) and microscopic anatomy. Gross anatomy (also called topographical anatomy, regional anatomy, or anthropotomy) is the study of anatomical structures that can be seen by unaided vision. Microscopic anatomy is the study of minute anatomical structures assisted with microscopes, which includes histology (the study of the organisation of tissues), and cytology (the study of cells). The history of anatomy has been characterized, over time, by a continually developing understanding of the functions of organs and structures in the body. Methods have also advanced dramatically, advancing from examination of animals through dissection of cadavers (dead human bodies) to technologically complex techniques developed in the 20th century. Anatomy should not be confused with anatomical pathology (also called morbid anatomy or histopathology), which is the study of the gross and microscopic appearances of diseased organs. # Superficial anatomy Superficial anatomy or surface anatomy is important in anatomy being the study of anatomical landmarks that can be readily seen from the contours or the surface of the body. With knowledge of superficial anatomy, physicians or veterinary surgeons gauge the position and anatomy of the associated deeper structures. # Human anatomy Human anatomy, including gross human anatomy and histology, is primarily the scientific study of the morphology of the adult human body. Generally, students of certain biological sciences, paramedics, physiotherapists, nurses and medical students learn gross anatomy and microscopic anatomy from anatomical models, skeletons, textbooks, diagrams, photographs, lectures and tutorials. The study of microscopic anatomy (or histology) can be aided by practical experience examining histological preparations (or slides) under a microscope; and in addition, medical students generally also learn gross anatomy with practical experience of dissection and inspection of cadavers (dead human bodies). Human anatomy, physiology and biochemistry are complementary basic medical sciences, which are generally taught to medical students in their first year at medical school. Human anatomy can be taught regionally or systemically; that is, respectively, studying anatomy by bodily regions such as the head and chest, or studying by specific systems, such as the nervous or respiratory systems. The major anatomy textbook, Gray's Anatomy, has recently been reorganized from a systems format to a regional format, in line with modern teaching methods. A thorough working knowledge of anatomy is required by all medical doctors, especially surgeons, and doctors working in some diagnostic specialities, such as histopathology and radiology. Academic human anatomists are usually employed by universities, medical schools or teaching hospitals. They are often involved in teaching anatomy, and research into certain systems, organs, tissues or cells. # Other branches Comparative anatomy relates to the comparison of anatomical structures (both gross and microscopic) in different animals. Anthropological anatomy or physical anthropology relates to the comparison of the anatomy of different races of humans. Artistic anatomy relates to anatomic studies for artistic reasons.

Rimantadine warnings and precautions # Warnings And Precautions GENERAL: An increased incidence of seizures has been reported in patients with a history of epilepsy who received the related drug amantadine In clinical trials of Flumadine, the occurrence of seizure-like activity was observed in a small number of patients with a history of seizures who were not receiving anticonvulsant medication while taking Flumadine. If seizures develop, Flumadine should be discontinued. The safety and pharmacokinetics of rimantadine in renal and hepatic insufficiency have only been evaluated after single dose administration. In a single dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40% lower and the elimination half-life was 1.6-fold greater than that in healthy age-matched controls. In a study of 14 persons with chronic liver disease (mostly stabilized cirrhotics), no alterations in the pharmacokinetics were observed after the administration of a single dose of rimantadine. However, the apparent clearance of rimantadine following a single dose to 10 patients with severe liver dysfunction was 50% lower than reported for healthy subjects. Because of the potential for accumulation of rimantadine and its metabolites in plasma, caution should be exercised when patients with renal or hepatic insufficiency are treated with rimantadine. Transmission of rimantadine resistant virus should be considered when treating patients whose contacts are at high risk for influenza A illness. influenza A virus strains resistant to rimantadine can emerge during treatment and such resistant strains have been shown to be transmissible and to cause typical influenza illness (Ref. 3). Although the frequency, rapidity, and clinical significance of the emergence of drug-resistant virus are not yet established, several small studies have demonstrated that 10% to 30% of patients with initially sensitive virus, upon treatment with rimantadine, shed rimantadine resistant virus. (Ref. 3, 4, 5, 6) Clinical response to rimantadine, although slower in those patients who subsequently shed resistant virus, was not significantly different from those who did not shed resistant virus. (Ref. 3) No data are available in humans that address the activity or effectiveness of rimantadine therapy in subjects infected with resistant virus. DRUG INTERACTIONS: cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of Flumadine was administered one hour after the initiation of cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of cimetidine). Acetaminophen: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. Live Attenuated influenza Vaccine (LAIV): The concurrent use of Flumadine with live attenuated influenza vaccine has not been evaluated. However, because of potential interference between these products, the live attenuated intranasal influenza vaccine should not be administered until 48 hours after cessation of Flumadine and Flumadine should not be administered until two weeks after the administration of live attenuated intranasal influenza vaccine unless medically indicated. The concern about potential interference arises principally from the potential for antiviral drugs to inhibit replication of live vaccine virus. ## CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY Carcinogenesis: Carcinogenicity studies in animals have not been performed. Mutagenesis: No mutagenic effects were seen when rimantadine was evaluated in several standard assays for mutagenicity. Impairment of Fertility: A reproduction study in male and female rats did not show detectable impairment of fertility at dosages up to 60 mg/kg/day (3 times the maximum human dose based on body surface area comparisons). PREGNANCY: Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. rimantadine is reported to cross the placenta in mice. rimantadine has been shown to be embryotoxic in rats when given at a dose of 200 mg/kg/day (11 times the recommended human dose based on body surface area comparisons). At this dose the embryotoxic effect consisted of increased fetal resorption in rats; this dose also produced a variety of maternal effects including ataxia, tremors, convulsions and significantly reduced weight gain. No embryotoxicity was observed when rabbits were given doses up to 50 mg/kg/day (5 times the recommended human dose based on body surface area comparisons). However, there was evidence of a developmental abnormality in the form of a change in the ratio of fetuses with 12 or 13 ribs. This ratio is normally about 50:50 in a litter but was 80:20 after rimantadine treatment. Nonteratogenic Effects: rimantadine was administered to pregnant rats in a peri- and postnatal reproduction toxicity study at doses of 30, 60 and 120 mg/kg/day (1.7, 3.4 and 6.8 times the recommended human dose based on body surface area comparisons). Maternal toxicity during gestation was noted at the two higher doses of rimantadine, and at the highest dose, 120 mg/kg/day, there was an increase in pup mortality during the first 2 to 4 days postpartum. Decreased fertility of the F1 generation was also noted for the two higher doses. For these reasons, Flumadine should be used during pregnancy only if the potential benefit justifies the risk to the fetus. NURSING MOTHERS: Flumadine should not be administered to nursing mothers because of the adverse effects noted in offspring of rats treated with rimantadine during the nursing period. rimantadine is concentrated in rat milk in a dose-related manner: 2 to 3 hours following administration of rimantadine, rat breast milk levels were approximately twice those observed in the serum. PEDIATRIC USE: In children, Flumadine is recommended for the prophylaxis of influenza A. The safety and effectiveness of Flumadine in the treatment of symptomatic influenza infection in children have not been established. Prophylaxis studies with Flumadine have not been performed in children below the age of 1 year.

# Summary: Lead exposure is a continuing urgent health problem for Roma in Kosovo. The Centers for Disease Control and Prevention (CDC), the World Health Organization (WHO) and the United Nations International Children's' Emergency Fund (UNICEF) have collaborated in blood lead surveillance of the Roma children living in displacement camps in Kosovo. In the last 3 rounds of blood lead testing, conducted between 2005 and 2007, on average, 30% of children tested had capillary blood lead levels > 45 µg/dL, the level at which CDC recommends chelation therapy. Few if any children in the camps have maintained a blood lead level < 10 µg/dL for their entire childhood. These children are at tremendous risk for a lifetime of developmental and behavioral disabilities and other adverse health conditions. The Cesmin Lug camp is the most highly contaminated camp and should be closed immediately. The situation in Cesmin Lug is made more critical because Roma living in Serbia and Montenegro are now moving into vacant dwellings in the camp. Dwellings that are currently vacant should be demolished immediately. These dwellings are not only contaminated by lead but a clear and present fire hazard. In addition, uncontrolled informal smelting at the now closed Kablar camp must be stopped. These activities result in lead exposure to children in both Cesmin Lug and Osterode Camps. Lack of data has hampered decision making and resulted in confusion on the part of Roma and others as to the seriousness of the problem and the extent of the environmental contamination. A periodic, systematic review of the data would provide important information about the quality of the children's clinical care. Reportedly 39 children have been chelated. Perhaps as many as 90 children are candidates for therapy. The actual number cannot be determined at this time. Lead exposure should be a priority for repatriation to the Roma Mahala. Plans should be developed for continued medical surveillance of these children when they are repatriated to Roma Mahala. # Background: Kosovo is a Province within the borders of the former Yugoslavia that is currently controlled by the United Nations (UN). This territory has experienced multiple infrastructure, economic, human rights, and public health problems as a result of the conflicts in the Balkans. International aid has been focused on maintaining peace and establishing basic services. However, economic development has recently become a priority for the UN Mission in Kosovo (UNMIK), the United States Office in Pristina (USOP) and USAID. The Trepca mining and smelting complex, established in the 1930s, constituted the biggest mining company in Europe. The Trepca smelter in Mitrovica extracted metals including zinc, arsenic, lead, and cadmium from the products of nearby mines. Trepca operations have been an important part of the Mitrovica economy in the past, providing employment in both the smelter and the mines to people in the region, but the UN halted operations in 2000 after UN peace keeper forces in the area were discovered to have high blood lead levels (BLLs). Work is underway to reopen the Trepca smelter and mining compound in North Mitrovica. Currently ( 2007) about 3000 people are employed in the facility. The Trepca board of directors has requested funding from a donor nation to purchase a briquetting machine to increase production in the secondary smelting operation. This fall the World Bank intends to begin discussions about reopening the Treca complex, potentially enabling many people to gain employment. Although the smelter has been closed since 2000, the environment remains heavily contaminated. Three mine tailing dams (2 unremediated and 1 remediated) are located in northern Mitrovica and the nearby town of Zvecan/ Zhikoc. Results from soil samples taken by staff of the World Health Organization (WHO) in 2004 as part of a health risk assessment for heavy metals in Mitrovica and Zvecan showed that more than 90% of the samples exceeded the UK limits for lead (450 mg/Kg), with many samples having levels more than 10 times higher than the limit; more than 40% exceeded the limit for arsenic levels; and almost 30% exceeded the limit for cadmium levels. Both the northern and southern areas of Mitrovica are contaminated by lead. However, the results of both environmental testing and blood testing indicate that Mitrovica is more contaminated north of the river where the Trepca smelter is located. The results of tests on drinking water show that generally drinking water quality appears to be acceptable. Testing conducted by WHO in the general Mitrovica area in 2004 found that BLLs in the general population had fallen; however, BLLs remained dangerously high in the Roma, Ashkali, and Egyptian (RAE) communities. The RAE, also referred to collectively as "Roma," have lived in Mitrovica for many years. Before the Balkan conflict (1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999) they lived in a southern Mitrovica neighborhood known as Roma Mahala. In the immediate period following the 1999 Kosovo conflict, Roma Mahala was destroyed. The Office of the United Nations High Commissioner for Refugees (UNHCR) constructed two internal displacement (IDP) camps as a temporary housing solution for the Roma who were left homeless. A third unofficial camp, Kablar, was developed after the occupation of French KFOR barracks in 2001. Unfortunately, the camps were established in highly lead-contaminated areas in northern Mitrovica and Zvecan/ Zhikoc. The camps are located within 3 kilometers of the Trepca smelter and within 300 meters of two mine tailing sites. In June 2005, reports of symptomatic lead poisoning among children in Mitrovica, Kosovo, reached the Centers for Disease Control and Prevention (CDC). The children most affected by the lead contamination in Mitrovica are the Roma whose homes were destroyed during the war and who have been relocated to camps on land contaminated with lead and other heavy metals near the Trepca smelter in Mitrovica. In addition, the Roma engage in informal smelting of car batteries and computers. Initial blood lead testing of children in the 3 IDP camps Cesmin Lug, Kablar and Zitkovac/Zhikoc indicated that all children had blood lead levels (BLLs) > 65 µg/dL, the highest value reported out using the hand held LeadCare analyzer. As a result, in July 2005 the World Health Organization (WHO) and the United Nations International Children's Emergency Fund (UNICEF) requested assistance from CDC. Specifically CDC was requested to make recommendations for 1) a medical facility to identify and treat children with lead poisoning, 2) outreach and health education to the affected community and 3) a strategy for primary prevention of childhood lead poisoning. During a 5-day visit in August 2005, CDC staff met with Roma community leaders, representatives from nongovernmental organizations (NGOs), and officials from United Nations agencies to discuss current and planned activities related to lead exposure and prevention of lead poisoning. A detailed plan for a heavy metals treatment facility was provided to WHO and UNICEF. CDC continued to maintain contact with these agencies providing technical assistance and support as needed through telephone calls and email. In January 2006, the Kosovo Office of UNICEF invited CDC to revisit the Mitrovica area. The main objectives of the 2-week visit in January 2006 were 1) to review the status of progress on the CDC recommendations for BLL surveillance and medical treatment of children with lead poisoning, 2) assist in the efforts to assess and remediate lead hazards in the three Roma camps (Cesmin Lug, Kablar,and Zitkovac/Zhikoc), and 3) evaluate the lead hazards at the proposed new camp location at Osterode. The inspection of Osterode camp determined that the camp was lead safe. As a result, UNMK requested and received $US 1 million from USOP to set up a medical treatment facility at Osterode camp. CDC continued to provide technical assistance and support regarding treating lead poisoning among Roma children and prevention of lead exposure. In August 2006, 2 laboratorians from the WHO-sponsored Public Health Institute in Pristina came to the environmental laboratory at CDC to be trained in the use of graphite furnace atomic absorption spectrophotometery for blood lead analysis. Since their visit the laboratory in Pristina has participated in a quality assurance and control program at CDC. The results of the proficiency testing indicate that the laboratory in Pristina meets standards for blood lead testing laboratories established in Europe and the United States. In May 2007, as a result of continued concern about the clinical services provided by the treatment unit in Osterode camp, the US State Department, USOP and USAID requested that CDC inspect the facility and make recommendations about future activities. What follows are the assessment of the IDP camps, the lead treatment center and ancillary services as well as recommendations for future activities to prevent childhood lead poisoning among the Roma. The visit was conducted by Dr. Mary Jean Brown Chief, Lead Poisoning Prevention Branch CDC and Mr. Barry Brooks Acting Team Lead, Lead Poisoning Prevention Branch CDC. # Assessment: Lead Contamination of the Sites: Cesmin Lug: This camp has at least 4 sources of lead exposure for children. 1)The camp is downwind of lead mine tailings, raising ambient soil and air lead levels. 2) There is evidence of informal lead smelting activity in the camp. Informal smelting is a cottage industry for the Roma. Ingots are collected by a local businessman in a building within easy walking distance of the camp. Currently Roma receive 30-40 cents per kilo of lead. Collection and distribution of the product is sophisticated and involves large corporations. According to the Trepca mine directors, the lead produced by the Roma finds its way to the world market. Burn areas in the camp adjacent to the houses are undoubtedly heavily contaminated. Children play in these areas, and the dust is walked into the house by children and adults, particularly those who don't wear shoes. 3) Many of the doors and window frames are painted with lead paint, and they are peeling profusely. 4) There is evidence of recent informal lead smelting in the old Kablar camp which is adjacent to Cesmin Lug. The education activities conducted by trained health education workers (facilitators) in the camps are undoubtedly responsible for moving the informal smelting activity from Cesmin Lug to Kablar. Nonetheless, the smoke and dust from lead smelting can be carried home by the individuals who are engaging in it and contaminate the home environment. Osterode: This camp has at least 2 sources of lead exposure for children. 1) The camp is downwind of lead mine tailings, raising ambient soil and air lead levels. 2) Individuals in Osterode may also be engaged in the informal lead smelting in the old Kablar camp. The smoke and dust from these activities can be carried home by the individuals who are engaging in them and contaminate the home environment. However, in 2006 the site was inspected by Mr. Brooks, a licensed lead inspector from CDC. The site was found to be lead-safe. Recommendations for maintaining lead safety─ including washing down paved surfaces every day─are in place and were visible during the visit in June 2007. In addition, families in Osterode are visited by health educators (facilitators) who reinforce the need for families to implement measures to decrease lead contamination including removal of shoes when entering the house and good hygiene. These activities were also in evidence during the June 2007 site visit. # Roma Mahala: There is no obvious source of lead exposure in the Mahala. The Trepca directors informed CDC that in the past the Mahala was perhaps the least contaminated area in Mitrovica. Although in the past there were reports that informal smelting was also occurring in the Mahala near the river, the onsite police and the headman deny this. The policeman could describe what to look for to identify a smelting site, i.e. burn areas and discarded battery casings. # Population: Most Roma camp residents are younger than 30 years of age. They appear in general good health, although oral health is quite a problem. The average age of first birth is about 15 years old for girls. The infants are well nourished and active. However, several toddlers appeared pale and listless. There was one report of a child with a seizure disorder and several complaints of back aches and shortness of breath among the few elderly people we talked to. A total of about 395 people live in Osterode and 134 in Cesman Lug (NCA census 4/3/07). At least at this time, 30 percent of the total number of residents of Osterode and Cesmin Lug camp do not have a right to return to the Mahala, because they did not live there in 1999. A total of 80 people are considered 'illegal' because they are not former residents of the lead-contaminated camps (Kablar, Cesmin Lug or Zitkovack Camps). Of these 80, 5 families (24 people) that cannot return to the Mahala live in Cesmin Lug. These include Roma families from Serbia and Montenegro that are reportedly moving into Cesmin Lug. It seems likely that at least 2 families have recently moved into Cesmin Lug from outside Kosovo, but this needs to be verified. # Blood Lead Surveillance Program: There are 300 children younger than 14 years old living in both camps; approximately 70 in Cesmin Lug (NCA census 4/3/07) and 230 in Osterode (214 by latest NCA census of 4/3/07). Both WHO and the clinic medical director estimated that 95% of these children have had at least one BLL test. The BLL data have been reported to parents but have not been formally released by WHO because interpretation of these data is difficult due to non-statndardized collection, relocation of families among the camps and to the Mahala and selection bias. The clinic medical director, WHO, and a cursory review of the clinic records by CDC's Dr.Brown, showed that 3 rounds of blood lead surveillance of about 100 children each were conducted recently: in Fall 2005, January 15-26, 2007, and June 4-8, 2007 Approximately 39 children in the first round, 32 children in the second round, and 29 children in the third round had capillary BLLs > 45 µg/dL. Attempts are made to collect venous BLLs during the surveillance screening; however, not all children will submit to the test. These children are recalled if necessary. All blood lead analysis is done at the Institute of Public Health in North Mitrovica, where capillary samples are analyzed using the hand held Lead Care analyzer. It is not clear what method is used for the venous confirmation. However, the Institue plans to purchase a graphite furnace atomic absorption spectrophotometer . # Lead Clinic: The clinic medical director in Osterode is following CDC recommendations for treatment; treating children with venous blood lead levels (BLLs) >45µg/dL with DMSA 200 mg/twice a day. He has modified the protocol slightly and is also treating children with first capillary BLLs >45µg/dL and follow up venous BLLs >35 µg/dL and ZPP > 40 µg/dL, because he has found that venous samples from the Public Health Institute in North Mitrovicia tend to be lower than those from the CDC quality assurance program or the capillary samples. The causes of this bias are unclear but may relate both to the instrumentation used in the laboratory at the Public Health Institute and the expected difference between venous and capillary BLL. Follow up of children was hampered by a 2-month-long job action by the physicians. This also hampered repeat testing of those children from the second round of surveillance testing. Children with elevated capillary tests in January, 2007 had repeat BLLs the first week of June according to the medical director. Of the 31/2 who required testing 15 have been repeated, 7 have moved to the Mahala and 9 ) have refused the test. Discrepancies in record keeping and movement within and into the camps makes a full accounting difficult, thus the reported number of individuals does not sum to the total. We were unable to determine the status of confirmatory testing for the 29 children tested during the third round of surveillance testing,. The medical director seemed unaware of this last round of surveillance testing; however, the records are in the clinic. # Ancillary Services: An early childhood education center provides PATCH education support to 10 children less than 6 years old whose BLLs are currently elevated, although if other children stop by they are not turned away. One child receives in-home education under this program. A nutritional survey on the Roma children less than 6 years old was conducted by WHO and identified malnutrition. Food packages are delivered to each family in both camps. Distribution occurs at Osterode camp. Families at Cesmin Lug come to Osterode to pick up the food. There are reports that families who live in the Mahala but who maintain a residence at one of the camps also may be receiving the supplemental food packages. The purpose of the food distribution is to reduce lead absorption among children by ensuring adequate iron, calcium and zinc intake. Although prevention of micro-nutrient deficiencies is essential for growth and overall good health, few data exist to support a supplemental food program to treat or prevent lead poisoning. Many Roma told us how important the food supplements were to them, and in the Mahala, families that no longer received the food supplements complained bitterly. However, the amount of snack food wrappers and other food-related litter in the camps indicate the families may have other sources of food available. Camp administrators feel that food distribution has lead to a 'culture of dependency' with the result that the Roma are not employed, have not been integrated in to the wider Mitrovica society and are reluctant to relocate to the Roma Mahala where food packages are available only for the first month of residence. # Recommendations

Niacin/lovastatin contraindications # Contraindications ADVICOR is contraindicated in patients with a known hypersensitivity to niacin, lovastatin or any component of this medication, active liver disease or unexplained persistent elevations in serum transaminases (see WARNINGS), active peptic ulcer disease, or arterial bleeding. Concomitant administration with strong CYP3A4 inhibitors (e.g.,itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone) (see WARNINGS, Myopathy/Rhabdomyolysis). Pregnancy and lactation - Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase, such as lovastatin, to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, ADVICOR is contraindicated in women who are pregnant and in lactating mothers. ADVICOR may cause fetal harm when administered to pregnant women. ADVICOR should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, ADVICOR should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).

Hemoglobin # Overview Hemoglobin, also spelled haemoglobin and abbreviated Hb, is the iron-containing oxygen-transport metalloprotein in the red blood cells of the blood in vertebrates and other animals. In mammals the protein makes up about 97% of the red cell’s dry content, and around 35% of the total content (including water). Hemoglobin transports oxygen from the lungs or gills to the rest of the body, such as to the muscles, where it releases its load of oxygen. Hemoglobin also has a variety of other gas-transport and effect-modulation duties, which vary from species to species, and may be quite diverse in invertebrates. The name hemoglobin is the concatenation of heme and globin, reflecting the fact that each subunit of hemoglobin is a globular protein with an embedded heme (or haem) group; each heme group contains an iron atom, and this is responsible for the binding of oxygen through ion-induced dipole forces. The most common type of hemoglobin in mammals contains four such subunits, each with one heme group. In humans, each heme group is able to bind one oxygen molecule, and thus, one hemoglobin molecule can bind four oxygen molecules. Mutations in the genes for the hemoglobin protein in humans result in a group of hereditary diseases termed the hemoglobinopathies, the best known of which is sickle-cell disease. Historically in human medicine, sickle-cell disease was the first disease to be understood in its mechanism of dysfunction, completely down to the molecular level. However, not all such globin-gene mutations result in illness. These mutations are formally recognized as hemoglobin variants rather than diseases. A (mostly) separate set of diseases involves underproduction of normal and sometimes abnormal hemoglobins, through problems and mutations in globin gene regulation. These diseases, which also often produce anemia, are called thalassemias. Hemoglobin (Hb) is synthesized in a complex series of steps. The heme portion is synthesized in a series of steps which occur in the mitochondria and the cytosol of the immature red blood cell, while the globin protein portions of the molecule are synthesized by ribosomes in the cytosol. Production of Hb continues in the cell throughout its early development from the proerythroblast to the reticulocyte in the bone marrow. At this point, the nucleus is lost in mammalian red blood cells, but not in birds and many other species. Even after the loss of the nucleus in mammals, residual ribosomal RNA allows further synthesis of Hb until the reticulocyte loses its RNA soon after entering the vasculature (this hemoglobin-synthetic RNA in fact gives the reticulocyte its reticulated appearance and name). The chemical empirical formula of the most common human hemoglobin is C738H1166N812O203S2Fe, but as noted above, hemoglobins vary widely across species, and even (through common mutations) slightly among subgroups of humans. # Structure In most humans, the hemoglobin molecule is an assembly of four globular protein subunits. Each subunit is composed of a protein chain tightly associated with a non-protein heme group. Each protein chain arranges into a set of alpha-helix structural segments connected together in a globin fold arrangement, so called because this arrangement is the same folding motif used in other heme/globin proteins such as myoglobin. This folding pattern contains a pocket which strongly binds the heme group. A heme group consists of an iron (Fe) ion (charged atom) held in a heterocyclic ring, known as a porphyrin. The iron ion, which is the site of oxygen binding, bonds with the four nitrogens in the center of the ring, which all lie in one plane. The iron is also bound strongly to the globular protein via the imidazole ring of the F8 histidine residue below the porphyrin ring. A sixth position can reversibly bind oxygen, completing the octahedral group of six ligands. Oxygen binds in an "end-on bent" geometry where one oxygen atom binds Fe and the other protrudes at an angle. When oxygen is not bound, a very weakly bonded water molecule fills the site, forming a distorted octahedron. The iron ion may either be in the Fe2+ or Fe3+ state, but ferrihemoglobin (methemoglobin) (Fe3+) cannot bind oxygen. In binding, oxygen temporarily oxidizes Fe to (Fe3+), so iron must exist in the +2 oxidation state in order to bind oxygen. The enzyme methemoglobin reductase reactivates hemoglobin found in the inactive (Fe3+) state by reducing the iron center. In adult humans, the most common hemoglobin type is a tetramer (which contains 4 subunit proteins) called hemoglobin A, consisting of two α and two β subunits non-covalently bound, each made of 141 and 146 amino acid residues, respectively. This is denoted as α2β2. The subunits are structurally similar and about the same size. Each subunit has a molecular weight of about 17,000 daltons, for a total molecular weight of the tetramer of about 68,000 daltons. Hemoglobin A is the most intensively studied of the hemoglobin molecules. The four polypeptide chains are bound to each other by salt bridges, hydrogen bonds, and hydrophobic interactions. There are two kinds of contacts between the α and β chains: α1β1 and α1β2. Oxyhemoglobin is formed during respiration when oxygen binds to the heme component of the protein hemoglobin in red blood cells. This process occurs in the pulmonary capillaries adjacent to the alveoli of the lungs. The oxygen then travels through the blood stream to be dropped off at cells where it is utilized in aerobic glycolysis and in the production of ATP by the process of oxidative phosphorylation. It does not, however, help to counteract a decrease in blood pH. Ventilation, or breathing, may reverse this condition by removal of carbon dioxide, thus causing a shift up in pH. Deoxyhemoglobin is the form of hemoglobin without the bound oxygen. The absorption spectra of oxyhemoglobin and deoxyhemoglobin differ. The oxyhemoglobin has significantly lower absorption of the 660 nm wavelength than deoxyhemoglobin, while at 940 nm its absorption is slightly higher. This difference is used for measurement of the amount of oxygen in patient's blood by an instrument called pulse oximeter. # Iron's oxidation state in oxyhemoglobin Assigning oxygenated hemoglobin's oxidation state is difficult because oxyhemoglobin is diamagnetic (no net unpaired electrons), but the low-energy electron configurations in both oxygen and iron are paramagnetic. Triplet oxygen, the lowest energy oxygen species, has two unpaired electrons in antibonding π- molecular orbitals. Iron(II) tends to be in a high-spin configuration where unpaired electrons exist in Eg antibonding orbitals. Iron(III) has an odd number of electrons and thus has unpaired electrons. All of these molecules are paramagnetic (have unpaired electrons), not diamagnetic, so an unintuitive distribution of electrons must exist to induce diamagnetism. The three logical possibilities are: - Low-spin Fe2+ binds to high-energy singlet oxygen. Both low-spin iron and singlet oxygen are diamagnetic. - Low-spin Fe3+ binds to .O2- (the superoxide ion) and the two unpaired electrons couple antiferromagnetically, giving diamagnetic properties. - Low-spin Fe4+ binds to O22-. Both are diamagnetic. X-ray photoelectron spectroscopy suggests iron has an oxidation state of approximately 3.2 and infrared stretching frequencies of the O-O bond suggests a bond length fitting with superoxide. The correct oxidation state of iron is thus the +3 state with oxygen in the -1 state. The diamagnetism in this configuration arises from the unpaired electron on superoxide aligning antiferromagnetically in the opposite direction from the unpaired electron on iron. The second choice being correct is not surprising because singlet oxygen and large separations of charge are both unfavorably high-energy states. Iron's shift to a higher oxidation state decreases the atom's size and allows it into the plane of the porphyrin ring, pulling on the coordinated histidine residue and initiating the allosteric changes seen in the globulins. The assignment of oxidation state, however, is only a formalism so all three models may contribute to some small degree. Early postulates by bioinorganic chemists claimed that possibility (1) (above) was correct and that iron should exist in oxidation state II (indeed iron oxidation state III as methemoglobin, when not accompanied by superoxide .O2- to "hold" the oxidation electron, is incapable of binding O2). The iron chemistry in this model was elegant, but the presence of singlet oxygen was never explained. It was argued that the binding of an oxygen molecule placed high-spin iron(II) in an octahedral field of strong-field ligands; this change in field would increase the crystal field splitting energy, causing iron's electrons to pair into the diamagnetic low-spin configuration. # Binding of ligands As illustrated above, when oxygen binds to the iron center, it causes contraction of the iron atom, and causes it to move back into the center of the porphyrin ring plane (see moving diagram). At the same time, the porphyrin ring plane itself is pushed away from the oxygen and toward the imidizole side chain of the histidine residue interacting at the other pole of the iron. The interaction here forces the ring plane sideways toward the outside of the tetramer, and also induces a strain on the protein helix containing the histidine as it moves nearer to the iron. This causes a tug on the peptide strand which tends to open up heme units in the remainder of the molecule, so that there is more room for oxygen molecules to bind at their heme sites. In the tetrameric form of normal adult hemoglobin, the binding of oxygen is thus a cooperative process. The binding affinity of hemoglobin for oxygen is increased by the oxygen saturation of the molecule, with the first oxygens bound influencing the shape of the binding sites for the next oxygens, in a way favorable for binding. This positive cooperative binding is achieved through steric conformational changes of the hemoglobin protein complex as discussed above, i.e. when one subunit protein in hemoglobin becomes oxygenated, this induces a conformational or structural change in the whole complex, causing the other subunits to gain an increased affinity for oxygen. As a consequence, the oxygen binding curve of hemoglobin is sigmoidal, or S-shaped, as opposed to the normal hyperbolic curve associated with noncooperative binding. Hemoglobin's oxygen-binding capacity is decreased in the presence of carbon monoxide because both gases compete for the same binding sites on hemoglobin, carbon monoxide binding preferentially in place of oxygen. Carbon dioxide occupies a different binding site on the hemoglobin. Carbon dioxide is more readily dissolved in deoxygenated blood, facilitating its removal from the body after the oxygen has been released to tissues undergoing metabolism. This increased affinity for carbon dioxide by the venous blood is known as the Haldane effect. Through the enzyme carbonic anhydrase, carbon dioxide reacts with water to give carbonic acid, which decomposes into bicarbonate and protons: Hence blood with high carbon dioxide levels is also lower in pH (more acidic). Hemoglobin can bind protons and carbon dioxide which causes a conformational change in the protein and facilitates the release of oxygen. Protons bind at various places along the protein, and carbon dioxide binds at the alpha-amino group forming carbamate. Conversely, when the carbon dioxide levels in the blood decrease (i.e., in the lung capillaries), carbon dioxide and protons are released from hemoglobin, increasing the oxygen affinity of the protein. This control of hemoglobin's affinity for oxygen by the binding and release of carbon dioxide and acid, is known as the Bohr effect. The binding of oxygen is affected by molecules such as carbon monoxide (CO) (for example from tobacco smoking, cars and furnaces). CO competes with oxygen at the heme binding site. Hemoglobin binding affinity for CO is 200 times greater than its affinity for oxygen, meaning that small amounts of CO dramatically reduce hemoglobin's ability to transport oxygen. When hemoglobin combines with CO, it forms a very bright red compound called carboxyhemoglobin. When inspired air contains CO levels as low as 0.02%, headache and nausea occur; if the CO concentration is increased to 0.1%, unconsciousness will follow. In heavy smokers, up to 20% of the oxygen-active sites can be blocked by CO. In similar fashion, hemoglobin also has competitive binding affinity for cyanide (CN-), sulfur monoxide (SO), nitrogen dioxide (NO2), and sulfide (S2-), including hydrogen sulfide (H2S). All of these bind to iron in heme without changing its oxidation state, but they nevertheless inhibit oxygen-binding, causing grave toxicity. The iron atom in the heme group must be in the ferrous (Fe2+) oxidation state to support oxygen and other gases' binding and transport. Oxidation to the ferric (Fe3+) state converts hemoglobin into hemiglobin or methaemoglobin (pronounced "MET-hemoglobin"), which cannot bind oxygen. Hemoglobin in normal red blood cells is protected by a reduction system to keep this from happening. Nitrogen dioxide and nitrous oxide are capable of converting a small fraction of hemoglobin to methemoglobin, however this is not usually of medical importance (nitrogen dioxide is poisonous by other mechanisms, and nitrous oxide is routinely used in surgical anesthesia in most people without undue methemoglobin buildup). In people acclimated to high altitudes, the concentration of 2,3-Bisphosphoglycerate (2,3-BPG) in the blood is increased, which allows these individuals to deliver a larger amount of oxygen to tissues under conditions of lower oxygen tension. This phenomenon, where molecule Y affects the binding of molecule X to a transport molecule Z, is called a heterotropic allosteric effect. A variant hemoglobin, called fetal hemoglobin (HbF, α2γ2), is found in the developing fetus, and binds oxygen with greater affinity than adult hemoglobin. This means that the oxygen binding curve for fetal hemoglobin is left-shifted (i.e., a higher percentage of hemoglobin has oxygen bound to it at lower oxygen tension), in comparison to that of adult hemoglobin. As a result, fetal blood in the placenta is able to take oxygen from maternal blood. Hemoglobin also carries nitric oxide in the globin part of the molecule. This improves oxygen delivery in the periphery and contributes to the control of respiration. NO binds reversibly to a specific cysteine residue in globin; the binding depends on the state (R or T) of the hemoglobin. The resulting S-nitrosylated hemoglobin influences various NO-related activities such as the control of vascular resistance, blood pressure and respiration. NO is released not in the cytoplasm of erythrocytes but is transported by an anion exchanger called AE1 out of them. # Types of hemoglobins in humans Hemoglobin variants are a part of the normal embryonic and fetal development, but may also be pathologic mutant forms of hemoglobin in a population (usually of humans), caused by variations in genetics. Some well-known hemoglobin such variants such as sickle-cell anemia are responsible for diseases, and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants. In the embryo: - Gower 1 (ζ2ε2) - Gower 2 (α2ε2) (PDB: 1A9W​) - Hemoglobin Portland (ζ2γ2) In the foetus: - Hemoglobin F (α2γ2) (PDB: 1FDH​) In adults: - Hemoglobin A (α2β2) (PDB: 1BZ0​) - The most common with a normal amount over 95% - Hemoglobin A2 (α2δ2) - δ chain synthesis begins late in the third trimester and in adults, it has a normal range of 1.5-3.5% - Hemoglobin F (α2γ2) - In adults Hemoglobin F is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in persons with sickle-cell disease. Variant forms which cause disease: - Hemoglobin S (α2βS2) - A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the β-chain gene, causing a change in the properties of hemoblobin which results in sickling of red blood cells. - Hemoglobin C (α2βC2) - Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia. # Degradation of hemoglobin in vertebrate animals When red cells reach the end of their life due to aging or defects, they are broken down, the hemoglobin molecule is broken up and the iron gets recycled. When the porphyrin ring is broken up, the fragments are normally secreted in the bile by the liver. This process also produces one molecule of carbon monoxide for every molecule of heme degraded ; this is one of the few natural sources of carbon monoxide production in the human body, and is responsible for the normal blood levels of carbon monoxide even in people breathing pure air. The other major final product of heme degradation is bilirubin. Increased levels of this chemical are detected in the blood if red cells are being destroyed more rapidly than usual. Improperly degraded hemoglobin protein or hemoglobin that has been released from the blood cells too rapidly can clog small blood vessels, especially the delicate blood filtering vessels of the kidneys, causing kidney damage. # Role in disease Decrease of hemoglobin, with or without an absolute decrease of red blood cells, leads to symptoms of anemia. Anemia has many different causes, although iron deficiency and its resultant iron deficiency anemia are the most common causes in the Western world. As absence of iron decreases heme synthesis, red blood cells in iron deficiency anemia are hypochromic (lacking the red hemoglobin pigment) and microcytic (smaller than normal). Other anemias are rarer. In hemolysis (accelerated breakdown of red blood cells), associated jaundice is caused by the hemoglobin metabolite bilirubin, and the circulating hemoglobin can cause renal failure. Some mutations in the globin chain are associated with the hemoglobinopathies, such as sickle-cell disease and thalassemia. Other mutations, as discussed at the beginning of the article, are benign and are referred to merely as hemoglobin variants. There is a group of genetic disorders, known as the porphyrias that are characterized by errors in metabolic pathways of heme synthesis. King George III of the United Kingdom was probably the most famous porphyria sufferer. To a small extent, hemoglobin A slowly combines with glucose at the terminal valine (an alpha aminoacid) of each β chain. The resulting molecule is often referred to as Hb A1c. As the concentration of glucose in the blood increases, the percentage of Hb A that turns into Hb A1c increases. In diabetics whose glucose usually runs high, the percent Hb A1c also runs high. Because of the slow rate of Hb A combination with glucose, the Hb A1c percentage is representative of glucose level in the blood averaged over a longer time (the half-life of red blood cells, which is typically 50-55 days). # Diagnostic use Hemoglobin levels are amongst the most commonly performed blood tests, usually as part of a full blood count or complete blood count. Results are reported in g/L, g/dL or mol/L. For conversion, 1 g/dL is 0.621 mmol/L. If the total hemoglobin concentration in the blood falls below a set point, this is called anemia. Normal values for hemoglobin levels are: - Women: 12.1 to 15.1 g/dl - Men: 13.8 to 17.2 g/dl - Children: 11 to 16 g/dl - Pregnant women: 11 to 12 g/dl Anemias are further subclassified by the size of the red blood cells, which are the cells which contain hemoglobin in vertebrates. They can be classified as microcytic (small sized red blood cells), normocytic (normal sized red blood cells), or macrocytic (large sized red blood cells). The hemoglobin is the typical test used for blood donation. A comparison with the hematocrit can be made by multiplying the hemoglobin by three. For example, if the hemoglobin is measured at 17, that compares with a hematocrit of .51. Blood glucose levels can vary widely throughout a day, so one or only a few samples from a patient analyzed for glucose may not be representative of long-term control of glucose levels. For this reason a blood sample may be analyzed for Hb A1c level, which is more representative of glucose control averaged over a longer time period (determined by the half-life of the individual's red blood cells, which is typically 50-55 days). People whose Hb A1c runs 6.0% or less show good longer-term glucose control. Hb A1c values which are more than 7.0% are elevated. This test is especially useful for diabetics. ## In radiologic imaging: fMRI and its uses with hemoglobin The FMRI machine may use the signal from oxyhemoglobin as it partially aligns these molecules with the magnetic field. The machine will then send a series of magnetic pulses at the participant's head or other body structure, slowly knocking the molecules out of alignment, and a radio wave is emitted when they come back into alignment. The fMRI machine can then pick up these signals and use them to make scans, which are cross-sectional maps showing blood flow. # Hemoglobin in the biological range of life Hemoglobin is by no means unique to vertebrates; there are a variety of oxygen transport and binding proteins throughout the animal (and plant) kingdom. Other organisms including bacteria, protozoans and fungi all have hemoglobin-like proteins whose known and predicted roles include the reversible binding of gaseous ligands. Since many of these proteins contain globins, and also the heme moiety (iron in a flat porphyrin support), these substances are often simply referred to as hemoglobins, even if their overall tertiary structure is very different from that of vertebrate hemoglobin. In particular, the distinction of “myoglobin” and hemoglobin in lower animals is often impossible, because some of these organisms do not contain muscles. Or they may have a recognizable separate circulatory system, but not one which deals with oxygen transport (for example, many insects and other arthropods). In all these groups, heme/globin containing molecules (even monomeric globin ones) which deal with gas-binding are referred to as hemoglobins. In addition to dealing with transport and sensing of oxygen, these molecules may also deal with NO, CO2, sulfide compounds, and even O2 scavenging in environments which must be anaerobic. They may even deal with detoxification of chlorinated materials in a manner analogous to heme-containing P450 enzymes and peroxidases. The structure of hemoglobins varies across species. Hemoglobin occurs in all kingdoms of organisms, but not in all organisms. Single-globin hemoglobins tend to be found in primitive species such as bacteria, protozoa, algae, and plants. Nematode worms, molluscs and crustaceans, however, many contain very large multisubunit molecules much larger than those in vertebrates. Particularly worth noting are chimeric hemoglobins found in fungi and giant annelids, which may contain both globin and other types of proteins. One of the most striking occurrences and uses of hemoglobin in organisms occurs in the (up to) 2.4 meter giant tube worm (Riftia pachyptila, also called Vestimentifera) which populates ocean volcanic vents at the sea floor. These worms have no digestive tract, but instead contain a population of bacteria constituting half the organism’s weight, which react H2S from the vent and O2 from the water to produce energy to make food from H2O and CO2. These organisms end with a deep red fan-like structure ("plume") which extends into the water and which absorbs H2S and O2 for the bacteria, and also absorbs CO2 for use as synthetic raw material (after the manner of photosynthetic plants). The bright red color of the structures results from several extraordinarily complex hemoglobins found in them which contain up to 144 globin chains (presumably each including associated heme structures). These tube worm hemoglobins are remarkable for being able to carry oxygen in the presence of sulfide, and indeed to also carry sulfide, without being completely "poisoned" or inhibited by this molecule, as hemoglobins in most other species are. # Other oxygen-binding proteins Myoglobin: Found in the muscle tissue of many vertebrates, including humans, it gives muscle tissue a distinct red or dark gray color. It is very similar to hemoglobin in structure and sequence, but is not a tetramer; instead, it is a monomer that lacks cooperative binding. It is used to store oxygen rather than transport it. Hemocyanin: The second most common oxygen transporting protein found in nature, it is found in the blood of many arthropods and molluscs. Uses copper prosthetic groups instead of iron heme groups and is blue in color when oxygenated. Hemerythrin: Some marine invertebrates and a few species of annelid use this iron containing non-heme protein to carry oxygen in their blood. Appears pink/violet when oxygenated, clear when not. Chlorocruorin: Found in many annelids, it is very similar to erythrocruorin, but the heme group is significantly different in structure. Appears green when deoxygenated and red when oxygenated. Vanabins: Also known as vanadium chromagens, they are found in the blood of sea squirts and are hypothesised to use the rare metal vanadium as its oxygen binding prosthetic group. Erythrocruorin: Found in many annelids, including earthworms, it is a giant free-floating blood protein containing many dozens—possibly hundreds—of iron- and heme-bearing protein subunits bound together into a single protein complex with a molecular mass greater than 3.5 million daltons. Pinnaglobin: Only seen in the mollusc Pinna squamosa. Brown manganese-based porphyrin protein. Leghemoglobin: In leguminous plants, such as alfalfa or soybeans, the nitrogen fixing bacteria in the roots are protected from oxygen by this iron heme containing, oxygen binding protein. # Hemoglobin in history and art Historically, an association between the color of blood and rust occurs in the association of the planet Mars, with the Roman god of war, since the planet is an orange-red which reminded the ancients of blood. Although the color of the planet is due to iron compounds in combination with oxygen in the Martian soil, it is a common misconception that the iron in hemoglobin and its oxides gives blood its red color. The color is actually due to the porphyrin moiety of hemoglobin to which the iron is bound, not the iron itself, although the ligation and redox state of the iron can influence the pi to pi- electronic transitions of the porphyrin and hence its optical characteristics. Artist Julian Voss-Andreae created a sculpture called "Heart of Steel (Hemoglobin)" in 2005 based on the protein's backbone. The sculpture was made from glass and weathering steel. The intentional rusting of the initially shiny work of art mirrors hemoglobin's fundamental chemical reaction of iron binding to oxygen.

Bursitis overview # Overview Bursitis is characterized by the inflammation of a bursa and the buildup of the fluid in the bursal sac. A bursa is a small, fluid-filled sac that acts as a cushion between a bone and other moving parts: muscles, tendons, or skin. Over 160 bursa are found throughout the body but relatively few of them can cause bursitis. Based on the nature of the inflammation, bursitis may be classified into 2 subtypes: septic and aseptic. The most common bursitis subtypes include subacromial, olecranon, trochanteric, prepatellar, and retrocalcaneal. Aseptic bursitis can be caused by overuse or repetitive injury to the joint, abnormal and bony structure, and/or crystal deposit in the bursa. Additionally, septic bursitis can be caused by bacterial infection of the bursa through a skin injury following repetitive trauma. Common causes of septic bursitis include Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus spp. Bursitis must be differentiated from tendonitis, cellulitis, osteoarthritis, ligamentous injuries, and septic arthritis. The symptoms of bursitis differ based on the location of the inflammation. Focal swelling, pain, and redness are symptoms common to all forms of bursitis. The diagnosis of bursitis is usually made clinically. There are no diagnostic lab findings associated with bursitis. However, patients with septic bursitis may have elevated ESR, CRP, and white blood cell count. Ultrasonography may be a useful tool for confirming the diagnosis of bursitis, while the aspiration of bursal fluids is usually reserved for the diagnosis of septic bursitis. Medical therapy for non-septic bursitis depends on the involved bursa and includes the RICE regimen (rest, ice, compression, elevation), NSAIDs, and/or corticosteroid injections. Restriction of activity is encouraged to prevent further injury and promote healing. Antimicrobials are the mainstay of therapy for septic bursitis. Surgical management is often reserved for non-responders. ## Classification Based on the nature of the inflammation, bursitis may classified into 2 subtypes: septic and aseptic. Common anatomic locations of bursitis include the shoulder, elbow, hip, knee, and ankle. The most common bursitis subtypes include: - Subacromial bursitis - Olecranon bursitis - Trochanteric bursitis - Prepatellar bursitis - Retrocalcaneal bursitis ## Pathophysiology Bursitis is characterized by acute or chronic inflammation of a bursa and buildup of fluid in the bursa sac. A bursa is a small, fluid-filled sac that acts as a cushion between a bone and other moving parts: muscles, tendons, or skin. Over 160 bursae are found throughout the body, though relatively few of them can cause bursitis. Aseptic bursitis can be caused by overuse and repetitive injuries to the joint, abnormal bony structure and crystal deposit in the bursa. It commonly affects the knee or elbow as a result of kneeling or leaning on the elbows longer than usual. Moreover, septic bursitis can be caused by bacterial infection of the bursa through the skin injury following repetitive trauma. ### Images The following images depict different cases of bursitis: - Prepatellar bursitis - By Thomas Kees - Own work (Original text: eigenes Archiv (selbst photographiert)), CC BY-SA 3.0 de, - Prepatellar bursitis - By Atropos235 - Own work, CC BY-SA 3.0, - Olecranon bursitis - By en:User:NJC123 - en:Image:Bursitis_Elbow_WC.JPG, Public Domain, ## Causes Common causes of bursitis include: Aseptic bursitis: - Prolonged pressure, overuse, or strenuous activity Elbows and knees are most commonly affected because they are rested upon more than many parts of the body with bursae and they also tend to endure the most repetitive use. Shoulder bursitis is more commonly due to overuse of the shoulder joint and muscles. - Elbows and knees are most commonly affected because they are rested upon more than many parts of the body with bursae and they also tend to endure the most repetitive use. - Shoulder bursitis is more commonly due to overuse of the shoulder joint and muscles. - Other inflammatory conditions (e.g., rheumatoid arthritis and spondyloarthritis) - Gout and pseudogout Septic bursitis: - Staphylococcus aureus - Staphylococcus epidermidis - Streptococcus spp ## Differential Diagnosis Bursitis symptoms and signs are relatively non-specific. Even after detailed history and physical examination, imaging studies are often necessary to rule out other musculoskeletal conditions. Bursitis must be differentiated from tendonitis, cellulitis, osteoarthritis, ligamentous injuries, and septic arthritis. ## Epidemiology and Demographics Bursitis accounts for 400 visits per 100,000 visits to primary care clinic. The exact prevalence and incidence of bursitis are unknown. ## Risk Factors Common risk factors in the development of bursitis include: - rheumatoid arthritis - osteoarthritis - gout or pseudogout - cellulitis - diabetes mellitus - use of systemic glucocorticoids - alcoholism - malignancy - leukopenia - having a hobby or job that involves repetitive motions (e.g., bicycling, playing baseball, gardening, setting tiles) ## Screening Screening for bursitis is not recommended. ## Natural History, Complications, and Prognosis Bursitis is often caused by overuse and repetitive injuries to the joint. Symptoms of bursitis may develop rapidly within 2 to 3 days in an acute form. Patients with bursitis usually present with edema, erythema, and tenderness over the involved joint. In most cases, after an appropriate lifestyle adjustment, bursitis will gradually clear within a few days to weeks without any long-term consequences. If left untreated, acute bursitis may lead to chronic bursitis, which can result in cicatricial adhesions, reduced mobility, and progressive pain. With proper treatment and an activities adjustment, septic and aseptic bursitis are associated with an excellent prognosis. # Diagnosis ## History Obtaining a complete history will be helpful in determining whether the bursitis is associated with any specific activities. ## Symptoms and Physical Examination ## Laboratory Findings The diagnosis of bursitis is usually made clinically. There are no diagnostic lab findings associated with bursitis. However, patients with septic bursitis may have elevated ESR, CRP, and white blood cells. ## X ray X ray is rarely required in patients with bursitis. X ray may be used as a diagnostic measure to support a clinical diagnosis of bursitis. Joint x ray is generally reserved for patients with histories of significant trauma. A standard x ray may be helpful in diagnosing a fracture or dislocation. ## CT CT scans are rarely required in patients with bursitis. CT scans are usually reserved for patients who do not respond to initial treatment. On a CT scan, superficial bursitis may be characterized by fluid density at the subcutaneous tissue. ## MRI MRI is rarely required in patients with bursitis. Due to the associated cost and time requirements, the utility of MRI is limited compere to ultrasound. MRI is often reserved for patients who are likely to have other medical conditions such as tumors, ligamentous injures, or tendon injuries. On MRI, bursitis is characterized by bursal fluid collection, subcutaneous edema, and joint effusion. ## Ultrasound Ultrasonography may be helpful in confirming a diagnosis of bursitis. On an ultrasound, bursitis may be characterized by bursal wall distention with presence of local hypoechoic or anechoic intra-bursal material, synovial proliferation, calcifications, and rheumatoid nodules. ## Other Diagnostic Studies Other diagnostic studies for bursitis include aspiration of the bursal fluid. Aspiration of bursal fluids is not recommended for the diagnosis of all types of bursitis. It is usually reserved for confirming a diagnosis of septic bursitis. # Treatment ## Medical Therapy Medical therapy for non-septic bursitis depends on the involved bursa and can include the RICE regimen (rest, ice, compression, elevation), NSAIDs, and/or corticosteroid injections. Restriction of activity is encouraged to prevent further injury and promote healing. Antimicrobials are the mainstay of therapy for septic bursitis. Surgical intervention is generally reserved for non-responders. ## Surgery Surgical intervention is not recommended for the management of bursitis. However, surgical techniques including bursectomy or longitudinal band release are usually reserved for patients with chronic, recurrent, or septic bursitis. ## Primary Prevention Effective measures for the primary prevention of bursitis include maintaining a healthy weight, taking regular breaks from repetitive tasks, using foam for knee- and elbow-pads, and practicing good posture. ## Secondary Prevention There are no established methods for secondary prevention of bursitis. However, a fast recovery may be facilitated by an adjustment in activities, the consistent use of foam for knee- or elbow-pads, and regular breaks during repetitive tasks.

# Table of Contents I # I. Introduction Multidrug-resistant organisms (MDROs), including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and certain gram-negative bacilli (GNB) have important infection control implications that either have not been addressed or received only limited consideration in previous isolation guidelines. Increasing experience with these organisms is improving understanding of the routes of transmission and effective preventive measures. Although transmission of MDROs is most frequently documented in acute care facilities, all healthcare settings are affected by the emergence and transmission of antimicrobial-resistant microbes. The severity and extent of disease caused by these pathogens varies by the population(s) affected and by the institution(s) in which they are found. Institutions, in turn, vary widely in physical and functional characteristics, ranging from long-term care facilities (LTCF) to specialty units (e.g., intensive care units , burn units, neonatal ICUs ) in tertiary care facilities. Because of this, the approaches to prevention and control of these pathogens need to be tailored to the specific needs of each population and individual institution. The prevention and control of MDROs is a national priority -one that requires that all healthcare facilities and agencies assume responsibility (1,2). The following discussion and recommendations are provided to guide the implementation of strategies and practices to prevent the transmission of MRSA, VRE, and other MDROs. The administration of healthcare organizations and institutions should ensure that appropriate strategies are fully implemented, regularly evaluated for effectiveness, and adjusted such that there is a consistent decrease in the incidence of targeted MDROs. Successful prevention and control of MDROs requires administrative and scientific leadership and a financial and human resource commitment (3)(4)(5). Resources must be made available for infection prevention and control, including expert consultation, laboratory support, adherence monitoring, and data analysis. Infection prevention and control professionals have found that healthcare personnel (HCP) are more receptive and adherent to the recommended control measures when organizational leaders participate in efforts to reduce MDRO transmission (3). # II. Background MDRO definition. For epidemiologic purposes, MDROs are defined as microorganisms, predominantly bacteria, that are resistant to one or more classes of antimicrobial agents (1). Although the names of certain MDROs describe resistance to only one agent (e.g., MRSA, VRE), these pathogens are frequently resistant to most available antimicrobial agents. These highly resistant organisms deserve special attention in healthcare facilities (2). In addition to MRSA and VRE, certain GNB, including those producing extended spectrum beta-lactamases (ESBLs) and others that are resistant to multiple classes of antimicrobial agents, are of particular concern 1 . In addition to Escherichia coli and Klebsiella pneumoniae, these include strains of Acinetobacter baumannii resistant to all antimicrobial agents, or all except imipenem, (6)(7)(8)(9)(10)(11)(12), and organisms such as Stenotrophomonas maltophilia (12)(13)(14), Burkholderia cepacia (15,16), and Ralstonia pickettii (17) that are intrinsically resistant to the broadest-spectrum antimicrobial agents. In some residential settings (e.g., LTCFs), it is important to control multidrug-resistant S. pneumoniae (MDRSP) that are resistant to penicillin and other broad-spectrum agents such as macrolides and fluroquinolones (18,19). Clinical importance of MDROs. In most instances, MDRO infections have clinical manifestations that are similar to infections caused by susceptible pathogens. However, options for treating patients with these infections are often extremely limited. For example, until recently, only vancomycin provided effective therapy for potentially lifethreatening MRSA infections and during the 1990's there were virtually no antimicrobial agents to treat infections caused by VRE. Although antimicrobials are now available for treatment of MRSA and VRE infections, resistance to each new agent has already emerged 1 Multidrug-resistant strains of M. tuberculosis are not addressed in this document because of the markedly different patterns of transmission and spread of the pathogen and the very different control interventions that are needed for prevention of M. tuberculosis infection. Current recommendations for prevention and control of tuberculosis can be found at: Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Settings, 2005 () # Management of Multidrug-Resistant Organisms In Healthcare Settings, 2006 Available from: / 6 of 74 Last update: February 15, 2017 in clinical isolates (31)(32)(33)(34)(35)(36)(37). Similarly, therapeutic options are limited for ESBL-producing isolates of gram-negative bacilli, strains of A. baumannii resistant to all antimicrobial agents except imipenem (8)(9)(10)(11)38) and intrinsically resistant Stenotrophomonas sp. (12)(13)(14)39). These limitations may influence antibiotic usage patterns in ways that suppress normal flora and create a favorable environment for development of colonization when exposed to potential MDR pathogens (i.e., selective advantage) (40). Increased lengths of stay, costs, and mortality also have been associated with MDROs (41)(42)(43)(44)(45)(46). Two studies documented increased mortality, hospital lengths of stay, and hospital charges associated with multidrug-resistant gram-negative bacilli (MDR-GNBs), including an NICU outbreak of ESBL-producing Klebsiella pneumoniae (47) and the emergence of third-generation cephalosporin resistance in Enterobacter spp. in hospitalized adults (48). Vancomycin resistance has been reported to be an independent predictor of death from enterococcal bacteremia (44,(49)(50)(51)(52)(53). Furthermore, VRE was associated with increased mortality, length of hospital stay, admission to the ICU, surgical procedures, and costs when VRE patients were compared with a matched hospital population (54). However, MRSA may behave differently from other MDROs. When patients with MRSA have been compared to patients with methicillin-susceptible S. aureus (MSSA), MRSAcolonized patients more frequently develop symptomatic infections (55,56). Furthermore, higher case fatality rates have been observed for certain MRSA infections, including bacteremia (57)(58)(59)(60)(61)(62), poststernotomy mediastinitis (63), and surgical site infections (64). These outcomes may be a result of delays in the administration of vancomycin, the relative decrease in the bactericidal activity of vancomycin (65), or persistent bacteremia associated with intrinsic characteristics of certain MRSA strains (66). Mortality may be increased further by S. aureus with reduced vancomycin susceptibility (VISA) (26,67). Also some studies have reported an association between MRSA infections and increased length of stay, and healthcare costs (46,61,62), while others have not (64). Finally, some hospitals have observed an increase in the overall occurrence of staphylococcal infections following the introduction of MRSA into a hospital or special-care unit (68,69). # Management of Multidrug-Resistant Organisms In Healthcare Settings, 2006 Available from: / 7 of 74 Last update: February 15, 2017 # III. Epidemiology of MDROs Trends. Prevalence of MDROs varies temporally, geographically, and by healthcare setting (70,71). For example, VRE emerged in the eastern United States in the early 1990s, but did not appear in the western United States until several years later, and MDRSP varies in prevalence by state (72). The type and level of care also influence the prevalence of MDROs. ICUs, especially those at tertiary care facilities, may have a higher prevalence of MDRO infections than do non-ICU settings (73,74). Antimicrobial resistance rates are also strongly correlated with hospital size, tertiary-level care, and facility type (e.g., LTCF) (75,76). The frequency of clinical infection caused by these pathogens is low in LTCFs (77,78). Nonetheless, MDRO infections in LTCFs can cause serious disease and mortality, and colonized or infected LTCF residents may serve as reservoirs and vehicles for MDRO introduction into acute care facilities (78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88). Another example of population differences in prevalence of target MDROs is in the pediatric population. Point prevalence surveys conducted by the Pediatric Prevention Network (PPN) in eight U.S. PICUs and 7 U.S. NICUs in 2000 found ≤4% of patients were colonized with MRSA or VRE compared with 10-24% were colonized with ceftazidime-or aminoglycoside-resistant gram-negative bacilli; < 3% were colonized with ESBL-producing gram negative bacilli. Despite some evidence that MDRO burden is greatest in adult hospital patients, MDRO require similar control efforts in pediatric populations as well (89). During the last several decades, the prevalence of MDROs in U.S. hospitals and medical centers has increased steadily (90,91). MRSA was first isolated in the United States in 1968. By the early 1990s, MRSA accounted for 20%-25% of Staphylococcus aureus isolates from hospitalized patients (92). In 1999, MRSA accounted for >50% of S. aureus isolates from patients in ICUs in the National Nosocomial Infection Surveillance (NNIS) system; in 2003, 59.5% of S. aureus isolates in NNIS ICUs were MRSA (93). A similar rise in prevalence has occurred with VRE (94). From 1990 to 1997, the prevalence of VRE in enterococcal isolates from hospitalized patients increased from <1% to approximately 15% ( 95). VRE accounted for almost 25% of enterococcus isolates in NNIS ICUs in 1999 (94), and 28.5% in 2003 (93). GNB resistant to ESBLs, fluoroquinolones, carbapenems, and aminoglycosides also have increased in prevalence. For example, in 1997, the SENTRY Antimicrobial Surveillance Program found that among K. pneumoniae strains isolated in the United States, resistance rates to ceftazidime and other third-generation cephalosporins were 6.6%, 9.7%, 5.4%, and 3.6% for bloodstream, pneumonia, wound, and urinary tract infections, respectively (95). In 2003, 20.6% of all K. pneumoniae isolates from NNIS ICUs were resistant to these drugs (93). Similarly, between 1999 and 2003, Pseudomonas aeruginosa resistance to fluoroquinolone antibiotics increased from 23% to 29.5% in NNIS ICUs (74). Also, a 3month survey of 15 Brooklyn hospitals in 1999 found that 53% of A. baumannii strains exhibited resistance to carbapenems and 24% of P. aeruginosa strains were resistant to imipenem ( 10). During 1994-2000, a national review of ICU patients in 43 states found that the overall susceptibility to ciprofloxacin decreased from 86% to 76% and was temporally associated with increased use of fluoroquinolones in the United States (96). Lastly, an analysis of temporal trends of antimicrobial resistance in non-ICU patients in 23 U.S. hospitals during 1996-1997 and 1998-1999 (97) found significant increases in the prevalence of resistant isolates including MRSA, ciprofloxacin-resistant P. aeruginosa, and ciprofloxacin-or ofloxacin-resistant E. coli. Several factors may have contributed to these increases including: selective pressure exerted by exposure to antimicrobial agents, particularly fluoroquinolones, outside of the ICU and/or in the community (7,96,98); increasing rates of community-associated MRSA colonization and infection (99,100); inadequate adherence to infection control practices; or a combination of these factors. # Important concepts in transmission. Once MDROs are introduced into a healthcare setting, transmission and persistence of the resistant strain is determined by the availability of vulnerable patients, selective pressure exerted by antimicrobial use, increased potential for transmission from larger numbers of colonized or infected patients ("colonization pressure") (101,102); and the impact of implementation and adherence to prevention efforts. Patients vulnerable to colonization and infection include those with severe disease, especially those with compromised host defenses from underlying medical conditions; recent surgery; or indwelling medical devices (e.g., # Management of Multidrug-Resistant Organisms In Healthcare Settings, 2006 Available from: / 9 of 74 Last update: February 15, 2017 urinary catheters or endotracheal tubes (103,104)). Hospitalized patients, especially ICU patients, tend to have more risk factors than non-hospitalized patients do, and have the highest infection rates. For example, the risk that an ICU patient will acquire VRE increases significantly once the proportion of ICU patients colonized with VRE exceeds 50% (101) or the number days of exposure to a VRE-patient exceeds 15 days (105). A similar effect of colonization pressure has been demonstrated for MRSA in a medical ICU (102). Increasing numbers of infections with MDROs also have been reported in non-ICU areas of hospitals (97). There is ample epidemiologic evidence to suggest that MDROs are carried from one person to another via the hands of HCP (106)(107)(108)(109). Hands are easily contaminated during the process of care-giving or from contact with environmental surfaces in close proximity to the patient (110)(111)(112)(113). The latter is especially important when patients have diarrhea and the reservoir of the MDRO is the gastrointestinal tract (114)(115)(116)(117). Without adherence to published recommendations for hand hygiene and glove use (111) HCP are more likely to transmit MDROs to patients. Thus, strategies to increase and monitor adherence are important components of MDRO control programs (106,118). Opportunities for transmission of MDROs beyond the acute care hospital results from patients receiving care at multiple healthcare facilities and moving between acute-care, ambulatory and/or chronic care, and LTC environments. System-wide surveillance at LDS Hospital in Salt Lake City, Utah, monitored patients identified as being infected or colonized with MRSA or VRE, and found that those patients subsequently received inpatient or outpatient care at as many as 62 different healthcare facilities in that system during a 5year span (119). # Role of colonized HCP in MDRO transmission. Rarely, HCP may introduce an MDRO into a patient care unit (120)(121)(122)(123). Occasionally, HCP can become persistently colonized with an MDRO, but these HCP have a limited role in transmission, unless other factors are present. Additional factors that can facilitate transmission, include chronic sinusitis (120), upper respiratory infection (123), and dermatitis (124). (125)(126)(127)(128). Historically, genetic analyses of MRSA isolated from patients in hospitals worldwide revealed that a relatively small number of MRSA strains have unique qualities that facilitate their transmission from patient to patient within healthcare facilities over wide geographic areas, explaining the dramatic increases in HAIs caused by MRSA in the 1980s and early 1990s (129). To date, most MRSA strains isolated from patients with CA-MRSA infections have been microbiologically distinct from those endemic in healthcare settings, suggesting that some of these strains may have arisen de novo in the community via acquisition of methicillin resistance genes by established methicillin-susceptible S. aureus (MSSA) strains (130)(131)(132). Two pulsed-field types, termed USA300 and USA400 according to a typing scheme established at CDC, have accounted for the majority of CA-MRSA infections characterized in the United States, whereas pulsed-field types USA100 and USA200 are the predominant genotypes endemic in healthcare settings (133). USA300 and USA400 genotypes almost always carry type IV of the staphylococcal chromosomal cassette (SCC) mec, the mobile genetic element that carries the mecA methicillin-resistance gene (133,134). This genetic cassette is smaller than types I through III, the types typically found in healthcare associated MRSA strains, and is hypothesized to be more easily transferable between S. aureus strains. CA-MRSA infection presents most commonly as relatively minor skin and soft tissue infections, but severe invasive disease, including necrotizing pneumonia, necrotizing fasciitis, severe osteomyelitis, and a sepsis syndrome with increased mortality have also been described in children and adults (134)(135)(136). Transmission within hospitals of MRSA strains first described in the community (e.g. USA300 and USA400) are being reported with increasing frequency (137)(138)(139)(140) (90). Infections with these strains have most commonly presented as skin disease in community settings. However, intrinsic virulence characteristics of the organisms can result in clinical manifestations similar to or potentially more severe than traditional healthcare-associated MRSA infections among hospitalized patients. The prevalence of MRSA colonization and infection in the surrounding community may therefore affect the selection of strategies for MRSA control in healthcare settings. # IV. MDRO Prevention and Control # Prevention of infections. Preventing infections will reduce the burden of MDROs in healthcare settings. Prevention of antimicrobial resistance depends on appropriate clinical practices that should be incorporated into all routine patient care. These include optimal management of vascular and urinary catheters, prevention of lower respiratory tract infection in intubated patients, accurate diagnosis of infectious etiologies, and judicious antimicrobial selection and utilization. Guidance for these preventive practices include the Campaign to Reduce Antimicrobial Resistance in Healthcare Settings (), a multifaceted, evidence-based approach with four parallel strategies: infection prevention; accurate and prompt diagnosis and treatment; prudent use of antimicrobials; and prevention of transmission. Campaign materials are available for acute care hospitals, surgical settings, dialysis units, LTCFs and pediatric acute care units. To reduce rates of central-venous-line associated bloodstream infections (CVL-BSIs) and ventilator-associated pneumonia (VAP), a group of bundled evidence-based clinical practices have been implemented in many U.S. healthcare facilities (118,(141)(142)(143)(144). One report demonstrated a sustained effect on the reduction in CVL-BSI rates with this approach (145). Although the specific effect on MDRO infection and colonization rates have not been reported, it is logical that decreasing these and other healthcare-associated infections will in turn reduce antimicrobial use and decrease opportunities for emergence and transmission of MDROs. 3. Eradication of endemic MRSA infections from two NICUs. The first NICU included implementation of ASC, Contact Precautions, use of triple dye on the umbilical cord, and systems changes to improve surveillance and adherence to recommended practices and to reduce overcrowding (152). The second NICU used ASC and Contact Precautions; surgical masks were included in the barriers used for Contact Precautions (153) 5. Control of an outbreak of VRE in a NICU over a 3-year period with implementation of ASC, other infection control measures such as use of a waterless hand disinfectant, and mandatory in-service education (155). 6. Eradication of MDR-strains of A. baumannii from a burn unit over a 16-month period with implementation of strategies to improve adherence to hand hygiene, isolation, environmental cleaning, and temporary unit closure (38). 7. In addition, more than 100 reports published during 1982-2005 support the efficacy of combinations of various control interventions to reduce the burden of MRSA, VRE, and MDR-GNBs (Tables 1 and 2). Case-rate reduction or pathogen eradication was reported in a majority of studies. 8. VRE was eradicated in seven special-care units (154,(156)(157)(158)(159)(160), two hospitals (161,162), and one LTCF (163). 9. MRSA was eradicated from nine special-care units (89,152,153,(164)(165)(166)(167)(168)(169), two hospitals (170), one LTCF (167), and one Finnish district (171). Furthermore, four MRSA reports described continuing success in sustaining low endemic MDRO rates for over 5 years (68,166,172,173). 10. An MDR-GNB was eradicated from 13 special-care units (8,9,38,(174)(175)(176)(177)(178)(179)(180) and two hospitals (11,181). These success stories testify to the importance of having dedicated and knowledgeable teams of healthcare professionals who are willing to persist for years, if necessary, to control MDROs. Eradication and control of MDROs, such as those reported, frequently required periodic reassessment and the addition of new and more stringent interventions over time (tiered strategy). For example, interventions were added in a stepwise fashion during a 3-year effort that eventually eradicated MRSA from an NICU (152). A series of interventions was adopted throughout the course of a year to eradicate VRE from a burn unit (154). Similarly, eradication of carbapenem-resistant strains of A. baumannii from a hospital required multiple and progressively more intense interventions over several years (11). Nearly all studies reporting successful MDRO control employed a median of 7 to 8 different interventions concurrently or sequentially (Table 1). These figures may underestimate the actual number of control measures used, because authors of these reports may have considered their earliest efforts routine (e.g., added emphasis on handwashing), and did not include them as interventions, and some "single measures" are, in fact, a complex combination of several interventions. The use of multiple concurrent control measures in these reports underscores the need for a comprehensive approach for controlling MDROs. Several factors affect the ability to generalize the results of the various studies reviewed, including differences in definition, study design, endpoints and variables measured, and period of follow-up. Two-thirds of the reports cited in Tables 1 and 2 involved perceived outbreaks, and one-third described efforts to reduce endemic transmission. Few reports described preemptive efforts or prospective studies to control MDROs before they had reached high levels within a unit or facility. With these and other factors, it has not been possible to determine the effectiveness of individual interventions, or a specific combination of interventions, that would be appropriate for all healthcare facilities to implement in order to control their target MDROs. 1. Administrative support. In several reports, administrative support and involvement were important for the successful control of the target MDRO (3,152,(182)(183)(184)(185), and authorities in infection control have strongly recommended such support (2,106,107,186). There are several examples of MDRO control interventions that require administrative commitment of fiscal and human resources. One is the use of ASC (8,38,68,107,114,151,152,167,168,183,184,(187)(188)(189)(190)(191)(192). Other interventions that require administrative support include: 1. implementing system changes to ensure prompt and effective communications e.g., computer alerts to identify patients previously known to be colonized/infected with MDROs (184,189,193,194); 2. providing the necessary number and appropriate placement of hand washing sinks and alcohol-containing hand rub dispensers in the facility (106,195); 3. maintaining staffing levels appropriate to the intensity of care required (152,(196)(197)(198)(199)(200)(201)(202); and 4. enforcing adherence to recommended infection control practices (e.g., hand hygiene, Standard and Contact Precautions) for MDRO control. Other measures that have been associated with a positive impact on prevention efforts, that require administrative support, are direct observation with feedback to HCP on adherence to recommended precautions and keeping HCP informed about changes in transmission rates (3,152,182,(203)(204)(205). A "How-to guide" for implementing change in ICUs, including analysis of structure, process, and outcomes when designing interventions, can assist in identification of needed administrative interventions (195). Lastly, participation in existing, or the creation of new, city-wide, state-wide, regional or national coalitions, to combat emerging or growing MDRO problems is an effective strategy that requires administrative support (146,151,167,188,206,207). 2. Education. Facility-wide, unit-targeted, and informal, educational interventions were included in several successful studies (3,189,193,(208)(209)(210)(211). The focus of the interventions was to encourage a behavior change through improved understanding of the problem MDRO that the facility was trying to control. Whether the desired change involved hand hygiene, antimicrobial prescribing patterns, or other outcomes, enhancing understanding and creating a culture that supported and promoted the desired behavior, were viewed as essential to the success of the intervention. Educational campaigns to enhance adherence to hand hygiene practices in conjunction with other control measures have been associated temporally with decreases in MDRO transmission in various healthcare settings (3,106,163). # Judicious use of antimicrobial agents. While a comprehensive review of antimicrobial stewardship is beyond the scope of this guideline, recommendations for control of MDROs must include attention to judicious antimicrobial use. A temporal association between formulary changes and decreased occurrence of a target MDRO was found in several studies, especially in those that focused on MDR-GNBs (98,177,209,(212)(213)(214)(215)(216)(217)(218). Occurrence of C. difficile-associated disease has also been associated with changes in antimicrobial use (219). Although some MRSA and VRE control efforts have attempted to limit antimicrobial use, the relative importance of this measure for controlling these MDROs remains unclear (193,220). Limiting antimicrobial use alone may fail to control resistance due to a combination of factors; including 1. the relative effect of antimicrobials on providing initial selective pressure, compared to perpetuating resistance once it has emerged; 2. inadequate limits on usage; or 3. insufficient time to observe the impact of this intervention. With the intent of addressing #2 and #3 above in the study design, one study demonstrated a decrease in the prevalence of VRE associated with a formulary switch from ticarcillin-clavulanate to piperacillin-tazobactam (221). The CDC Campaign to Prevent Antimicrobial Resistance that was launched in 2002 provides evidence-based principles for judicious use of antimicrobials and tools for implementation (222) . This effort targets all healthcare settings and focuses on effective antimicrobial treatment of infections, use of narrow spectrum agents, treatment of infections and not contaminants, avoiding excessive duration of therapy, and restricting use of broad-spectrum or more potent antimicrobials to treatment of serious infections when the pathogen is not known or when other effective agents are unavailable. Achieving these objectives would likely diminish the selective pressure that favors proliferation of MDROs. Strategies for influencing antimicrobial prescribing patterns within (223)(224)(225)(226); computer-assisted management programs (227)(228)(229); and active efforts to remove redundant antimicrobial combinations (230). A systematic review of controlled studies identified several successful practices. These include social marketing (i.e. consumer education), practice guidelines, authorization systems, formulary restriction, mandatory consultation, and peer review and feedback. It further suggested that online systems that provide clinical information, structured order entry, and decision support are promising strategies (231). These changes are best accomplished through an organizational, multidisciplinary, antimicrobial management program (232). # Surveillance for MDROs isolated from routine clinical cultures. Antibiograms. The simplest form of MDRO surveillance is monitoring of clinical microbiology isolates resulting from tests ordered as part of routine clinical care. This method is particularly useful to detect emergence of new MDROs not previously detected, either within an individual healthcare facility or community-wide. In addition, this information can be used to prepare facility-or unit-specific summary antimicrobial susceptibility reports that describe pathogen-specific prevalence of resistance among clinical isolates. Such reports may be useful to monitor for changes in known resistance patterns that might signal emergence or transmission of MDROs, and also to provide clinicians with information to guide antimicrobial prescribing practices (233 -235). (205,236,237). Such measures may be useful for monitoring MDRO trends and assessing the impact of prevention programs, although they have limitations. Because they are based solely on positive culture results without accompanying clinical information, they do not distinguish colonization from infection, and may not fully demonstrate the burden of MDRO-associated disease. Furthermore, these measures do not precisely measure acquisition of MDRO colonization in a given population or location. Isolating an MDRO from a clinical culture obtained from a patient several days after admission to a given unit or facility does not establish that the patient acquired colonization in that unit. On the other hand, patients who acquire MDRO colonization may remain undetected by clinical cultures (107). Despite these limitations, incidence measures based on clinical culture results may be highly correlated with actual MDRO transmission rates derived from information using ASC, as demonstrated in a recent multicenter study (237). These results suggest that incidence measures based on clinical cultures alone might be useful surrogates for monitoring changes in MDRO transmission rates. # MDRO Incidence Based on Clinical # MDRO Infection Rates. Clinical cultures can also be used to identify targeted MDRO infections in certain patient populations or units (238,239). This strategy requires investigation of clinical circumstances surrounding a positive culture to distinguish colonization from infection, but it can be particularly helpful in defining the clinical impact of MDROs within a facility. # Molecular typing of MDRO isolates. Many investigators have used molecular typing of selected isolates to confirm clonal transmission to enhance understanding of MDRO transmission and the effect of interventions within their facility (38,68,89,92,138,152,190,193,236,240). # Surveillance for MDROs by detecting asymptomatic colonization Another form of MDRO surveillance is the use of active surveillance cultures (ASC) to identify patients who are colonized with a targeted MDRO (38,107,241). This approach is based upon the observation that, for some MDROs, detection of colonization may be delayed or missed completely if culture results obtained in the course of routine clinical care are the primary means of identifying colonized patients (8,38,107,114,151,153,167,168,183,184,187,189,(191)(192)(193)(242)(243)(244). Several authors report having used ASC when new pathogens emerge in order to define the epidemiology of the particular agent (22,23,107,190). In addition, the authors of several reports have concluded that ASC, in combination with use of Contact Precautions for colonized patients, contributed directly to the decline or eradication of the target MDRO (38,68,107,151,153,184,217,242). However, not all studies have reached the same conclusion. Poor control of MRSA despite use of ASC has been described (245). A recent study failed to identify crosstransmission of MRSA or MSSA in a MICU during a 10 week period when ASC were obtained, despite the fact that culture results were not reported to the staff (246). The investigators suggest that the degree of cohorting and adherence to Standard Precautions might have been the important determinants of transmission prevention, rather than the use of ASC and Contact Precautions for MRSA-colonized patients. The authors of a systematic review of the literature on the use of isolation measures to control healthcare-associated MRSA concluded that there is evidence that concerted efforts that include ASC and isolation can reduce MRSA even in endemic settings. However, the authors also noted that methodological weaknesses and inadequate reporting in published research make it difficult to rule out plausible alternative explanations for reductions in MRSA acquisition associated with these interventions, and therefore concluded that the precise contribution of active surveillance and isolation alone is difficult to assess (247). Mathematical modeling studies have been used to estimate the impact of ASC use in control of MDROs. One such study evaluating interventions to decrease VRE transmission indicated that use of ASC (versus no cultures) could potentially decrease transmission 39% and that with pre-emptive isolation plus ASC, transmission could be decreased 65% (248). Another mathematical model examining the use of ASC and isolation for control of MRSA predicted that isolating colonized or infected patients on the basis of clinical culture results is unlikely to be successful at controlling MRSA, whereas use of active surveillance and isolation can lead to successful control, even in settings where MRSA is highly endemic. ( 249) There is less literature on the use of ASC in controlling MDR-GNBs. Active surveillance cultures have been used as part of efforts to successful control of MDR-GNBs in outbreak settings. The experience with ASC as part of successful control efforts in endemic settings is mixed. One study reported successful reduction of extended-spectrum beta-lactamase -producing Enterobacteriaceae over a six year period using a multifaceted control program that included use of ASC (245). Other reports suggest that use of ASC is not necessary to control endemic MDR-GNBs. (250,251). More research is needed to determine the circumstances under which ASC are most beneficial ( 252), but their use should be considered in some settings, especially if other control measures have been ineffective. When use of ASC is incorporated into MDRO prevention programs, the following should be considered: - The decision to use ASC as part of an infection prevention and control program requires additional support for successful implementation, including: 1. personnel to obtain the appropriate cultures, 2. microbiology laboratory personnel to process the cultures, 3. mechanism for communicating results to caregivers, 4. concurrent decisions about use of additional isolation measures triggered by a positive culture (e.g. Contact Precautions) and 5. mechanism for assuring adherence to the additional isolation measures. - The populations targeted for ASC are not well defined and vary among published reports. Some investigators have chosen to target specific patient populations considered at high risk for MDRO colonization based on factors such as location (e.g. ICU with high MDRO rates), antibiotic exposure history, presence of underlying diseases, prolonged duration of stay, exposure to other MDRO-colonized patients, patients transferred from other facilities known to have a high prevalence of MDRO carriage, or having a history of recent hospital or nursing home stays (107,151,253 from all patients admitted to units experiencing high rates of colonization/infection with the MDROs of interest, unless they are already known to be MDRO carriers (153,184,242,254). In an effort to better define target populations for active surveillance, investigators have attempted to create prediction rules to identify subpopulations of patients at high risk for colonization on hospital admission (255,256). Decisions about which populations should be targeted for active surveillance should be made in the context of local determinations of the incidence and prevalence of MDRO colonization within the intervention facility as well as other facilities with whom patients are frequently exchanged (257). - Optimal timing and interval of ASC are not well defined. In many reports, cultures were obtained at the time of admission to the hospital or intervention unit or at the time of transfer to or from designated units (e.g., ICU) (107). In addition, some bacilli can make the process of isolating a specific MDR-GNB a relatively labor-intensive process (38,190,241,250 (268). The impact of rapid testing on the effectiveness of active surveillance as a prevention strategy, however, has not been fully determined. Rapid identification of MRSA in one study was associated with a significant reduction in MRSA infections acquired in the medical ICU, but not the surgical ICU (265). A mathematical model characterizing MRSA transmission dynamics predicted that, in comparison to conventional culture methods, the use of rapid detection tests may decrease isolation needs in settings of low-endemicity and result in more rapid reduction in prevalence in highly-endemic settings (249). - Some MDRO control reports described surveillance cultures of healthcare personnel during outbreaks, but colonized or infected healthcare personnel are rarely the source of ongoing transmission, and this strategy should be reserved for settings in which specific healthcare personnel have been epidemiologically implicated in the transmission of MDROs (38,92,(152)(153)(154)188). MDRO control efforts frequently involved changes in isolation practices, especially during outbreaks. In the majority of reports, Contact Precautions were implemented for all patients found to be colonized or infected with the target 2). Some facilities also preemptively used Contact Precautions, in conjunction with ASC, for all new admissions or for all patients admitted to a specific unit, until a negative screening culture for the target MDRO was reported (30,184,273). Contact precautions are intended to prevent transmission of infectious agents, including epidemiologically important microorganisms, which are transmitted by direct or indirect contact with the patient or the patient's environment. A singlepatient room is preferred for patients who require Contact Precautions. When a single-patient room is not available, consultation with infection control is necessary to assess the various risks associated with other patient placement options (e.g., cohorting, keeping the patient with an existing roommate). HCP caring for patients on Contact Precautions should wear a gown and gloves for all interactions that may involve contact with the patient or potentially contaminated areas in the patient's environment. Donning gown and gloves upon room entry and discarding before exiting the patient room is done to contain pathogens, especially those that have been implicated in transmission through environmental contamination (e.g., VRE, C. difficile, noroviruses and other intestinal tract agents; RSV) (109,111,(274)(275)(276)(277). Cohorting and other MDRO control strategies. In several reports, cohorting of patients (152,153,167,183,184,188,189,217,242), cohorting of staff (184,217,242,278), use of designated beds or units (183,184), and even unit closure (38,146,159,161,279,280) were necessary to control transmission. Some authors indicated that implementation of the latter two strategies were the turning points in their control efforts; however, these measures usually followed many other actions to prevent transmission. In one, two-center study, moving MRSA-positive patients into single rooms or cohorting these patients in designated bays failed to reduce transmission in ICUs. However, in this study adherence to recommendations for hand hygiene between patient contacts was only 21% (281) acquiring MDROs (282). Additional studies are needed to define the specific contribution of using single-patient rooms and/or cohorting on preventing transmission of MDROs. # Duration of Contact Precautions. The necessary duration of Contact Precautions for patients treated for infection with an MDRO, but who may continue to be colonized with the organism at one or more body sites, remains an unresolved issue. Patients may remain colonized with MDROs for prolonged periods; shedding of these organisms may be intermittent, and surveillance cultures may fail to detect their presence (84,250,283). The 1995 HICPAC guideline for preventing the transmission of VRE suggested three negative stool/perianal cultures obtained at weekly intervals as a criterion for discontinuation of Contact Precautions (274). One study found these criteria generally reliable (284). However, this and other studies have noted a recurrence of VRE positive cultures in persons who subsequently receive antimicrobial therapy and persistent or intermittent carriage of VRE for more than 1 year has been reported (284)(285)(286). Similarly, colonization with MRSA can be prolonged (287,288). Studies demonstrating initial clearance of MRSA following decolonization therapy have reported a high frequency of subsequent carriage (289,290). There is a paucity of information in the literature on when to discontinue Contact Precautions for patients colonized with a MDR-GNB, possibly because infection and colonization with these MDROs are often associated with outbreaks. Despite the uncertainty about when to discontinue Contact Precautions, the studies offer some guidance. In the context of an outbreak, prudence would dictate that Contact Precautions be used indefinitely for all previously infected and known colonized patients. Likewise, if ASC are used to detect and isolate patients colonized with MRSA or VRE, and there is no decolonization of these patients, it is logical to assume that Contact Precautions would be used for the duration of stay in the setting where they were first implemented. In general, it seems reasonable to discontinue Contact Precautions when three or more surveillance cultures for the target MDRO are repeatedly negative over the course of a week or two in a patient who has not received antimicrobial therapy for several weeks, especially in the absence of a draining wound, profuse respiratory secretions, or evidence implicating the specific patient in ongoing transmission of the MDRO within the facility. # Barriers used for contact with patients infected or colonized with MDROs. Three studies evaluated the use of gloves with or without gowns for all patient contacts to prevent VRE acquisition in ICU settings (30,105,273). Two of the studies showed that use of both gloves and gowns reduced VRE transmission (30,105) while the third showed no difference in transmission based on the barriers used (273). One study in a LTCF compared the use of gloves only, with gloves plus contact isolation, for patients with four MDROs, including VRE and MRSA, and found no difference (86). However, patients on contact isolation were more likely to acquire MDR-K. pneumoniae strains that were prevalent in the facility; reasons for this were not specifically known. In addition to differences in outcome, differing methodologies make comparisons difficult. Specifically, HCP adherence to the recommended protocol, the influence of added precautions on the number of HCPpatient interactions, and colonization pressure were not consistently assessed. # Impact of Contact Precautions on patient care and well-being. There are limited data regarding the impact of Contact Precautions on patients. Two studies found that HCP, including attending physicians, were half as likely to enter the rooms of (291), or examine (292), patients on Contact Precautions. Other investigators have reported similar observations on surgical wards (293). Two studies reported that patients in private rooms and on barrier precautions for an MDRO had increased anxiety and depression scores (294,295). Another study found that patients placed on Contact Precautions for MRSA had significantly more preventable adverse events, expressed greater dissatisfaction with their treatment, and had less documented care than control patients who were not in isolation (296). Therefore, when patients are placed on Contact Precautions, efforts must be made by the healthcare team to counteract these potential adverse effects. (109-111, 297, 298). While environmental cultures are not routinely recommended (299), environmental cultures were used in several studies to document contamination, and led to interventions that included the use of dedicated noncritical medical equipment (217,300), assignment of dedicated cleaning personnel to the affected patient care unit (154), and increased cleaning and disinfection of frequently-touched surfaces (e.g., bedrails, charts, bedside commodes, doorknobs). A common reason given for finding environmental contamination with an MDRO was the lack of adherence to facility procedures for cleaning and disinfection. In an educational and observational intervention, which targeted a defined group of housekeeping personnel, there was a persistent decrease in the acquisition of VRE in a medical ICU (301). Therefore, monitoring for adherence to recommended environmental cleaning practices is an important determinant for success in controlling transmission of MDROs and other pathogens in the environment (274,302). In the MDRO reports reviewed, enhanced environmental cleaning was frequently undertaken when there was evidence of environmental contamination and ongoing transmission. Rarely, control of the target MDRO required vacating a patient care unit for complete environmental cleaning and assessment (175,279). 7. Decolonization. Decolonization entails treatment of persons colonized with a specific MDRO, usually MRSA, to eradicate carriage of that organism. Although some investigators have attempted to decolonize patients harboring VRE (220), few have achieved success. However, decolonization of persons carrying MRSA in their nares has proved possible with several regimens that include topical mupirocin alone or in combination with orally administered antibiotics (e.g., rifampin in combination with trimethoprim-sulfamethoxazole or ciprofloxacin) plus the use of an antimicrobial soap for bathing (303). In one report, a 3-day regimen of baths with povidone-iodine and nasal therapy with mupirocin resulted in eradication of nasal MRSA colonization (304). These and other methods of MRSA decolonization have been thoroughly reviewed. (303,(305)(306)(307). Decolonization regimens are not sufficiently effective to warrant routine use. Therefore, most healthcare facilities have limited the use of decolonization to MRSA outbreaks, or other high prevalence situations, especially those affecting special-care units. Several factors limit the utility of this control measure on a widespread basis: 1. identification of candidates for decolonization requires surveillance cultures; 2. candidates receiving decolonization treatment must receive follow-up cultures to ensure eradication; and 3. recolonization with the same strain, initial colonization with a mupirocin-resistant strain, and emergence of resistance to mupirocin during treatment can occur (289,303,(308)(309)(310). HCP implicated in transmission of MRSA are candidates for decolonization and should be treated and culture negative before returning to direct patient care. In contrast, HCP who are colonized with MRSA, but are asymptomatic, and have not been linked epidemiologically to transmission, do not require decolonization. # IV. Discussion This review demonstrates the depth of published science on the prevention and control of MDROs. Using a combination of interventions, MDROs in endemic, outbreak, and non-endemic settings have been brought under control. However, despite the volume of literature, an appropriate set of evidence-based control measures that can be universally applied in all healthcare settings has not been definitively established. This is due in part to differences in study methodology and outcome measures, including an absence of randomized, controlled trials comparing one MDRO control measure or strategy with another. Additionally, the data are largely descriptive and quasi-experimental in design (311). Few reports described preemptive efforts or prospective studies to control MDROs before they had reached high levels within a unit or facility. Furthermore, small hospitals and LTCFs are infrequently represented in the literature. A number of questions remain and are discussed below. # Impact on other MDROS from interventions targeted to one MDRO. Only one report described control efforts directed at more than one MDRO, i.e., MDR-GNB and MRSA (312). Several reports have shown either decreases or increases in other pathogens with efforts to control one MDRO. For example, two reports on VRE control efforts demonstrated an increase in MRSA following the prioritization of VRE patients to private rooms and cohort beds (161). Similarly an outbreak of Serratia marcescens was temporally associated with a concurrent, but unrelated, outbreak of MRSA in an NICU (313). In contrast, Wright and colleagues reported a decrease in MRSA and VRE acquisition in an ICU during and after their successful effort to eradicate an MDRstrain of A. baumannii from the unit (210). Colonization with multiple MDROs appears to be common (314,315). One study found that nearly 50% of residents in a skilled-care unit in a LTCF were colonized with a target MDRO and that 26% were co-colonized with >1 MDRO; a detailed analysis showed that risk factors for colonization varied by pathogen (316). One review of the literature (317) reported that patient risk factors associated with colonization with MRSA, VRE, MDR-GNB, C. difficile and Candida sp were the same. This review concluded that control programs that focus on only one organism or one antimicrobial drug are unlikely to succeed because vulnerable patients will continue to serve as a magnet for other MDROs. Costs. Several authors have provided evidence for the cost-effectiveness of approaches that use ASC (153,191,253,318,319). However, the supportive evidence often relied on assumptions, projections, and estimated attributable costs of MDRO infections. Similar limitations apply to a study suggesting that gown use yields a cost benefit in controlling transmission of VRE in ICUs (320). To date, no studies have directly compared the benefits and costs associated with different MDRO control strategies. # Feasibility. The subject of feasibility, as it applies to the extrapolation of results to other healthcare settings, has not been addressed. For example, smaller hospitals and LTCFs may lack the on-site laboratory services needed to obtain ASC in a timely manner. and preemptive placement of patients on Contact Precautions in these settings. However, with the growing problem of antimicrobial resistance, and the recognized role of all healthcare settings for control of this problem, it is imperative that appropriate human and fiscal resources be invested to increase the feasibility of recommended control strategies in every setting. # This factor could limit the applicability of an aggressive program based on obtaining ASC # Factors that influence selection of MDRO control measures. Although some common principles apply, the preceding literature review indicates that no single approach to the control of MDROs is appropriate for all healthcare facilities. Many factors influence the choice of interventions to be applied within an institution, including: - Type and significance of problem MDROs within the institution. Many facilities have an MRSA problem while others have ESBL-producing K. pneumoniae. Some facilities have no VRE colonization or disease; others have high rates of VRE colonization without disease; and still others have ongoing VRE outbreaks. The magnitude of the problem also varies. Healthcare facilities may have very low numbers of cases, e.g., with a newly introduced strain, or may have prolonged, extensive outbreaks or colonization in the population. Between these extremes, facilities may have low or high levels of endemic colonization and variable levels of infection. - Population and healthcare-settings. The presence of high-risk patients (e.g., transplant, hematopoietic stem-cell transplant) and special-care units (e.g. adult, pediatric, and neonatal ICUs; burn; hemodialysis) will influence surveillance needs and could limit the areas of a facility targeted for MDRO control interventions. Although it appears that MDRO transmission seldom occurs in ambulatory and outpatient settings, some patient populations (e.g., hemodialysis, cystic fibrosis) and patients receiving chemotherapeutic agents are at risk for colonization and infection with MDROs. Furthermore, the emergence of VRSA within the outpatient setting (22,23,25) demonstrates that even these settings need to make MDRO prevention a priority. Differences of opinion on the optimal strategy to control MDROs. Published guidance on the control of MDROs reflects areas of ongoing debate on optimal control strategies. A key issue is the use of ASC in control efforts and preemptive use of Contact Precautions pending negative surveillance culture results (107,321,322). The various guidelines currently available exhibit a spectrum of approaches, which their authors deem to be evidence-based. One guideline for control of MRSA and VRE, the Society for Healthcare seek appropriate guidance and adopt effective measures that fit their circumstances and needs. Most studies have been in acute care settings; for non-acute care settings (e.g., LCTF, small rural hospitals), the optimal approach is not well defined. 3). As a rule, these reports indicate that facilities confronted with an MDRO problem selected a combination of control measures, implemented them, and reassessed their impact. In some cases, new measures were added serially to further enhance control efforts. This evidence indicates that the control of MDROs is a dynamic process that requires a systematic approach tailored to the problem and healthcare setting. # Two-tiered approach for control of MDROs. Reports describing successful control of MDRO transmission in healthcare facilities have included seven categories of interventions (Table The nature of this evidence gave rise to the two-tiered approach to MDRO control recommended in this guideline. This approach provides the flexibility needed to prevent and control MDRO transmission in every kind of facility addressed by this guideline. Detailed recommendations for MDRO control in all healthcare settings follow and are summarized in Table 3 (Tier 1). Table 3, which applies to all healthcare settings, contains two tiers of activities. In the first tier are the baseline level of MDRO control activities designed to ensure recognition of MDROs as a problem, involvement of healthcare administrators, and provision of safeguards for managing unidentified carriers of MDROs. With the emergence of an MDRO problem that cannot be controlled with the basic set of infection control measures, additional control measures should be selected from the second tier of interventions presented in Table 3 (Tier 2). Decisions to intensify MDRO control activity arise from surveillance observations and assessments of the risk to patients in various settings. Circumstances that may trigger these decisions include: - Identification of an MDRO from even one patient in a facility or special unit with a highly vulnerable patient population (e.g., an ICU, NICU, burn unit) that had previously not encountered that MDRO. - Failure to decrease the prevalence or incidence of a specific MDRO (e.g., incidence of resistant clinical isolates) despite infection control efforts to stop its transmission. (Statistical process control charts or other validated methods that account for normal variation can be used to track rates of targeted MDROs) (205,325,326). The combination of new or increased frequency of MDRO isolates and patients at risk necessitates escalation of efforts to achieve or re-establish control, i.e., to reduce rates of transmission to the lowest possible level. Intensification of MDRO control activities should begin with an assessment of the problem and evaluation of the effectiveness of measures in current use. Once the problem is defined, appropriate additional control measures should be selected from the second tier of Table 3. A knowledgeable infection prevention and control professional or healthcare epidemiologist should make this determination. This approach requires support from the governing body and medical staff of the facility. Once interventions are implemented, ongoing surveillance should be used to determine whether # V. Prevention of Transmission of Multidrug Resistant Organisms The CDC/HICPAC system for categorizing recommendations is as follows: Category IA Strongly recommended for implementation and strongly supported by welldesigned experimental, clinical, or epidemiologic studies. Category IB Strongly recommended for implementation and supported by some experimental, clinical, or epidemiologic studies and a strong theoretical rationale. Category IC Required for implementation, as mandated by federal and/or state regulation or standard. Category II Suggested for implementation and supported by suggestive clinical or epidemiologic studies or a theoretical rationale. No recommendation Unresolved issue. Practices for which insufficient evidence or no consensus regarding efficacy exists. (3,146,151,154,182,185,194,205,208,210,242,327,328) (3,105,182,184,189,242,273,312,330). # V.A. General recommendations for all healthcare settings independent of the prevalence of multidrug resistant organism (MDRO) infections or the population served. (See # Category IB V.A.1.b. # Category IB V.A.1.f. Implement systems to designate patients known to be colonized or infected with a targeted MDRO and to notify receiving healthcare facilities and personnel prior to transfer of such patients within or between facilities. (87, 151) Category IB V.A.1.g. Support participation of the facility or healthcare system in local, regional, and national coalitions to combat emerging or growing MDRO problems. (41,146,151,167,188,206,207,211,331). Category IB V.A.1.h. Provide updated feedback at least annually to healthcare providers and administrators on facility and patient-care-unit trends in MDRO infections. Include information on changes in prevalence or incidence of infection, results of assessments for system failures, and action plans to improve adherence to and effectiveness of recommended infection control practices to prevent MDRO transmission. (152,154,159,184,204,205,242,312,332) with MDROs and prevention strategies. (38,152,154,173,176,189,190,203,204,217,242,330,333,334) MDR-Acinetobacter baumannii) MDROs. (8,154,177,190,193,209,254,347,(350)(351)(352)(353) Category IB V.A.4.b. In all healthcare organizations, establish systems to ensure that clinical microbiology laboratories (in-house and out-sourced) promptly notify infection control staff or a medical director/ designee when a novel resistance pattern for that facility is detected. (9,22,154,162,169) Category IB V.A.4.c. In hospitals and LTCFs, develop and implement laboratory protocols for storing isolates of selected MDROs for molecular typing when needed to confirm transmission or delineate the epidemiology of the MDRO within the healthcare setting. (7,8,38,140,153,154,187,190,208,217,354,355) (152,154,183,193,205,209,217,242,300,325,326,364,365) Category IA V.A.4.e.i. Specify isolate origin (i.e., location and clinical service) in MDRO monitoring protocols in hospitals and other large multiunit facilities with high-risk patients. (8, 38, 152-154, 217, 358, 361) Category IB V.A.4.e.ii. Establish a baseline (e.g., incidence) for targeted MDRO isolates by reviewing results of clinical cultures; if more timely or localized information is needed, perform baseline point prevalence studies of colonization in high-risk units. When possible, distinguish colonization from infection in analysis of these data. (152,153,183,184,189,190,193,205,242,365) (8,22,151,152,154,189,190,193,208,240,366) V.A.5.c.i. In acute-care hospitals, implement Contact Precautions routinely for all patients infected with target MDROs and for patients that have been previously identified as being colonized with target MDROs (e.g., patients transferred from other units or facilities who are known to be colonized). (11,38,68,114,151,183,188,204,217,242,304) (8, 11, 38, 68, 114, 152-154, 183-185, 189, 190, 193, 194, 209, 217, 242, 312, 364, 365). Category IB V.B.1.a.i. When incidence or prevalence of MDROs are not decreasing despite implementation of and correct adherence to the routine control measures described above, intensify MDRO control efforts by adopting one or more of the interventions described below. (92,152,183,184,193,365) (3, 68, 146, 151-154, 167, 184, 190, 193, 242, 328, 377). Category IB V.B.2.b. Provide necessary leadership, funding, and day-to-day oversight to implement interventions selected. Involve the governing body and leadership of the healthcare facility or system that have organizational responsibility for this and other infection control efforts. (8,38,152,154,184,189,190,208) and training, availability of consumable and durable resources, communication processes, policies and procedures, and adherence to recommended infection control measures (e.g., hand hygiene and Standard or Contact Precautions). Develop, implement, and monitor action plans to correct system failures. (3,8,38,152,154,172,173,175,188,196,198,199,208,217,280,323,379,380) Provide individual or unit-specific feedback when available. (3,38,152,154,159,170,182,183,189,190,193,194,204,205,209,215,218,312) Category IB # Category IB # V.A.5.c. Use of Contact Precautions # V.B.4. Judicious use of antimicrobial agents Review the role of antimicrobial use in perpetuating the MDRO problem targeted for intensified intervention. Control and improve antimicrobial use as indicated. Antimicrobial agents that may be targeted include vancomycin, third-generation cephalosporins, and anti-anaerobic agents for VRE (217); third-generation cephalosporins for ESBLs (212,214,215); and quinolones and carbapenems (80,156,166,174,175,209,218,242,254,329,334,335,337,341). Category IB V.B.5. Surveillance V.B.5.a. Calculate and analyze prevalence and incidence rates of targeted MDRO infection and colonization in populations at risk; when possible, distinguish colonization from infection (152,153,183,184,189,190,193,205,215,242,365). Category IB and patients known to have been previously infected or colonized with an MDRO). (8, 38, 68, 114, 151-154, 167, 168, 183, 184, 187-190, 192, 193, 217, 242) ICUs, and at periodic intervals as needed to assess MDRO transmission. (8,151,154,159,184,208,215,242,387) (183,184,189,193,242,339,392) Category IB V.B.7.a.i. Place MDRO patients in single-patient rooms. (6,151,158,160,166,170,187,208,240,282,(393)(394)(395) Category IB V.B.7.a.ii. Cohort patients with the same MDRO in designated areas (e.g., rooms, bays, patient care areas. (8,151,152,159,161,176,181,183,184,188,208,217,242,280,339,344) despite the implementation of the enhanced control measures described above. (Refer to state or local regulations that may apply upon closure of hospital units or services.) (9,38,146,159,161,168,175,205,279,280,332,339,396) (38,104,151,156,159,163,181,217,323,329,367,389,390,394) (38, 154, 159, 165, 172, 173, 175, 178-181, 193, 205, 208, 217, 279, 301, 327, 339, 397) Category IB V.B.8.c. Monitor (i.e., supervise and inspect) cleaning performance to ensure consistent cleaning and disinfection of surfaces in close proximity to the patient and those likely to be touched by the patient and HCP (e.g., bedrails, carts, bedside commodes, doorknobs, faucet handles). (8,38,109,111,154,169,180,208,217,301,333,398) (152,168,170,172,183,194,304) Category II V.B.9.b. When decolonization for MRSA is used, perform susceptibility testing for the decolonizing agent against the target organism in the individual being treated or the MDRO strain that is epidemiologically implicated in Cohorting. In the context of this guideline, this term applies to the practice of grouping patients infected or colonized with the same infectious agent together to confine their care to one area and prevent contact with susceptible patients (cohorting patients). During outbreaks, healthcare personnel may be assigned to a cohort of patients to further limit opportunities for transmission (cohorting staff). Contact Precautions. Contact Precautions are a set of practices used to prevent transmission of infectious agents that are spread by direct or indirect contact with the patient or the patient's environment. Contact Precautions also apply where the presence of excessive wound drainage, fecal incontinence, or other discharges from the body suggest an increased transmission risk. A single patient room is preferred for patients who require Contact Precautions. When a single patient room is not available, consultation with infection control is helpful to assess the various risks associated with other patient placement options (e.g., cohorting, keeping the patient with an existing roommate). In multi-patient rooms, ≥3 feet spatial separation of between beds is advised to reduce the opportunities for inadvertent sharing of items between the infected/colonized patient and other patients. Healthcare personnel caring for patients on Contact Precautions wear a gown and gloves for all interactions that may involve contact with the patient or potentially contaminated areas in the patient's environment. Donning of gown and gloves upon room entry, removal before exiting the patient room and performance of hand hygiene immediately upon exiting are done to contain pathogens. # Category # Antimicrobial resistance implications: - Resistance to first-line therapies (e.g., MRSA, VRE, VISA, VRSA, ESBLproducing organisms). - Unusual or usual agents with unusual patterns of resistance within a facility, (e.g., the first isolate of Burkholderia cepacia complex or Ralstonia spp. in non-CF patients or a quinolone-resistant strain of Pseudomonas in a facility. - Difficult to treat because of innate or acquired resistance to multiple classes of antimicrobial agents (e.g., Stenotrophomonas maltophilia, Acinetobacter spp.). all surfaces of hands); or 4. surgical hand antisepsis (antiseptic hand wash or antiseptic hand rub performed preoperatively by surgical personnel to eliminate transient hand flora and reduce resident hand flora). # Healthcare-associated infection (HAI). An infection that develops in a patient who is cared for in any setting where healthcare is delivered (e.g., acute care hospital, chronic care facility, ambulatory clinic, dialysis center, surgicenter, home) and is related to receiving health care (i.e., was not incubating or present at the time healthcare was provided). In ambulatory and home settings, HAI would apply to any infection that is associated with a medical or surgical intervention performed in those settings. Home care. A wide-range of medical, nursing, rehabilitation, hospice, and social services delivered to patients in their place of residence (e.g., private residence, senior living center, assisted living facility). Home health-care services include care provided by home health aides and skilled nurses, respiratory therapists, dieticians, physicians, chaplains, and volunteers; provision of durable medical equipment; home infusion therapy; and physical, speech, and occupational therapy. institutions for the developmentally disabled, residential care facilities, assisted living facilities, retirement homes, adult day health care facilities, rehabilitation centers, and long-term psychiatric hospitals. # Infection prevention and control professional (ICP # Mask. A term that applies collectively to items used to cover the nose and mouth and includes both procedure masks and surgical masks (). # Multidrug-resistant organisms (MDROs). In general, bacteria (excluding M. tuberculosis) that are resistant to one or more classes of antimicrobial agents and usually are resistant to all but one or two commercially available antimicrobial agents (e.g., MRSA, VRE, extended spectrum beta-lactamase -producing or intrinsically resistant gramnegative bacilli). # Nosocomial infection. Derived from two Greek words "nosos" (disease) and "komeion" (to take care of). Refers to any infection that develops during or as a result of an admission to an acute care facility (hospital) and was not incubating at the time of admission. # Standard Precautions. A group of infection prevention practices that apply to all patients, regardless of suspected or confirmed diagnosis or presumed infection status. Standard Precautions are a combination and expansion of Universal Precautions and Body Substance Isolation. Standard Precautions are based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents. Standard Precautions includes hand hygiene, and depending on the anticipated exposure, use of gloves, gown, mask, eye protection, or face shield. Also, equipment or items in the patient environment likely to have been contaminated with infectious fluids must be handled in a manner to prevent transmission of infectious agents, (e.g. wear gloves for handling, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient). Institute one or more of the interventions described below when 1. incidence or prevalence of MDROs are not decreasing despite the use of routine control measures; or 2. the first case or outbreak of an epidemiologically important MDRO (e.g., VRE, MRSA, VISA, VRSA, MDR-GNB) is identified within a healthcare facility or unit (IB) Continue to monitor the incidence of target MDRO infection and colonization; if rates do not decrease, implement additional interventions as needed to reduce MDRO transmission.

Embryology of the gallbladder and the biliary tract Synonyms and keywords: Synonym 1; Synonym 2; Synonym 3 Please help WikiDoc by adding content here. It's easy! Click here to learn about editing. # Overview # Historical Perspective - was first discovered by , a , in during/following . - In , mutations were first identified in the pathogenesis of . - In , the first was developed by to treat/diagnose . # Classification - may be classified according to into subtypes/groups: - Other variants of include , , and . # Pathophysiology - The pathogenesis of is characterized by , , and . - The gene/Mutation in has been associated with the development of , involving the pathway. - On gross pathology, , , and are characteristic findings of . - On microscopic histopathological analysis, , , and are characteristic findings of . # Causes - may be caused by either , , or . - is caused by a mutation in the , , or gene. - There are no established causes for . # Differentiating from other Diseases - must be differentiated from other diseases that cause , , and , such as: # Epidemiology and Demographics - The prevalence of is approximately per 100,000 individuals worldwide. - In , the incidence of was estimated to be cases per 100,000 individuals in . ## Age - Patients of all age groups may develop . - is more commonly observed among patients aged years old. - is more commonly observed among . ## Gender - affects men and women equally. - are more commonly affected with than . - The to ratio is approximately to 1. ## Race - There is no racial predilection for . - usually affects individuals of the race. - individuals are less likely to develop . # Risk Factors - Common risk factors in the development of are , , , and . # Natural History, Complications and Prognosis - The majority of patients with remain asymptomatic for . - Early clinical features include , , and . - If left untreated, of patients with may progress to develop , , and . - Common complications of include , , and . - Prognosis is generally , and the of patients with is approximately . # Diagnosis ## Diagnostic Criteria - The diagnosis of is made when at least of the following diagnostic criteria are met: ## Symptoms - is usually asymptomatic. - Symptoms of may include the following: ## Physical Examination - Patients with usually appear . - Physical examination may be remarkable for: ## Laboratory Findings - There are no specific laboratory findings associated with . - A is diagnostic of . - An concentration of is diagnostic of . - Other laboratory findings consistent with the diagnosis of include , , and . ## Imaging Findings - There are no findings associated with . - is the imaging modality of choice for . - On , is characterized by , , and . - may demonstrate , , and . ## Other Diagnostic Studies - may also be diagnosed using . - Findings on include , , and . # Treatment ## Medical Therapy - There is no treatment for ; the mainstay of therapy is supportive care. - The mainstay of therapy for is and . - acts by . - Response to can be monitored with every . ## Surgery - Surgery is the mainstay of therapy for . - in conjunction with is the most common approach to the treatment of . - can only be performed for patients with . ## Prevention - There are no primary preventive measures available for . - Effective measures for the primary prevention of include , , and . - Once diagnosed and successfully treated, patients with are followed-up every . Follow-up testing includes , , and .

Laparoscopic cerclage for cervical incompetence to prevent late miscarriage or preterm birth Evidence-based recommendations on laparoscopic cerclage for cervical incompetence to prevent late miscarriage or preterm birth. This involves placing a stitch around the upper part of the cervix to keep it closed. # Recommendations Current evidence on the safety and efficacy of laparoscopic cerclage for cervical incompetence to prevent late miscarriage or preterm birth is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page. Patient selection should be done by a multidisciplinary team experienced in the management and prevention of preterm delivery.# The condition, current treatments and procedure # The condition Cervical incompetence may be caused by a congenital weakness of the cervix, or previous obstetric or gynaecological trauma. It is characterised by painless dilatation of the cervix in the second or third trimester, followed by second trimester miscarriage or premature rupture of the membranes and preterm delivery. The condition is usually diagnosed after 1 or more late second trimester pregnancy losses or early third trimester delivery, and after other causes have been excluded. # Current treatments Cervical incompetence is traditionally treated by transvaginal cervical cerclage. This involves placing a strong suture or tape around the cervix, via the vagina, and tightening it to keep the cervix closed. The procedure is typically done at the end of the first trimester or the beginning of the second trimester. The suture or tape is then usually removed at around 37 weeks of gestation to allow delivery. Cervical cerclage using a transabdominal approach may be needed if transvaginal cerclage is technically difficult or has proved ineffective. With this approach, caesarean section is necessary to deliver the baby. # The procedure Laparoscopic cervical cerclage can be done during pregnancy or in women who are not pregnant. Under general anaesthesia, the peritoneal cavity is insufflated with carbon dioxide through a needle inserted into the umbilicus. Several small incisions are made to provide access for the laparoscope and surgical instruments. In women who are not pregnant, a dilator may initially be inserted into the cervix through the vagina for uterine manipulation. The bladder is dissected away from the uterus and a suture or tape is secured around the cervical isthmus, above the cardinal and uterosacral ligaments. As with the open transabdominal approach, caesarean section is necessary to deliver the baby. The suture or tape may be left in place for future pregnancies.

FOXRED1 FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1), also known as H17, or FP634 is an enzyme that in humans is encoded by the FOXRED1 gene. FOXRED1 is an oxidoreductase and complex I-specific molecular chaperone involved in the assembly and stabilization of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in FOXRED1 have been associated with Leigh syndrome and infantile-onset mitochondrial encephalopathy. # Structure FOXRED1 is located on the q arm of chromosome 11 in position 14.2 and has 12 exons. The FOXRED1 gene produces a 53.8 kDa protein composed of 486 amino acids. Alternatively spliced transcript variants have been observed for this gene. FOXRED1 contains an oxidoreductase FAD-binding domain and is homologous to FAD-binding proteins dimethylglycine dehydrogenase, sarcosine dehydrogenase, L-pipecolic acid oxidase, peroxisomal sarcosine oxidase, and pyrvuvate dehydrogenase regulatory subunit. FOXRED1's structural similarities to sarcosine oxidase (MSOX) predict that tyrosine residues Y410 and Y411 make up the site of covalent attachment of FAD. Additionally, a phenyl moiety at p. 359 is thought to be critical for function. Finally, FOXRED1 is a matrix-directed protein that is thought to be imported through the presence of a mitochondrial membrane potential rather than through a cleavable targeting signal. However, others suggest that it contains a 23 amino acid N-terminal mitochondrial localization sequence and that this sequence is cleaved upon entry to form the mature protein. # Function The FOXRED1 gene encodes an enzyme that is localized in the mitochondria and which helps in the assembly and stabilization of NADH:ubiquinone oxidoreductase, a large multi-subunit enzyme in the mitochondrial respiratory chain. NADH:ubiquinone oxidoreductase (complex I) is involved in several physiological activities in the cell, including metabolite transport and ATP synthesis. Complex I catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. The encoded protein of FOXRED1 is an oxidoreductase and complex I-specific molecular chaperone. It plays a role in the mid-to-late stages of complex I intermediate assembly and is important for the assembly, stabilization, and function of complex I. It is proposed that FOXRED1 functions in a complex with core subunit NDUFS3 as well as accessory subunits NDUFA5, NDUFA10, NDUFB10 and NDUFS5. # Clinical Significance Mutations in FOXRED1 can result in mitochondrial deficiencies and associated disorders. A disorder of the mitochondrial respiratory chain can cause a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. Pathogenic mutations of FOXRED1 have included c.1054C>T; p.R352W, c.694C>T; p.Q232X, and c.1289A>G; p.N430S. Symptoms due to these mutations have included lactic acidosis, hypertrophic cardiomyopathy, and optic atrophy. Clinically, these variants have been associated with Leigh syndrome and infantile-onset mitochondrial encephalopathy. Survival with FOXRED1 mutations appears to be more common than in other complex I deficiencies and overexpression of mutant forms can lead to rescued complex I activity indicating that FOXRED1 activity can be compensated for to some degree. # Interactions FOXRED1 co-immunoprecipitates with complex I subunits NDUFB10, NDUFS5, NDUFA10, NDUFA8, NDUFS3 and NDUFA5 and may be associated with import machinery Tom20, Tom22 and MPP as well as chaperones mtHsp70, Hsp60, and Hsp10. In addition to co-complexes and potential associations, FOXRED1 has been confirmed to have protein-protein interactions with EXOSC10.

Growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in human development. It is a type of mitogen which is specific only to certain kinds of cells. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored and secreted by somatotropic cells within the lateral wings of the anterior pituitary gland. GH is a stress hormone that stimulates production of IGF-1 and raises the concentration of glucose and free fatty acids. A recombinant form of hGH called somatropin (INN) is used as a prescription drug to treat children's growth disorders and adult growth hormone deficiency. In the United States, it is only available legally from pharmacies, by prescription from a doctor. In recent years in the United States, some doctors have started to prescribe growth hormone in GH-deficient older patients (but not on healthy people) to increase vitality. While legal, the efficacy and safety of this use for HGH has not been tested in a clinical trial. At this time, HGH is still considered a very complex hormone, and many of its functions are still unknown. In its role as an anabolic agent, HGH has been used by competitors in sports since at least 1982, and has been banned by the IOC and NCAA. Traditional urine analysis does not detect doping with HGH, so the ban was unenforceable until the early 2000s, when blood tests that could distinguish between natural and artificial HGH were starting to be developed. Blood tests conducted by WADA at the 2004 Olympic Games in Athens, Greece targeted primarily HGH. Use of the drug for performance enhancement is not currently approved by the FDA. GH has been studied for use in raising livestock more efficiently in industrial agriculture and several efforts have been made to obtain governmental approval to use GH in livestock production. These uses have been controversial. In the United States, the only FDA-approved use of GH for livestock is the use of a cow-specific form of GH called bovine somatotropin for increasing milk production in dairy cows. Retailers are permitted to label containers of milk as produced with or without bovine somatotropin. # Nomenclature The names somatotropin (STH) or somatotropic hormone refer to the growth hormone produced naturally in animals and extracted from carcasses. Hormone extracted from human cadavers is abbreviated hGH. The main growth hormone produced by recombinant DNA technology has the approved generic name (INN) somatropin and the brand name Humatrope, and is properly abbreviated rhGH in the scientific literature. Since its introduction in 1992 Humatrope has been a banned sports doping agent, and in this context is referred to as HGH. # Biology ## Gene Genes for human growth hormone, known as growth hormone 1 (somatotropin; pituitary growth hormone) and growth hormone 2 (placental growth hormone; growth hormone variant), are localized in the q22-24 region of chromosome 17 and are closely related to human chorionic somatomammotropin (also known as placental lactogen) genes. GH, human chorionic somatomammotropin, and prolactin belong to a group of homologous hormones with growth-promoting and lactogenic activity. ## Structure The major isoform of the human growth hormone is a protein of 191 amino acids and a molecular weight of 22,124 daltons. The structure includes four helices necessary for functional interaction with the GH receptor. It appears that, in structure, GH is evolutionarily homologous to prolactin and chorionic somatomammotropin. Despite marked structural similarities between growth hormone from different species, only human and Old World monkey growth hormones have significant effects on the human growth hormone receptor. Several molecular isoforms of GH exist in the pituitary gland and are released to blood. In particular, a variant of approximately 20 kDa originated by an alternative splicing is present in a rather constant 1:9 ratio, while recently an additional variant of ~ 23-24 kDa has also been reported in post-exercise states at higher proportions. This variant has not been identified, but it has been suggested to coincide with a 22 kDa glycosylated variant of 23 kDa identified in the pituitary gland. Furthermore, these variants circulate partially bound to a protein (growth hormone-binding protein, GHBP), which is the truncated part of the growth hormone receptor, and an acid-labile subunit (ALS). ## Regulation Secretion of growth hormone (GH) in the pituitary is regulated by the neurosecretory nuclei of the hypothalamus. These cells release the peptides Growth hormone-releasing hormone (GHRH or somatocrinin) and Growth hormone-inhibiting hormone (GHIH or somatostatin) into the hypophyseal portal venous blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion. Somatotropic cells in the anterior pituitary gland then synthesize and secrete GH in a pulsatile manner, in response to these stimuli by the hypothalamus. The largest and most predictable of these GH peaks occurs about an hour after onset of sleep with plasma levels of 13 to 72 ng/mL. Otherwise there is wide variation between days and individuals. Nearly fifty percent of GH secretion occurs during the third and fourth NREM sleep stages. Surges of secretion during the day occur at 3- to 5-hour intervals. The plasma concentration of GH during these peaks may range from 5 to even 45 ng/mL. Between the peaks, basal GH levels are low, usually less than 5 ng/mL for most of the day and night. Additional analysis of the pulsatile profile of GH described in all cases less than 1 ng/ml for basal levels while maximum peaks were situated around 10-20 ng/mL. A number of factors are known to affect GH secretion, such as age, sex, diet, exercise, stress, and other hormones. Young adolescents secrete GH at the rate of about 700 μg/day, while healthy adults secrete GH at the rate of about 400 μg/day. Sleep deprivation generally suppresses GH release, particularly after early adulthood. Stimulators of growth hormone (GH) secretion include: - peptide hormones GHRH (somatocrinin) through binding to the growth hormone-releasing hormone receptor (GHRHR) ghrelin through binding to growth hormone secretagogue receptors (GHSR) - GHRH (somatocrinin) through binding to the growth hormone-releasing hormone receptor (GHRHR) - ghrelin through binding to growth hormone secretagogue receptors (GHSR) - sex hormones increased androgen secretion during puberty (in males from testes and in females from adrenal cortex) estrogen - increased androgen secretion during puberty (in males from testes and in females from adrenal cortex) - estrogen - clonidine and L-DOPA by stimulating GHRH release - α4β2 nicotinic agonists, including nicotine, which also act synergistically with clonidine. - hypoglycemia, arginine and propranolol by inhibiting somatostatin release - deep sleep - niacin as nicotinic acid (Vitamin B3) - fasting - vigorous exercise Inhibitors of GH secretion include: - GHIH (somatostatin) from the periventricular nucleus - circulating concentrations of GH and IGF-1 (negative feedback on the pituitary and hypothalamus) - hyperglycemia - glucocorticoids - dihydrotestosterone In addition to control by endogenous and stimulus processes, a number of foreign compounds (xenobiotics such as drugs and endocrine disruptors) are known to influence GH secretion and function. ## Function File:Endocrine growth regulation.svg Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other protein hormones, GH acts by interacting with a specific receptor on the surface of cells. Increased height during childhood is the most widely known effect of GH. Height appears to be stimulated by at least two mechanisms: - Because polypeptide hormones are not fat-soluble, they cannot penetrate cell membranes. Thus, GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathway. Through this mechanism GH directly stimulates division and multiplication of chondrocytes of cartilage. - GH also stimulates, through the JAK-STAT signaling pathway, the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin. The liver is a major target organ of GH for this process and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it what appears to be both an endocrine and an autocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth. In addition to increasing height in children and adolescents, growth hormone has many other effects on the body: - Increases calcium retention, and strengthens and increases the mineralization of bone - Increases muscle mass through sarcomere hypertrophy - Promotes lipolysis - Increases protein synthesis - Stimulates the growth of all internal organs excluding the brain - Plays a role in homeostasis - Reduces liver uptake of glucose - Promotes gluconeogenesis in the liver - Contributes to the maintenance and function of pancreatic islets - Stimulates the immune system - Increases deiodination of T4 to T3 # Clinical significance ## Excess The most common disease of GH excess is a pituitary tumor composed of somatotroph cells of the anterior pituitary. These somatotroph adenomas are benign and grow slowly, gradually producing more and more GH. For years, the principal clinical problems are those of GH excess. Eventually, the adenoma may become large enough to cause headaches, impair vision by pressure on the optic nerves, or cause deficiency of other pituitary hormones by displacement. Prolonged GH excess thickens the bones of the jaw, fingers and toes, resulting heaviness of the jaw and increased size of digits, referred to as acromegaly. Accompanying problems can include sweating, pressure on nerves (e.g. carpal tunnel syndrome), muscle weakness, excess sex hormone-binding globulin (SHBG), insulin resistance or even a rare form of type 2 diabetes, and reduced sexual function. GH-secreting tumors are typically recognized in the fifth decade of life. It is extremely rare for such a tumor to occur in childhood, but, when it does, the excessive GH can cause excessive growth, traditionally referred to as pituitary gigantism. Surgical removal is the usual treatment for GH-producing tumors. In some circumstances, focused radiation or a GH antagonist such as pegvisomant may be employed to shrink the tumor or block function. Other drugs like octreotide (somatostatin agonist) and bromocriptine (dopamine agonist) can be used to block GH secretion because both somatostatin and dopamine negatively inhibit GHRH-mediated GH release from the anterior pituitary. ## Deficiency The effects of growth hormone (GH) deficiency vary depending on the age at which they occur. Alterations in somatomedin can result in growth hormone deficiency with two known mechanisms; failure of tissues to respond to somatomedin, or failure of the liver to produce somatomedin. Major manifestations of GH deficiency in children are growth failure, the development of a short stature, and delayed sexual maturity. In adults, somatomedin alteration contributes to increased osteoclast activity, resulting in weaker bones that are more prone to pathologic fracture and osteoporosis. However, deficiency is rare in adults, with the most common cause being a pituitary adenoma. Other adult causes include a continuation of a childhood problem, other structural lesions or trauma, and very rarely idiopathic GHD. Adults with GHD "tend to have a relative increase in fat mass and a relative decrease in muscle mass and, in many instances, decreased energy and quality of life". Diagnosis of GH deficiency involves a multiple-step diagnostic process, usually culminating in GH stimulation tests to see if the patient's pituitary gland will release a pulse of GH when provoked by various stimuli. # Psychological effects ## Quality of life Several studies, primarily involving patients with GH deficiency, have suggested a crucial role of GH in both mental and emotional well-being and maintaining a high energy level. Adults with GH deficiency often have higher rates of depression than those without. While GH replacement therapy has been proposed to treat depression as a result of GH deficiency, the long-term effects of such therapy are unknown. ## Cognitive function GH has also been studied in the context of cognitive function, including learning and memory. GH in humans appears to improve cognitive function and may be useful in the treatment of patients with cognitive impairment that is a result of GH deficiency. # Medical uses ## Replacement therapy Treatment with exogenous GH is indicated only in limited circumstances, and needs regular monitoring due to the frequency and severity of side-effects. GH is used as replacement therapy in adults with GH deficiency of either childhood-onset or adult-onset (usually as a result of an acquired pituitary tumor). In these patients, benefits have variably included reduced fat mass, increased lean mass, increased bone density, improved lipid profile, reduced cardiovascular risk factors, and improved psychosocial well-being. ## Other approved uses GH can be used to treat conditions that produce short stature but are not related to deficiencies in GH. However, results are not as dramatic when compared to short stature that is solely attributable to deficiency of GH. Examples of other causes of shortness often treated with GH are Turner syndrome, chronic renal failure, Prader–Willi syndrome, intrauterine growth restriction, and severe idiopathic short stature. Higher ("pharmacologic") doses are required to produce significant acceleration of growth in these conditions, producing blood levels well above normal ("physiologic"). Despite the higher doses, side-effects during treatment are rare, and vary little according to the condition being treated. One version of rHGH has also been FDA approved for maintaining muscle mass in wasting due to AIDS. ## Off-label use Off-label prescription of HGH is controversial and may be illegal. Claims for GH as an anti-aging treatment date back to 1990 when the New England Journal of Medicine published a study wherein GH was used to treat 12 men over 60. At the conclusion of the study, all the men showed statistically significant increases in lean body mass and bone mineral density, while the control group did not. The authors of the study noted that these improvements were the opposite of the changes that would normally occur over a 10- to 20-year aging period. Despite the fact the authors at no time claimed that GH had reversed the aging process itself, their results were misinterpreted as indicating that GH is an effective anti-aging agent. This has led to organizations such as the controversial American Academy of Anti-Aging Medicine promoting the use of this hormone as an "anti-aging agent". A Stanford University School of Medicine meta-analysis of clinical studies on the subject published in early 2007 showed that the application of GH on healthy elderly patients increased muscle by about 2 kg and decreased body fat by the same amount. However, these were the only positive effects from taking GH. No other critical factors were affected, such as bone density, cholesterol levels, lipid measurements, maximal oxygen consumption, or any other factor that would indicate increased fitness. Researchers also did not discover any gain in muscle strength, which led them to believe that GH merely let the body store more water in the muscles rather than increase muscle growth. This would explain the increase in lean body mass. GH has also been used experimentally to treat multiple sclerosis, to enhance weight loss in obesity, as well as in fibromyalgia, heart failure, Crohn's disease and ulcerative colitis, and burns. GH has also been used experimentally in patients with short bowel syndrome to lessen the requirement for intravenous total parenteral nutrition. In 1990, the US Congress passed an omnibus crime bill, the Crime Control Act of 1990, that amended the Federal Food, Drug, and Cosmetic Act, that classified anabolic steroids as controlled substances and added a new section that stated that a person who "knowingly distributes, or possesses with intent to distribute, human growth hormone for any use in humans other than the treatment of a disease or other recognized medical condition, where such use has been authorized by the Secretary of Health and Human Services" has committed a felony. The Drug Enforcement Administration of the US Department of Justice considers off-label prescribing of HGH to be illegal, and to be a key path for illicit distribution of HGH. This section has also been interpreted by some doctors, most notably the authors of a commentary article published in the Journal of the American Medical Association in 2005, as meaning that prescribing HGH off-label may be considered illegal. And some articles in the popular press, such as those criticizing the pharmaceutical industry for marketing drugs for off-label use (which is clearly illegal) have made strong statements about whether doctors can prescribe HGH off-label: "Unlike other prescription drugs, HGH may be prescribed only for specific uses. U.S. sales are limited by law to treat a rare growth defect in children and a handful of uncommon conditions like short bowel syndrome or Prader-Willi syndrome, a congenital disease that causes reduced muscle tone and a lack of hormones in sex glands." At the same time, anti-aging clinics where doctors prescribe, administer, and sell HGH to people are big business. In a 2012 article in Vanity Fair, when asked how HGH prescriptions far exceed the number of adult patients estimated to have HGH-deficiency, Dragos Roman, who leads a team at the FDA that reviews drugs in endocrinology, said "The F.D.A. doesn't regulate off-label uses of H.G.H. Sometimes it's used appropriately. Sometimes it's not." ## Side-effects Injection-site reaction is common. More rarely, patients can experience joint swelling, joint pain, carpal tunnel syndrome, and an increased risk of diabetes. In some cases, the patient can produce an immune response against GH. GH may also be a risk factor for Hodgkin's lymphoma. One survey of adults that had been treated with replacement cadaver GH (which has not been used anywhere in the world since 1985) during childhood showed a mildly increased incidence of colon cancer and prostate cancer, but linkage with the GH treatment was not established. # Performance enhancement The first description of the use of GH as a doping agent was Dan Duchaine's "Underground Steroid handbook" which emerged from California in 1982; it is not known where and when GH was first used this way. Athletes in many sports have used human growth hormone in order to attempt to enhance their athletic performance. Some recent studies have not been able to support claims that human growth hormone can improve the athletic performance of professional male athletes. Many athletic societies ban the use of GH and will issue sanctions against athletes who are caught using it. However, because GH is a potent endogenous protein, it is very difficult to detect GH doping. In the United States, GH is legally available only by prescription from a medical doctor. # Dietary supplements To capitalize on the idea that GH might be useful to combat aging, companies selling dietary supplements have websites selling products linked to GH in the advertising text, with medical-sounding names described as "HGH Releasers". Typical ingredients include amino acids, minerals, vitamins, and/or herbal extracts, the combination of which are described as causing the body to make more GH with corresponding beneficial effects. In the United States, because these products are marketed as dietary supplements it is illegal for them to contain GH, which is a drug. Also, under United States law, products sold as dietary supplements cannot have claims that the supplement treats or prevents any disease or condition, and the advertising material must contain a statement that the health claims are not approved by the FDA. The FTC and the FDA do enforce the law when they become aware of violations. # Agricultural use In the United States, it is legal to give a bovine GH to dairy cows to increase milk production, and is legal to use GH in raising cows for beef; see article on Bovine somatotropin, cattle feeding, dairy farming and the beef hormone controversy. The use of GH in poultry farming is illegal in the United States. Similarly, no chicken meat for sale in Australia is administered hormones. Several companies have attempted to have a version of GH for use in pigs (porcine somatotropin) approved by the FDA but all applications have been withdrawn. # Drug development history The identification, purification and later synthesis of growth hormone is associated with Choh Hao Li. Genentech pioneered the first use of recombinant human growth hormone for human therapy in 1981. Prior to its production by recombinant DNA technology, growth hormone used to treat deficiencies was extracted from the pituitary glands of cadavers. Attempts to create a wholly synthetic HGH failed. Limited supplies of HGH resulted in the restriction of HGH therapy to the treatment of idiopathic short stature. Very limited clinical studies of growth hormone derived from an Old World monkey, the rhesus macaque, were conducted by John C. Beck and colleagues in Montreal, in the late 1950s. The study published in 1957, which was conducted on "a 13-year-old male with well-documented hypopituitarism secondary to a crainiophyaryngioma," found that: "Human and monkey growth hormone resulted in a significant enhancement of nitrogen storage ... (and) there was a retention of potassium, phosphorus, calcium, and sodium. ... There was a gain in body weight during both periods. ... There was a significant increase in urinary excretion of aldosterone during both periods of administration of growth hormone. This was most marked with the human growth hormone. ... Impairment of the glucose tolerance curve was evident after 10 days of administration of the human growth hormone. No change in glucose tolerance was demonstrable on the fifth day of administration of monkey growth hormone." The other study, published in 1958, was conducted on six people: the same subject as the Science paper; an 18-year-old male with statural and sexual retardation and a skeletal age of between 13 and 14 years; a 15-year-old female with well-documented hypopituitarism secondary to a craniopharyngioma; a 53-year-old female with carcinoma of the breast and widespread skeletal metastases; a 68-year-old female with advanced postmenopausal osteoporosis; and a healthy 24-year-old medical student without any clinical or laboratory evidence of systemic disease. In 1985, unusual cases of Creutzfeldt–Jakob disease were found in individuals that had received cadaver-derived HGH ten to fifteen years previously. Based on the assumption that infectious prions causing the disease were transferred along with the cadaver-derived HGH, cadaver-derived HGH was removed from the market. In 1985, biosynthetic human growth hormone replaced pituitary-derived human growth hormone for therapeutic use in the U.S. and elsewhere. As of 2005, recombinant growth hormones available in the United States (and their manufacturers) included Nutropin (Genentech), Humatrope (Lilly), Genotropin (Pfizer), Norditropin (Novo), and Saizen (Merck Serono). In 2006, the U.S. Food and Drug Administration (FDA) approved a version of rHGH called Omnitrope (Sandoz). A sustained-release form of growth hormone, Nutropin Depot (Genentech and Alkermes) was approved by the FDA in 1999, allowing for fewer injections (every 2 or 4 weeks instead of daily); however, the product was discontinued by Genentech/Alkermes in 2004 for financial reasons (Nutropin Depot required significantly more resources to produce than the rest of the Nutropin line).

Adaptive behavior # Overview Adaptive behavior is a type of behavior that is used to adapt to another type of behavior or situation. This is often characterized by a kind of behavior that allows an individual to substitute an unconstructive or disruptive behavior to something more constructive. These behaviors are most often social or personal behaviors. For example a constant repetitive action could be re-focused on something that creates or builds something. In other words the behavior can be adapted to something else. A maladaptive behavior is a behavior or trait that is not adaptive — it is counterproductive to the individual. Maladaptivity is frequently used as an indicator of abnormality or mental dysfunction, since its assessment is relatively free from subjectivity. However, many behaviors considered moral can be apparently maladaptive, such as dissent or abstinence. # Scope (General Definition) The William Heward book Exceptional Children defines adaptive behavior, as the effectiveness or degree with which the individual meets the standards of personal independence and social responsibility expected of his age and social group (Heward). Adaptive behavior also refers to the typical performance of individuals without disabilities in meeting environmental expectations. Adaptive behavior changes according to a person’s age, cultural expectations, and environmental demands! # Determination ## Behavior scales To determine a student’s adaptive behavior capacities, professionals focus on the student’s conceptual skills, social skills, and practical skills. To measure adaptive skills, professionals use adaptive behavior scales that have been normed on individuals with and without disabilities. Most adaptive behavior scales are completed by interviewing a parent, a teacher, or another individual who are familiar with the student’s daily activities. Students may have a combination of strengths and needs in any or all of the areas regarding conceptual, social and practical skills. # Specialized behavior ## Tendencies The adaptive skills exhibited by a person with mental retardation are critical factors in determining the supports he/she requires for success in school, work, community, and home environments. Children with mental retardation tend to have substantial deficits in adaptive behavior. These limitations can take many forms and tend to occur across domains of functioning. Limitations in self-care skills and social relationships, as well as behavioral excesses are common characteristics of individuals with mental retardation. Individuals with mental retardation who require extensive supports are often taught basic self care skills such as dressing, eating, and hygiene (Heward). Direct instruction and environmental supports, such as added prompts and simplified routines are necessary to ensure that deficits in these adaptive areas do not come to seriously limit one’s quality of life (Heward). ## Lifestyle Most children with milder forms of mental retardation learn how to take care of their basic needs, but they often require training in self- management skills to achieve the levels of performance necessary for eventual independent living. Making and sustaining friendships and personal relationships present significant challenges for many persons with mental retardation. Limited cognitive processing skills, poor language development, and unusual or inappropriate behaviors can seriously impede interacting with others. Teaching students with mental retardation appropriate social and interpersonal skills is one of the most important functions of special education. Students with mental retardation more often exhibit behavior problems than children without disabilities (Heward). Some of the behaviors observed by students with mental retardation are difficulties accepting criticism, limited self control, and bizarre and inappropriate behaviors. Depending on the severity of the mental retardation generally there is a higher the incidence of behavior problems (Heward).

Butorphanol Injection (patient information) # About your treatment Your doctor has ordered butorphanol, an analgesic (painkiller), to relieve your pain. The drug will be injected into a large muscle (such as your buttock or hip) or a vein. You will probably receive butorphanol every 3 to 4 hours as needed for pain. Your doctor may also order other pain medications to make you more comfortable. This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. Your health care provider (doctor, nurse, or pharmacist) may measure the effectiveness and side effects of your treatment using laboratory tests and physical examinations. It is important to keep all appointments with your doctor and the laboratory. The length of treatment depends on how you respond to the medication. # Precautions Before administering butorphanol: - tell your doctor and pharmacist if you are allergic to butorphanol or any other drugs. - tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially antidepressants; medications for cough, cold, or allergies; naloxone (Narcan); naltrexone (ReVia); other pain relievers; sedatives; sleeping pills; tranquilizers; and vitamins. - tell your doctor if you have or have ever had breathing difficulties including asthma and other respiratory diseases, liver or kidney disease, severe inflammatory bowel disease, or a history of drug dependence. - tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking butorphanol, call your doctor. - if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking butorphanol. - you should know that this drug may make you drowsy. Do not drive a car or operate machinery until you know how butorphanol will affect you. - remember that alcohol can add to the drowsiness caused by this drug. # Administering your medication Before you administer butorphanol, look at the solution closely. It should be clear and free of floating material. Observe the solution container to make sure there are no leaks. Do not use the solution if it is discolored, if it contains particles, or if the container leaks. Use a new solution, but show the damaged one to your health care provider. It is important that you use your medication exactly as directed. Butorphanol can be habit forming. Do not administer it more often or for a longer period than your doctor tells you. Do not change your dosing schedule without talking to your health care provider. # Side effects ## Minor side effects Butorphanol may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away: - upset stomach - vomiting - dry mouth - stomach pain - dizziness - lightheadedness - drowsiness - headache - difficulty sleeping - constipation - itchy skin - unpleasant taste - confusion or hallucinations - unusual weakness - nervousness, anxiety, or agitation ## Severe side effects If you experience either of the following symptoms, call your doctor immediately: - difficulty breathing - fainting If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online or by phone . # Storing your medication Your health care provider will probably give you a several-day supply of butorphanol at a time and provide you with directions on how to prepare each dose. Store the vials at room temperature. Store your medication only as directed. Make sure you understand what you need to store your medication properly. Keep your supplies in a clean, dry place when you are not using them, and keep all medications and supplies out of the reach of children. Your health care provider will tell you how to throw away used needles, syringes, tubing, and containers to avoid accidental injury. # Signs of infection If you are receiving butorphanol in your vein or under your skin, you need to know the symptoms of a catheter-related infection (an infection where the needle enters your vein or skin). If you experience any of these effects near your intravenous catheter, tell your health care provider as soon as possible: - tenderness - warmth - irritation - drainage - redness - swelling - pain # Brand names - Stadol® - Stadol® NS®

Chiropractic - Economics Chiropractic Main Article Chiropractic is the largest alternative medical profession in the U.S. and is the 3rd largest doctoral profession behind only medicine and dentistry in North America. # Utilization and satisfaction rates The percentage of population that utilize chiropractic care at any given time generally fall into a range from 6% to 12% in the U.S. and Canada, with a global high of 20% in Alberta. The vast majority who seek chiropractic care do so for relief from back and neck pain and other neuromusculoskeletal complaints; most do so specifically for low back pain. Complementary and alternative medicine (CAM) practitioners such as chiropractors are often used as a complementary form of care to primary medical intervention. Satisfaction rates are typically higher for chiropractic care compared to medical care, with quality of communication seeming to be a consistent predictor of patient satisfaction with chiropractors. Despite high patient satisfaction scores, utilization of chiropractic care is sensitive to the costs incurred by the co-payment by the patient. The use of chiropractic is growing modestly; CAM as a whole is seeing wholesale increases. Employment of U.S. chiropractors is expected to increase 14% between 2006 and 2016, faster than the average for all occupations. A 2008 survey stated that 69% of DC chiropractors disagree with the categorization of chiropractic as CAM, with 27% having some preference for the term "integrated medicine." # Cost-effectiveness A 2006 qualitative review found that the research literature suggests that chiropractic obtains at least comparable outcomes to alternatives with potential cost savings. A 2006 UK systematic cost-effectiveness review found that the reported cost-effectiveness of chiropractic manipulation compares favorably with other treatments for back pain, but that reports are based on data from clinical trials without sham controls and that the specific cost-effectiveness of the treatment (as opposed to non-specific effects) remains uncertain. A 2005 systematic review of economic evaluations of conservative treatments for low back pain found that significant quality problems in available studies meant that definite conclusions could not be drawn about the most cost-effective intervention. The cost-effectiveness of maintenance chiropractic care is unknown.

Irreversible electroporation for primary liver cancer Evidence-based recommendations on irreversible electroporation for primary liver cancer in adults. This involves passing short electrical pulses of high-voltage current into the cancer cells. # Recommendations Evidence on the safety of irreversible electroporation for primary liver cancer shows serious but infrequent and well-recognised complications. Evidence on its efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. Patient selection should be done by a multidisciplinary team. The procedure should only be done in specialist centres by clinicians with experience and specific training. Further research could be in the form of case series or registry-based research. It should include: details of patient selection; tumour position and size; long-term outcomes including overall survival, progression-free survival and tumour regression; and patient-reported outcomes including quality of life.# The condition, current treatments and procedure # The condition The most common primary liver cancers are hepatocellular carcinoma and cholangiocarcinoma. # Current treatments Treatment for primary liver cancer depends on several factors, including the exact location and stage of the cancer, the patient's liver function and any patient-related comorbidities. For most patients, treatment with curative intent is not possible. The treatment options include surgical excision, chemotherapy (either systemic or local hepatic artery infusion), transarterial chemoembolisation, percutaneous ethanol injection, and thermal ablation techniques such as cryotherapy, radiofrequency and microwave ablation. Liver transplantation (with curative intent) may be appropriate for some patients. # The procedure The aim of irreversible electroporation (IRE) is to destroy cancerous cells by subjecting them to short pulses of high-voltage direct current. This creates multiple holes in the cell membrane, irreversibly damaging the cell's homeostasis mechanisms and leading to cell death. IRE for primary liver cancer is done with the patient under general anaesthesia. A neuromuscular blocking agent is used to prevent muscle spasms. Needle-like electrodes are introduced percutaneously into the tumour under imaging guidance (either CT or, less commonly, ultrasound). The distance between the electrodes is confirmed by imaging. This is to ensure that the electrodes are correctly placed parallel to each other, and that enough current flow would be generated to ensure IRE. The procedure may also be done through an open surgical or laparoscopic approach, although the percutaneous route is the most common. Electrodes are repositioned under imaging guidance to extend the zone of electroporation until the entire tumour and an appropriate margin have been ablated. The number of ablations is determined by the volume of the target tumour. When the ablation procedure is completed, further imaging may be done to confirm the extent of the ablation.

Semantic memory # Overview Semantic memory refers to the memory of meanings, understandings, and other concept-based knowledge unrelated to specific experiences. The conscious recollection of factual information and general knowledge about the world, generally thought to be independent of context and personal relevance. Semantic and episodic memory together make up the category of declarative memory, which is one of the two major divisions in memory. The counterpart to declarative, or explicit memory, is procedural memory, or implicit memory. Semantic memory includes generalized knowledge that does not involve memory of a specific event. For instance, you can answer a question like "Are wrenches pets or tools?" without remembering any specific event in which you learned that wrenches are tools. # History The notion of semantic memory was first introduced following a conference in 1972 between Endel Tulving, of the University of Toronto, and W. Donaldson on the role of organization in human memory. Tulving constructed a proposal to distinguish between episodic memory and what he termed semantic memory. He was mainly influenced by the ideas of Reiff and Scheers, who in 1959 made the distinction between two primary forms of memory. One form titled remembrances and the other memoria. The remembrance concept dealt with memories that contained the experiences of an autobiographic index, whereas the memoria’ concept dealt with those memories without the experiences of an autobiographic index. Semantic memory was to reflect our knowledge of the world around us. It holds generic information that is more than likely acquired across various contexts and is able to be used across different situations. According to Madigan in his book titled Memory, semantic memory is the sum of all knowledge you have obtained- whether it be your vocabulary, understanding of math, and all the facts you know. The use of semantic memory is quite different from that of episodic memory. Semantic memory refers to general facts and meanings we share with others whereas episodic memory refers to unique and concrete personal experiences. Tulving's proposal of this distinction between semantic and episodic memory was widely accepted mainly because it allowed the separate conceptualization of knowledge of the world. Tulving discusses these separate systems of conceptualization of episodic and semantic memory in his book titled Elements of Episodic Memory. He states that both episodic and semantic memory differ in regards to several factors including:1)the characteristics of their operations, 2) the kind of information they process, and 3) their application to the real world as well as the memory laboratory. Before this proposal by Tulving this area of human memory had been neglected by experimental psychologists. A number of experimenters have conducted tests to determine the validity of Tulving’s hypothesized distinction of episodic and semantic memory. # Empirical evidence ## Kihlstrom (1980)- Experiment 1 In this study four groups of University students, varying in their levels of hypnotic susceptibility, were hypnotized. While under hypnosis they learned a list of 16 common words using a multi-trial free recall method. Once the subjects were able to perfectly recall the list twice in succession they were told that after awakening they would not remember having learned any of the words while under hypnosis. However, given the signal of the experimenter not only will they remember having learned the words but they will also remember the words from the list. During stage one of the experiment (after subjects were awakened) the number of words recalled by the subjects were used as a measure of performance for the episodic task of free recall. Most subjects remembered learning the list of words. During the second stage the measure of semantic memory performance was assessed. Each subject was given a semantic free association test (where stimulus words were given to elicit the learned words). As mentioned previously, the subjects represented various levels of hypnotic susceptibility as determined by their scores on the Stanford Hypnotic Susceptibility Scale. They were grouped according to their score. The semantic free association probabilities were relatively the same across various hypnotized groups. However the episodic free recall probabilities were significantly different across the groups. The percentage increased as the hypnotizability of subjects decreased. The subjects in the very high susceptibility group recalled almost nothing, whereas the medium and low groups recalled 86% of the learned words. Because the free association test was not related to the hypnotic susceptibility of the subjects shows that amnesia presented after hypnosis determined the memory for the word-events that occurred in the study phase. This study provides evidence that supports the episodic/semantic distinction hypothesized by Tulving. ## Jacob and Dallas (1981) This study was not created to solely provide evidence for the distinction of semantic and episodic memory stores. However, they did use the experimental dissociation method which provides evidence for Tulving’s hypothesis. Part one Subjects were presented with 60 words (one at a time) and were asked different questions. - Some questions asked were to cause the subject to pay attention to the visual appearance: Is the word typed in bold letters? - Some questions caused the participants to pay attention to the sound of the word: Does the word rhyme with ball? - Some questions caused the subjects to pay attention to the meaning of the word: Does the word refer to a form of communication? - Half of the questions were “no” answers and the other half “yes” Part Two In the second phase of the experiment 60 “old words”- seen in stage one and “20 new words” not shown in stage one were presented to the subjects one at a time. The subjects were given one of two tasks: - Perceptual Identification task (semantic): The words were flashed on a video-screen for 35ms and the subjects were required to say what the word was. - Episodic Recognition Task: Subjects were presented with each word and had to decide whether they had seen the word in the previous stage of the experiment. Results: - The percentages correct in the Semantic task (perceptual identification) did not change with the encoding conditions of appearance, sound, or meaning. - The percentages for the episodic task increased from the appearance condition (.50), to the sound condition (.63), to the meaning condition (.86). - The effect was also greater for the “yes” encoding words than the “no” encoding words. (see stage one) Conclusion: It displays a strong distinction of performance of episodic and semantic tasks, thus supporting Tulving’s hypothesis. # Models The essence of semantic memory is that its contents are not tied to any particular instance of experience, as in episodic memory. Instead, what is stored in semantic memory is the "gist" of experience, an abstract structure that applies to a wide variety of experiential objects and which may be said to delineate categorical and functional relationships between such objects. Thus, a complete theory of semantic memory must account not only for the representational structure of such "gists", but also for how they can be extracted from experience. Numerous models of semantic memory have been proposed; they are summarized below. ## Network models Networks of various sorts play an integral part in many theories of semantic memory. Generally speaking, a network is composed of a set of nodes connected by links. The nodes may represent concepts, words, perceptual features, or nothing at all. The links may be weighted such that some are stronger than others or, equivalently, have a length such that some links take longer to traverse than others. All these features of networks have been employed in models of semantic memory, examples of which are found below. ### Teachable Language Comprehender (TLC) One of the first examples of a network model of semantic memory is the Teachable Language Comprehender (TLC). In this model, each node is a word, representing a concept (like "Bird"). With each node is stored a set of properties (like "can fly" or "has wings") as well as pointers (i.e., links) to other nodes (like "Chicken"). A node is directly linked to those nodes of which it is either a subclass or superclass (i.e., "Bird" would be connected to both "Chicken" and "Animal"). Thus, TLC is a hierarchical knowledge representation in that high-level nodes representing large categories are connected (directly or indirectly, via the nodes of subclasses) to many instances of those categories, whereas nodes representing specific instances are at a lower level, connected only to their superclasses. Furthermore, properties are stored at the highest category level to which they apply. For example, "is yellow" would be stored with "Canary", "has wings" would be stored with "Bird" (one level up), and "can move" would be stored with "Animal" (another level up). Nodes may also store negations of the properties of their superordinate nodes (i.e., "NOT-can fly" would be stored with "penguin"). This provides an economy of representation in that properties are only stored at the category level at which they become essential, that is, at which point they become critical features (see below). Processing in TLC is a form of spreading activation. That is, when a node becomes active, that activation spreads to other nodes via the links between them. In that case, the time to answer the question "Is a chicken a bird?" is a function of how far the activation between the nodes for "Chicken" and "Bird" must spread, i.e., the number of links between the nodes "Chicken" and "Bird". The original version of TLC did not put weights on the links between nodes. This version performed comparably to humans in many tasks, but failed to predict that people would respond faster to questions regarding more typical category instances than those involving less typical instances. Collins and Quillian later updated TLC to include weighted connections to account for this effect. This updated TLC is capable of explaining both the familiarity effect and the typicality effect. Its biggest advantage is that it clearly explains priming: you are more likely to retrieve information from memory if related information (the "prime") has been presented a short time before. There are still a number of memory phenomena for which TLC has no account, including why people are able to respond quickly to obviously false questions (like "is a chicken a meteor?"), when the relevant nodes are very far apart in the network. ### Semantic networks TLC is an instance of a more general class of models known as semantic networks. In a semantic network, each node is to be interpreted as representing a specific concept, word, or feature. That is, each node is a symbol. Semantic networks generally do not employ distributed representations for concepts, as may be found in a neural network. The defining feature of a semantic network is that its links are almost always directed (that is, they only point in one direction, from a base to a target) and the links come in many different types, each one standing for a particular relationship that can hold between any two nodes. Processing in a semantic network often takes the form of spreading activation (see above). Semantic networks see the most use in models of discourse and logical comprehension, as well as in Artificial Intelligence. In these models, the nodes correspond to words or word stems and the links represent syntactic relations between them. For an example of a computational implementation of semantic networks in knowledge representation, see Cravo and Martins (1993). ## Feature models One may view semantic categories as being composed of relatively unstructured sets of features. The semantic feature-comparison model, proposed by Smith, Shoben, and Rips (1974), describes memory as being composed of feature lists for different concepts. According to this view, the relations between categories would not be directly retrieved, they would be indirectly computed. For example, subjects might verify a sentence by comparing the feature sets that represent its subject and predicate concepts. Such computational feature-comparison models include the ones proposed by Meyer (1970), Rips (1975), Smith, et al. (1974). Early work in perceptual and conceptual categorization assumed that categories had critical features and that category membership could be determined by logical rules for the combination of features. More recent theories have accepted that categories may have an ill-defined or "fuzzy" structure and have proposed probabilistic or global similarity models for the verification of category membership. ## Associative models The "association"—a relationship between two pieces of information—is a fundamental concept in psychology, and associations at various levels of mental representation are essential to models of memory and cognition in general. The set of associations among a collection of items in memory is equivalent to the links between nodes in a network, where each node corresponds to a unique item in memory. Indeed, neural networks and semantic networks may be characterized as associative models of cognition. However, associations are often more clearly represented as an NxN matrix, where N is the number of items in memory. Thus, each cell of the matrix corresponds to the strength of the association between the row item and the column item. Learning of associations is generally believed to be a Hebbian process; that is, whenever two items in memory are simultaneously active, the association between them grows stronger, and the more likely either item is to activate the other. See below for specific operationalizations of associative models. ### Search of Associative Memory (SAM) A standard model of memory that employs association in this manner is the Search of Associative Memory (SAM) model. Though SAM was originally designed to model episodic memory, it's mechanisms are sufficient to support some semantic memory representations, as well. In SAM, when any two items simultaneously occupy a working memory buffer, the strength of their association is incremented. Thus, items that co-occur more often are more strongly associated. Items in SAM are also associated with a specific context, where the strength of that association determined by how long each item is present in a given context. In SAM, then, memories consist of a set of associations between items in memory and between items and contexts. The presence of a set of items and/or a context is more likely to evoke, then, some subset of the items in memory. The degree to which items evoke one another—either by virtue of their shared context or their co-occurrence—is an indication of the items’ semantic relatedness. ### ACT-R: a production system model The ACT (Adaptive Control of Thought) (and later ACT-R (Adaptive Control of Thought-Rational)) theory of cognition represents declarative memory (of which semantic memory is a part) with "chunks", which consist of a label, a set of defined relationships to other chunks (i.e., "this is a _", or "this has a _"), and any number of chunk-specific properties. Chunks, then, can be mapped as a semantic network, given that each node is a chunk with its unique properties, and each link is the chunk’s relationship to another chunk. In ACT, a chunk’s activation decreases as a function of the time since the chunk was created and increases with the number of times the chunk has been retrieved from memory. Chunks can also receive activation from Gaussian noise, and from their similarity to other chunks. For example, if "chicken" is used as a retrieval cue, "canary" will receive activation by virtue of its similarity to the cue (i.e., both are birds, etc.). When retrieving items from memory, ACT looks at the most active chunk in memory; if it is above threshold, it is retrieved, otherwise an "error of omission" has occurred, i.e., the item has been forgotten. There is, additionally, a retrieval latency, which varies inversely with the amount by which the activation of the retrieved chunk exceeds the retrieval threshold. This latency is used in measuring the response time of the ACT model, to compare it to human performance. While ACT is a model of cognition in general, and not memory in particular, it nonetheless posits certain features of the structure of memory, as described above. In particular, ACT models memory as a set of related symbolic chunks which may be accessed by retrieval cues. While the model of memory employed in ACT is similar in some ways to a semantic network, the processing involved is more akin to an associative model. ## Statistical models Some models characterize the acquisition of semantic information as a form of statistical inference from a set of discrete experiences, distributed across a number of "contexts". Though these models differ in specifics, they generally employ an (Item x Context) matrix where each cell represents the number of times an item in memory has occurred in a given context. Semantic information is gleaned by performing a statistical analysis of this matrix. Many of these models bear similarity to the algorithms used in search engines (for example, see Griffiths, et al., 2007 and Anderson, 1990), though it is not yet clear whether they really use the same computational mechanisms. ### Latent Semantic Analysis (LSA) Perhaps the most popular of these models is Latent Semantic Analysis (LSA). In LSA, a T x D matrix is constructed from a text corpus where T is the number of terms in the corpus and D is the number of documents (here "context" is interpreted as "document" and only words--or word phrases--are considered as items in memory). Each cell in the matrix is then transformed according to the equation: \mathbf{M}_{t,d}'=\frac{\ln{(1 + \mathbf{M}_{t,d})}}{-\sum_{i=0}^D P(i|t) \ln{P(i|t)}} where P(i|t) is the probability that context i is active, given that item t has occurred (this is obtained simply by dividing the raw frequency, \mathbf{M}_{t,d} by the total of the item vector, \sum_{i=0}^D \mathbf{M}_{t,i}). This transformation--applying the logarithm, then dividing by the entropy of the item over all contexts--provides for greater differentiation between items and effectively weights items by their ability to predict context, and vice versa (that is, items that appear across many contexts, like "the" or "and", will be weighted less, reflecting their lack of semantic information). A Singular Value Decomposition (SVD) is then performed on the matrix \mathbf{M}', which allows the number of dimensions in the matrix to be reduced, thus clustering LSA's semantic representations and providing for indirect association between items. For example, "cat" and "dog" may never appear together in the same context, so their close semantic relationship may not be well-captured by LSA's original matrix \mathbf{M}. However, by performing the SVD and reducing the number of dimensions in the matrix, the context vectors of "cat" and "dog"--which would be very similar--would migrate toward one another and perhaps merge, thus allowing "cat" and "dog" to act as retrieval cues for each other, even though they may never have co-occurred. The degree of semantic relatedness of items in memory is given by the cosine of the angle between the items' context vectors (ranging from 1 for perfect synonyms to 0 for no relationship). Essentially, then, two words are closely semantically related if they appear in similar types of documents. ### Hyperspace Analogue to Language (HAL) The Hyperspace Analogue to Language (HAL) model considers context only as the words that immediately surround a given word. HAL computes an NxN matrix, where N is the number of words in its lexicon, using a 10-word reading frame that moves incrementally through a corpus of text. Like in SAM (see above), any time two words are simultaneously in the frame, the association between them is increased, that is, the corresponding cell in the NxN matrix is incremented. The amount by which the association is incremented varies inversely with the distance between the two words in the frame (specifically, \Delta=11-d, where d is the distance between the two words in the frame). As in LSA (see above), the semantic similarity between two words is given by the cosine of the angle between their vectors (dimension reduction may be performed on this matrix, as well). In HAL, then, two words are semantically related if they tend to appear with the same words. Note that this may hold true even when the words being compared never actually co-occur (i.e., "chicken" and "canary"). # Location of semantic memory in the brain The cognitive neuroscience of semantic memory is a somewhat controversial issue with two dominant views. On the one hand, many researchers and clinicians believe that semantic memory is stored by the same brain systems involved in episodic memory. These include the medial temporal lobes (MTL) and hippocampal formation. In this system, the hippocampal formation "encodes" memories, or makes it possible for memories to form at all, and the cortex stores memories after the initial encoding process is completed. Recently, new evidence has been presented in support of a more precise interpretation of this hypothesis. The hippocampal formation includes, among other structures: the hippocampus itself, the entorhinal cortex, and the perirhinal cortex. These latter two make up the "parahippocampal cortices". Amnesics with damage to the hippocampus but some spared parahippocampal cortex were able to demonstrate some degree of intact semantic memory despite a total loss of episodic memory. This strongly suggests that encoding of information leading to semantic memory does not have its physiological basis in the hippocampus. (Vargha-Khadem et al.) Other researchers believe the hippocampus is only involved in episodic memory and spatial cognition. This then raises the question where semantic memory may be located. Some believe semantic memory lives in temporal neocortex. Others believe that semantic knowledge is widely distributed across all brain areas. To illustrate this latter view, consider your knowledge of dogs. Researchers holding the 'distributed semantic knowledge' view believe that your knowledge of the sound a dog makes exists in your auditory cortex, whilst your ability to recognize and imagine the visual features of a dog resides in your visual cortex. Perhaps all these representations are indexed by the left temporal pole, a region particularly vulnerable to damage in semantic dementia. # Neural correlates and biological workings The hippocampal areas are important to semantic memory's involvement with declarative memory. The left inferior prefrontal cortex (PFC) and the left posterior temporal areas are other areas involved in semantic memory use. Temporal lobe damage affecting the lateral and medial cortexes have been related to semantic impairments. Damage to different areas of the brain affect semantic memory differently. A brain scan indicates that the left hippocampal areas show an increase in activity during use. During semantic retrieval, two regions in the right middle frontal gyrus and the area of the right inferior temporal gyrus similarly show an increase in activity. Damage to areas involved in semantic memory result in different effects, depending on the area and type of damage. For instance, Lambon, Lowe, & Rogers (2007) found that category specific impairments can occur where patients have different knowledge deficits for one semantic category over another, depending on location and type of damage. Category-specific impairments might indicate that knowledge may rely differentially upon sensory and motor properties encoded in separate areas (Farah and McClelland, 1991). Category-specific impairments can involve cortical regions where living and nonliving things are represented and where feature and conceptual relationships are represented. Depending on the damage to the semantic system, one type might be favored over the other. In many cases, there is a point where one domain is better than the other (ie - representation of living and nonliving things over feature and conceptual relationships or vice versa) Different diseases and disorders can affect the biological workings of semantic memory. A variety of studies have been done in an attempt to determine the effects on varying aspects of semantic memory. For example, Lambon, Lowe, & Rogers (2007) studied the different effects semantic dementia and herpes simplex virus encephalitis have on semantic memory. They found that semantic dementia has a more generalized semantic impairment. Additionally, deficits in semantic memory as a result of herpes simplex virus encephalitis tend to have more category-specific impairments. Other disorders that affect semantic memory - such as Alzheimer's disease - has been observed clinically as errors in naming, recognizing, or describing objects. Whereas researchers have attributed such impairment to degradation of semantic knowledge (Koenig et. al 2007). Various neural imaging and research points to semantic memory and episodic memory resulting from distinct areas in the brain. Still other research suggests that both semantic memory and episodic memory are part of a singular declarative memory system, yet represent different sectors and parts within the greater whole. Different areas within the brain are activated depending on whether semantic or episodic memory is accessed. Certain experts are still arguing whether or not the two types of memory are from distinct systems or whether the neural imaging makes it appear that way as a result of the activation of different mental processes during retrieval. # Disorders In order to understand semantic memory disorders, one must first understand how these disorders affect memory. Semantic memory disorders fractionate into two categories. Semantic category specific impairments and modality specific impairments are apparent in disorders of semantic memory. Understanding these types of impairments will give insight into how disorders of semantic memory function. ## Semantic category specific impairments Category specific impairments can result in widespread, patchy damage or localized damage. Category specific impairments can be broken down into four categories. Perceptual and functional features, topographic organization, informativeness and intercorrelations are areas of decreased functioning in disorders of semantic memory (Warrington and Shallice, 1984). Alzheimer's disease is a semantic memory disorder characterized by category specific impairments. Alzheimer's disease results in naming errors as well as errors describing and naming objects.Semantic dementia is another disorder associated with semantic memory. Semantic dementia is a language disorder characterized by a deterioration in understanding and recognizing words. Impairments include difficulty in generating familiar words, difficulty naming objects and difficulties with visual recognition. Research suggests that the temporal lobe might be responsible for category specific impairments of semantic memory disorders. In addition to category specific impairments, modality specific impairments are included in disorders of semantic memory (Cohen et al. 2002). ## Modality specific impairments Semantic memory is also discussed in reference to modality. Different components represent information from different sensorimotor channels. Modality specific impairments are divided into separate subsystems on the basis of input modality. Examples of different input modalities include visual, auditory and tactile input. Modality specific impairments are also divided into subsystems based on the type of information. Visual vs. verbal and perceptual vs. functional information are examples of information types. Modality specificity can account for category specific impairments in semantic memory disorders. Damage to visual semantics primarily impairs knowledge of living things, and damage to functional semantics primarily impairs knowledge of nonliving things. ## Semantic refractory access and semantic storage disorders Semantic memory disorders fall into two groups. Semantic refractory access disorders are contrasted with semantic storage disorders according to four factors. Temporal factors, response consistency, frequency and semantic relatedness are the four factors used to differentiate between semantic refractory access and semantic storage disorders. A key feature of semantic refractory access disorders is temporal distortions. Decreases in response time to certain stimuli are noted when compared to natural response times. Response consistency is the next factor. In access disorders you see inconsistencies in comprehending and responding to stimuli that have been presented many times. Temporal factors impact response consistency. In storage disorders, you do not see an inconsistent response to specific items like you do in refractory access disorders. Stimulus frequency determines performance at all stages of cognition. Extreme word frequency effects are common in semantic storage disorders while in semantic refractory access disorders word frequency effects are minimal. The comparison of 'close' and 'distant' groups tests semantic relatedness. 'Close' groupings have words that are related because they are drawn from the same category. For example, a listing of clothing types would be a 'close' grouping. 'Distant' groupings contain words with broad categorical differences. Non-related words would fall into this group. Comparing close and distant groups shows that in access disorders semantic relatedness had a negative effect. This is not observed in semantic storage disorders. Category specific and modality specific impairments are important components in access and storage disorders of semantic memory. # Present and future research Semantic memory has had a comeback in interest in the past 15 years, due in part to the development of functional neuroimaging methods such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), which have been used to address some of the central questions about our understanding of semantic memory. Rather than any one brain region playing a dedicated and privileged role in the representation or retrieval of all sorts of semantic knowledge, semantic memory is a collection of functionally and anatomically distinct systems, where each attribute-specific system is tied to a sensorimotor modality (i.e. vision) and even more specifically to a property within that modality (i.e. color). Neuroimaging studies also suggest a distinction between semantic processing and sensorimotor processing. A new idea that is still at the early stages of development is that semantic memory, like perception, can be subdivided into types of visual information – color, size, form, and motion. Thompson-Schill (2003) found that the left or bilateral ventral temporal cortex appears to be involved in retrieval of knowledge of color and form, the left lateral temporal cortex in knowledge of motion, and the parietal cortex in knowledge of size. Neuroimaging studies suggest a large, distributed network of semantic representations that are organized minimally by attribute, and perhaps additionally by category. These networks include "extensive regions of ventral (form and color knowledge) and lateral (motion knowledge) temporal cortex, parietal cortex (size knowledge), and premotor cortex (manipulation knowledge). Other areas, such as more anterior regions of temporal cortex, may be involved in the representation of nonperceptual (e.g. verbal) conceptual knowledge, perhaps in some categorically-organized fashion."

Standing gradient osmosis # Overview Water absorption at the colon typically proceeds against a transmucosal osmotic pressure gradient. The standing gradient osmosis is a term used to describe the reabsorption of water against the osmotic gradiet at the colon. This hypertonic fluid creates an osmotic pressure that drives water into the lateral intercellular spaces by osmosis via tight junctions and adjacent cells, which then in turn moves across the basement membrane and into the capillaries.

Dolutegravir # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Dolutegravir is a antiviral that is FDA approved for the treatment of HIV-1 infection. Common adverse reactions include hyperglycemia, increased serum lipase level, headache, insomnia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dolutegravir in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dolutegravir in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The recommended dose of Dolutegravir in pediatric patients aged 12 years and older and weighing at least 40 kg is 50 mg administered orally once daily. - If efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin are coadministered, the recommended dose of Dolutegravir is 50 mg twice daily. - Safety and efficacy of Dolutegravir have not been established in pediatric patients younger than 12 years or weighing less than 40 kg, or in pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir). ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dolutegravir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dolutegravir in pediatric patients. # Contraindications Dolutegravir is contraindicated in patients: - With previous hypersensitivity reaction to dolutegravir - Receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events. # Warnings - Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving Dolutegravir in Phase 3 clinical trials. Discontinue Dolutegravir and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with Dolutegravir or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. Dolutegravir is contraindicated in patients who have experienced a previous hypersensitivity reaction to dolutegravir. - Patients with underlying hepatitis B or hepatitis C may be at increased risk for worsening or development of transaminase elevations with use of Dolutegravir In some cases the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with Dolutegravir are recommended in patients with underlying hepatic disease such as hepatitis B or hepatitis C. - Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. - Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Dolutegravir During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia PCP, or tuberculosis), which may necessitate further evaluation and treatment. - Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment. # Adverse Reactions ## Clinical Trials Experience ### Treatment in Adult Subjects - The safety assessment of Dolutegravir in HIV‑1‑infected treatment-naïve subjects is based on the analyses of 96-week data from 2 international, multicenter, double-blind trials, SPRING-2 (ING113086) and SINGLE (ING114467) and 48-week data from the international, multicenter, open-label FLAMINGO (ING114915) trial. - In SPRING-2, 822 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) treatment (either abacavir sulfate and lamivudine or emtricitabine/tenofovir TRUVADA®). There were 808 subjects included in the efficacy and safety analyses. Through 96 weeks, the rate of adverse events leading to discontinuation was 2% in both treatment arms. - In SINGLE, 833 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg with fixed-dose abacavir sulfate and lamivudine (EPZICOM) once daily or fixed-dose efavirenz/emtricitabine/tenofovir once daily. Through 96 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving Dolutegravir 50 mg once daily + EPZICOM and 12% in subjects receiving once daily. - Treatment-emergent ADRs of moderate to severe intensity observed in at least 2% of subjects in either treatment arm in SPRING-2 and SINGLE trials are provided in Table 2. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. - In addition, Grade 1 insomnia was reported by 1% and less than 1% of subjects receiving Dolutegravir and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 4% for Dolutegravir and , respectively. These events were not treatment limiting. - In a multicenter, open-label trial (FLAMINGO), 243 subjects received Dolutegravir 50 mg once daily versus 242 subjects who received darunavir 800 mg/ritonavir 100 mg once daily, both in combination with investigator-selected NRTI background regimen (either EPZICOM or TRUVADA). There were 484 subjects included in the efficacy and safety analyses. Through 48 weeks, the rates of adverse events leading to discontinuation were 2% in subjects receiving Dolutegravir and 4% in subjects receiving darunavir/ritonavir. The ADRs observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE. - Treatment-experienced, Integrase Strand Transfer Inhibitor-naïve Subjects: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 HIV‑1‑infected, antiretroviral treatment-experienced adults were randomized and received either Dolutegravir 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving Dolutegravir 50 mg once daily + background regimen and 4% in subjects receiving raltegravir 400 mg twice daily + background regimen. - The only treatment-emergent ADR of moderate to severe intensity with at least 2% frequency in either treatment group was diarrhea, 2% (6 of 354) in subjects receiving Dolutegravir 50 mg once daily + background regimen and 1% (5 of 361) in subjects receiving raltegravir 400 mg twice daily + background regimen. - Treatment-experienced, Integrase Strand Transfer Inhibitor-experienced Subjects: In a multicenter, open-label, single-arm trial (ING112574, VIKING-3), 183 HIV‑1‑infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received Dolutegravir 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. The rate of adverse events leading to discontinuation was 4% of subjects at Week 48. - Treatment-emergent ADRs in VIKING-3 were generally similar compared with observations with the 50-mg once-daily dose in adult Phase 3 trials. The following ADRs occurred in less than 2% of treatment-naïve or treatment-experienced subjects receiving Dolutegravir in a combination regimen in any one trial. These events have been included because of their seriousness and assessment of potential causal relationship. - Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, vomiting. - General Disorders: Fatigue. - Hepatobiliary Disorders: Hepatitis. - Musculoskeletal Disorders: Myositis. - Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. - Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus. - Treatment-naïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects are presented in Table 3. The mean change from baseline observed for selected lipid values is presented in Table 4. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. - Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE. Treatment-experienced, Integrase Strand Transfer Inhibitor-naïve Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naïve (SPRING-2 and SINGLE) trials. - The most common treatment-emergent laboratory abnormalities (greater than 5% for Grades 2 to 4 combined) observed in VIKING-3 at Week 48 were elevated ALT (9%), AST (8%), cholesterol (10%), creatine kinase (6%), hyperglycemia (14%), and lipase (10%). Two percent (4 of 183) of subjects had a Grade 3 to 4 treatment-emergent hematology laboratory abnormality, with neutropenia (2% ) being the most frequently reported. - In Phase 3 trials, subjects with hepatitis B and/or hepatitis C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to that observed in subjects without hepatitis B or hepatitis C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or hepatitis C co-infected compared with HIV mono-infected subjects receiving Dolutegravir were observed in 18% vs. 3% with the 50-mg once-daily dose and 13% vs. 8% with the 50-mg twice-daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or hepatitis C at the start of therapy with Dolutegravir, particularly in the setting where anti-hepatitis therapy was withdrawn. - Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 48 to 96 weeks. In treatment-naïve subjects, a mean change from baseline of 0.15 mg per dL (range: -0.32 mg per dL to 0.65 mg per dL) was observed after 96 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment-experienced subjects. ### Clinical Trials Experience in Pediatric Subjects - IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of approximately 160 HIV‑1‑infected pediatric subjects aged 6 weeks to less than 18 years, of which 23 treatment-experienced, INSTI-naïve subjects aged 12 to less than 18 years were enrolled. - The adverse reaction profile was similar to that for adults. Grade 2 ADRs reported in at least 1 subject were rash (n = 1), abdominal pain (n = 1), and diarrhea (n = 1). No Grade 3 or 4 ADRs were reported. The Grade 3 laboratory abnormalities were elevated total bilirubin and lipase reported in 1 subject each. No Grade 4 laboratory abnormalities were reported. The changes in mean serum creatinine were similar to those observed in adults. ## Postmarketing Experience There is limited information regarding Dolutegravir Postmarketing Experience in the drug label. # Drug Interactions ### Effect of Dolutegravir on the Pharmacokinetics of Other Agents - In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC50 = 1.93 µM) and multidrug and toxin extrusion transporter (MATE) 1 (IC50 = 6.34 µM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin). In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 µM) and OAT3 (IC50 = 1.97 µM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3. - In vitro, dolutegravir did not inhibit (IC50 greater than 50 μM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1), UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters. - In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs: tenofovir, methadone, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol. Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, boceprevir, and telaprevir. ### Effect of Other Agents on the Pharmacokinetics of Dolutegravir - Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration. - Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, telaprevir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir. ### Established and Other Potentially Significant Drug Interactions - Table 5 provides clinical recommendations as a result of drug interactions with Dolutegravir These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and dolutegravir was shown to cross the placenta in animal studies, this drug should be used during pregnancy only if clearly needed. - To monitor maternal-fetal outcomes of pregnant women with HIV exposed to Dolutegravir and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. - Reproduction studies have been performed in rats and rabbits at doses up to 27 times the human dose of 50 mg twice daily and have revealed no evidence of impaired fertility or harm to the fetus due to Dolutegravir. - Oral administration of dolutegravir to pregnant rats at doses up to 1,000 mg per kg daily, approximately 27 times the 50-mg twice-daily human clinical exposure based on AUC, from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity, or teratogenicity. - Oral administration of dolutegravir to pregnant rabbits at doses up to 1,000 mg per kg daily, approximately 0.4 times the 50‑mg twice-daily human clinical exposure based on AUC, from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity. In rabbits, maternal toxicity (decreased food consumption, scant/no feces/urine, suppressed body weight gain) was observed at 1,000 mg per kg. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dolutegravir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dolutegravir during labor and delivery. ### Nursing Mothers - The Centers for Disease Control and Prevention recommend that HIV‑1‑infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Studies in lactating rats and their offspring indicate that dolutegravir was present in rat milk. It is not known whether dolutegravir is excreted in human milk. - Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, instruct mothers not to breastfeed. ### Pediatric Use - Safety and efficacy of Dolutegravir have not been established in pediatric patients younger than 12 years, weighing less than 40 kg, or in any pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir). - The safety, virologic, and immunologic responses in subjects who received Dolutegravir were evaluated in 23 treatment-experienced, INSTI-naïve, HIV‑1–infected subjects aged 12 to less than 18 years in an open-label, multicenter, dose-finding clinical trial, IMPAACT P1093. Pharmacokinetic parameters, evaluated in 9 subjects weighing at least 40 kg receiving 50 mg daily and 1 subject (weighing 37 kg) receiving 35 mg once daily, were similar to adults receiving 50 mg once daily. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults. ### Geriatic Use - Clinical trials of Dolutegravir did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of Dolutegravir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Dolutegravir with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dolutegravir with respect to specific racial populations. ### Renal Impairment - Dolutegravir plasma concentrations were decreased in subjects with severe renal impairment compared with those in matched healthy controls. However, no dosage adjustment is necessary for treatment-naïve or treatment-experienced and INSTI-naïve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to Dolutegravir or other coadministered antiretroviral agents. Dolutegravir has not been studied in patients on dialysis. ### Hepatic Impairment - No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, Dolutegravir is not recommended for use in patients with severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dolutegravir in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dolutegravir in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Dolutegravir Administration in the drug label. ### Monitoring There is limited information regarding Dolutegravir Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Dolutegravir and IV administrations. # Overdosage - There is no known specific treatment for overdose with Dolutegravir If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. # Pharmacology ## Mechanism of Action - Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM. ## Structure - The empirical formula is C20H18F2N3NaO5 and the molecular weight is 441.36 g per mol. It has the following structural formula: ## Pharmacodynamics - In a randomized, dose-ranging trial, HIV‑1‑infected subjects treated with dolutegravir monotherapy demonstrated rapid and dose-dependent antiviral activity with mean declines from baseline to Day 11 in HIV-1 RNA of 1.5, 2.0, and 2.5 log10 for dolutegravir 2 mg, 10 mg, and 50 mg once daily, respectively. This antiviral response was maintained for 3 to 4 days after the last dose in the 50-mg group. - In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3–fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours postdose. - The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3‑arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo. ## Pharmacokinetics - The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV‑1–infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV‑1–infected subjects. The non-linear exposure of dolutegravir following 50 mg twice daily compared with 50 mg once daily in HIV‑1–infected subjects (Table 6) was attributed to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir 50 mg twice daily in clinical trials. Dolutegravir was administered without regard to food in these trials. Table 6. Dolutegravir Steady-state Pharmacokinetic Parameter Estimates in HIV‑1–Infected Adults Parameter - Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24 h ranging from 1.2 to 1.5. - Dolutegravir plasma concentrations increased in a less than dose-proportional manner above 50 mg. Dolutegravir is a P‑gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established. - Dolutegravir may be taken with or without food. Food increased the extent of absorption and slowed the rate of absorption of dolutegravir. Low-, moderate-, and high-fat meals increased dolutegravir AUC(0-∞) by 33%, 41%, and 66%; increased Cmax by 46%, 52%, and 67%; and prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively. - Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis. - Cerebrospinal Fluid (CSF): In 12 treatment-naïve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 13.2 ng per mL (range: 3.74 ng per mL to 18.3 ng per mL) 2 to 6 hours postdose after 16 weeks of treatment. The clinical relevance of this finding has not been established. - Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After a single oral dose of dolutegravir, 53% of the total oral dose was excreted unchanged in feces. Thirty-one percent of the total oral dose was excreted in urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was low (less than 1% of the dose). - Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L per hour based on population pharmacokinetic analyses. - Polymorphisms in Drug‑metabolizing Enzymes: In a meta-analysis of healthy subject trials, subjects with UGT1A1 (n = 7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n = 41). ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg, and rats were administered doses of up to 50 mg per kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 14-fold higher than those in humans at the recommended dose of 50 mg twice daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 10-fold and 15-fold higher in males and females, respectively, than those in humans at the recommended dose of 50 mg twice daily. - Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay. - In a study conducted in rats, there were no effects on mating or fertility with dolutegravir up to 1,000 mg per kg per day. This dose is associated with an exposure that is approximately 24 times higher than the exposure in humans at the recommended dose of 50 mg twice daily. # Clinical Studies The efficacy of Dolutegravir is based on analyses of data from 3 trials, SPRING-2 (ING113086), SINGLE (ING114467), and FLAMINGO (ING114915), in treatment-naïve, HIV‑1‑infected subjects (n = 2,125); one trial, SAILING (ING111762), in treatment-experienced, INSTI-naïve HIV‑1‑infected subjects (n = 715); and from VIKING-3 (ING112574) trial in INSTI-experienced HIV‑1‑infected subjects (n = 183). The use of Dolutegravir in pediatric patients aged 12 years and older is based on evaluation of safety, pharmacokinetics, and efficacy through 24 weeks in a multicenter, open-label trial in subjects (n = 23) without INSTI resistance. ### Adult Subjects - In SPRING-2, 822 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual NRTI treatment (either abacavir sulfate and lamivudine EPZICOM or emtricitabine/tenofovir TRUVADA). There were 808 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 36 years, 13% female, 15% non-white, 11% had hepatitis B and/or hepatitis C virus co-infection, 2% were CDC Class C (AIDS), 28% had HIV-1 RNA greater than 100,000 copies per mL, 48% had CD4+ cell count less than 350 cells per mm3, and 39% received EPZICOM; these characteristics were similar between treatment groups. - In SINGLE, 833 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg once daily with fixed-dose abacavir sulfate and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir. At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis C co-infection (hepatitis B virus co-infection was excluded), 4% were CDC Class C (AIDS), 32% had HIV-1 RNA greater than 100,000 copies per mL, and 53% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups. Week 96 outcomes for SPRING-2 and SINGLE are provided in Table 12. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. - Virologic outcomes were also comparable across baseline characteristics including CD4+ cell count, age, and use of EPZICOM or TRUVADA as NRTI background regimen. The median change in CD4+ cell counts from baseline were 276 cells per mm3 in the group receiving Dolutegravir and 264 cells per mm3 for the raltegravir group at 96 weeks. - There was no treatment-emergent resistance to dolutegravir or to the NRTI background. - Treatment differences were maintained across baseline characteristics including CD4+ cell count, age, gender, and race. - The adjusted mean changes in CD4+ cell counts from baseline were 325 cells per mm3 in the group receiving Dolutegravir + EPZICOM and 281 cells per mm3 for the group at 96 weeks. The adjusted difference between treatment arms and 95% CI was 44.0 cells per mm3 (14.3 cells per mm3, 73.6 cells per mm3) (adjusted for pre-specified stratification factors: baseline HIV-1 RNA, baseline CD4+ cell count, and multiplicity). - There was no treatment-emergent resistance to dolutegravir, abacavir, or lamivudine. - In FLAMINGO, 485 subjects were randomized and received at least 1 dose of either Dolutegravir 50 mg once daily (n = 243) or darunavir + ritonavir 800 mg/100 mg once daily (n = 242), both in combination with investigator-selected NRTI background regimen (either fixed-dose abacavir and lamivudine or fixed-dose emtricitabine/tenofovir disoproxil fumarate ). There were 484 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 34 years, 15% female, 28% non-white, 10% had hepatitis B and/or C virus co-infection, 3% were CDC Class C (AIDS), 25% had HIV‑1 RNA greater than 100,000 copies per mL, and 35% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups. Overall response rates by Snapshot algorithm through Week 48 were 90% for Dolutegravir and 83% for darunavir/ritonavir. The adjusted difference in proportion and 95% CI was 7.1% (0.9%, 13.2%). No treatment-emergent primary resistance substitutions were observed in either treatment group. Treatment-experienced, Integrase Strand Transfer Inhibitor-naïve Subjects - In the international, multicenter, double-blind trial (SAILING), 719 HIV‑1‑ infected, antiretroviral treatment-experienced adults were randomized and received either Dolutegravir 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least 1 fully active agent. There were 715 subjects included in the efficacy and safety analyses. At baseline, the median age was 43 years, 32% were female, 50% non-white, 16% had hepatitis B and/or hepatitis C virus co-infection, 46% were CDC Class C (AIDS), 20% had HIV-1 RNA greater than 100,000 copies per mL, and 72% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups. All subjects had at least 2-class antiretroviral treatment resistance, and 49% of subjects had at least 3-class antiretroviral treatment resistance at baseline. Week 48 outcomes for SAILING are shown in Table 13. ### Treatment-experienced, Integrase Strand Transfer Inhibitor-experienced Subjects - VIKING-3 examined the effect of Dolutegravir 50 mg twice daily over 7 days of functional monotherapy, followed by optimized background therapy (OBT) with continued treatment of Dolutegravir 50 mg twice daily. - In the multicenter, open-label, single-arm VIKING-3 trial, 183 HIV‑1‑infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received Dolutegravir 50 mg twice daily with the current failing background regimen for 7 days, then received Dolutegravir with OBT from Day 8. A total of 183 subjects enrolled: 133 subjects with INSTI resistance at screening and 50 subjects with only historical evidence of resistance (and not at screening). At baseline, median age of subjects was 48 years; 23% were female, 29% non-white, and 20% had hepatitis B and/or hepatitis C virus co-infection. Median baseline CD4+ cell count was 140 cells per mm3, median duration of prior antiretroviral treatment was 13 years, and 56% were CDC Class C. Subjects showed multiple-class antiretroviral treatment resistance at baseline: 79% had greater than or equal to 2 NRTI, 75% greater than or equal to 1 NNRTI, and 71% greater than or equal to 2 PI major substitutions; 62% had non-R5 virus. - Mean reduction from baseline in HIV-1 RNA at Day 8 (primary endpoint) was 1.4 log10 (95% CI: 1.3 log10, 1.5 log10). Response at Week 48 was affected by baseline INSTI substitutions. - After the functional monotherapy phase, subjects had the opportunity to re-optimize their background regimen when possible. Week 48 virologic outcomes for VIKING-3 are shown in Table 14. # How Supplied - Dolutegravir Tablets, 50 mg, are yellow, round, film-coated, biconvex tablets debossed with SV 572 on one side and 50 on the other side. - Bottle of 30 tablets with child-resistant closure NDC 49702-228-13. ## Storage - Store at 25°C (77°F); excursions permitted 15° to 30°C (59° to 86°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Dolutegravir Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Dolutegravir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tivicay # Look-Alike Drug Names There is limited information regarding Dolutegravir Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

General guidelines on creating chapters and microchapters # Overview The following is a guide to creating your chapters and microchapters. A chapter is a collection of smaller chapters called microchapters. For instance, the disease pericarditis is a chapter composed of multiple microchapters such as pericarditis overview, pericarditis pathophysiology, pericarditis treatment etc. Microchapters have been created to allow users to access the content they are looking for more efficiently, and to improve the speed with which the chapters load and display on mobile devices. Please see the following chapters which are excellent examples of how create and structure chapters and microchapters: - Pericarditis # Grammar Consider substitution for overworked words and phrases with more specific terms such as those below: - About -> Regarding - Gave or Give -> Administer # Microchapter Guidelines - Goal: The purpose of the microchapter system is to structure each chapter under specific nomenclature so as to allow search engines to efficiently browse and tag the content. It is critical that every page maintain sitewide consistency or the microchapter system loses its efficacy. - All the microchapters should start with the same pagename. Examples include Pericarditis overview, Pericarditis pathophysiology, Pericarditis treatment etc. - Only the first word of each chapter is capitalized. - All the microchapters in the template on the right hand side should be present on the home page of the main chapter. - All microchapters should contain the template on the right-hand side. - The template is located here - It is not necessary to have a microchapter for every title listed in the template. When necessary, please delete irrelevant chapter titles from the microchapter template. Often there are no primary or secondary prevention strategies. For example, there is no primary prevention strategy for pericarditis. This link is therefore missing from the template. # The Navigation Box at the top of the Page - This navigation box appears only on the disease home page. - If the picture at the top is illustrative, you can retain it, or you can find a copyleft image that better illustrates the condition. - Remove the links to e medicine. # Synonyms and Keywords Use google to search for synonyms and use the another word for it website. This text is bolded and italicized. # Related Chapters - Do not use the phrase "see also". There tends to be confusion that the chapters you are linking to are the same or a similar topic. - For this reason we use the terminology "Related chapters:" # Appropriate Copyleft Sources - National Library of Medicine - Diseases Database - Centers for Disease Control - Clinfowiki: The Clinical Research Informatics Wiki - The Clinical Informatics Wiki - Consumer Health Information (Toronto Public Library) - Demystifying Depression # Patient information page # Overview - Goal: To provide a brief description of the high points of the condition, focused primarily on the background of diagnosis and treatment of the condition. This text will appear on all Google searches and must be perfected. The grammar must be perfect. - This text will appear on all Google searches and must be perfected. - The grammar must be perfect. - Appropriate content: There is an overview of the pathophysiology of the disease, the epidemiology and demographics, the common causes and prognosis of the disease. There is a summary of the diagnosis and treatment of the disease. (See Chronic stable angina overview.) # Historical Perspective - Goal: To provide background on the history of how the disease/condition was discovered and has been studied over time. - Appropriate content: Notable scientists who studied the condition Background on when the disease was first discovered Notable outbreaks or condition-specific events in history Landmark changes in approaches to studying the disease - Notable scientists who studied the condition - Background on when the disease was first discovered - Notable outbreaks or condition-specific events in history - Landmark changes in approaches to studying the disease - Remember: This is not the chapter for patient history or natural history. # Classification - Goal: To provide information on any condition-specific classification schema that may exist. - Appropriate content: Subclassifications within the condition. Ordinal levels of organizing the condition. (I.E. Severity of the disease) - Subclassifications within the condition. - Ordinal levels of organizing the condition. (I.E. Severity of the disease) - Remember: This is an optional microchapter and is not part of the initial microchapter template for this reason. Content must be substantial in itself to support creating an entire page on the classification scheme. # Pathophysiology - Goal: Explain the biologic mechanism underlying the disease state. - Appropriate content: A description of the embryological or developmental abnormalities, molecular abnormalities, genetic abnormalities, pathogenesis and pathology images May include information on overall classifications of the disease. I have searched for copyleft images of pathology specimens and videos on you tube. I have searched The Pathology Wiki and Ask Dr. Wiki for images. - May include information on overall classifications of the disease. - I have searched for copyleft images of pathology specimens and videos on you tube. - I have searched The Pathology Wiki and Ask Dr. Wiki for images. # Causes - Search the The Diseases Database to assure that the differential diagnosis is complete. - Be sure to select the option may be caused by or feature of +. - Goal: To provide a comprehensive list of all potential underlying causes of the condition as categorized by organ system. - Appropriate content: Common causes - Common causes - Complete differential diagnosis table, listed by organ system Differential diagnosis of causes of the disease, in alphabetical order - Complete differential diagnosis table, listed by organ system - Differential diagnosis of causes of the disease, in alphabetical order - Remember: This is not the chapter to describe what the disease causes. That is the chapter on natural history and complications. This is also not the chapter where guidance is provided how to distinguish the disorder from other disorders. That is the chapter on differentiating (the condition) from other diseases. DO NOT rename this section to be etiology. - This is also not the chapter where guidance is provided how to distinguish the disorder from other disorders. That is the chapter on differentiating (the condition) from other diseases. - DO NOT rename this section to be etiology. The code for the table below should be copied from below or the following page Differential_diagnosis_by_organ_system_table: ## Complete Differential Diagnosis of the Causes of ... (By organ system) # Differentiating PAGENAME from other diseases - Search the the diseases database to assure that the differential diagnosis is complete. - Goal: To provide information on a systemic method to identify other potential diseases. - Appropriate content: Commonly associated conditions with similar signs and symptoms Known conditions to exclude Differentiating physical examination characteristics from similar diseases (a table like Pericarditis differential diagnosis may be useful) Guidance on interpretation of physical examination findings Guidance on interpretation of laboratory result findings Information on potential shortcomings of various diagnostic protocols - Commonly associated conditions with similar signs and symptoms - Known conditions to exclude - Differentiating physical examination characteristics from similar diseases (a table like Pericarditis differential diagnosis may be useful) - Guidance on interpretation of physical examination findings - Guidance on interpretation of laboratory result findings - Information on potential shortcomings of various diagnostic protocols - Remember: Please review the original versions of the chapter to assure that the differential diagnosis is complete and has not been erased. # Epidemiology and Demographics - Goal: To provide facts and figures surrounding the determinants and distribution of disease. - Appropriate content: A description of the characteristics of the population at-risk (gender, race, age, social economic status, dietary considerations, geographic location, environmental conditions) and any facts or figures surrounding the distribution of the disease burden in a population. Common measures: crude and adjusted measurements of incidence, prevalence, mortality, morbidity, hazard ratios, relative risk, odds ratios, etc. Figures showing stratified distribution of disease. Information on exposure-outcome relationships indicating the disease as the outcome. Information on potential bias surrounding the study of the disease. - Common measures: crude and adjusted measurements of incidence, prevalence, mortality, morbidity, hazard ratios, relative risk, odds ratios, etc. - Figures showing stratified distribution of disease. - Information on exposure-outcome relationships indicating the disease as the outcome. - Information on potential bias surrounding the study of the disease. - Remember: This is not the chapter to describe clinical trial results as it relates to the disease. This chapter is a background perspective on the overall distribution and determination of disease in the population. # Risk Factors - Goal: To provide information on well-defined determinants of disease. - Appropriate content: A description of stratified characteristics that are widely agreed to have a correlational relationship between exposure and disease outcome. May include: lifestyle/behavioral habits, environmental exposures, genetic/inherited characteristics, etc. - May include: lifestyle/behavioral habits, environmental exposures, genetic/inherited characteristics, etc. - Remember: Risk factors are associated with a correlation and are not the causation to disease. Direct causation is covered in the cause section. # Screening - Goal: To define a general overview of methodologies employed within a population to detect the disease before overt physiologic manifestation. - Appropriate content: A description of tests used to indicate the likely presence or absence of a disease or condition in people not presenting symptoms. Advantages and disadvantages Sensitivity and specificity (false positives, false negatives) + positive predictive value and negative predictive value Questions to consider: Why screen? What diseases are appropriate for screening? How do we assess whether a screening test is suitable? How do we assess whether a screening program works? What is the value of screening for those screened? The role of bias (lead time bias, length time bias, selection bias, overdiagnosis, etc.) - Advantages and disadvantages - Sensitivity and specificity (false positives, false negatives) + positive predictive value and negative predictive value - Questions to consider: Why screen? What diseases are appropriate for screening? How do we assess whether a screening test is suitable? How do we assess whether a screening program works? What is the value of screening for those screened? - The role of bias (lead time bias, length time bias, selection bias, overdiagnosis, etc.) - Remember: Screening is a pre-diagnostic mechanism. Information pertaining to the utilization of tests that provide quantitative physiological measurements to confirm and determine the progress of the disease or condition belongs in the respective diagnostic testing modality chapter. The testing modality chapters are intended to elaborate on disease progression characteristics. # Natural History, Complications and Prognosis - Goal: To provide information on the natural progression of disease without treatment, complications that arise because of the disease and because of disease treatment, and the anticipated and actual outcomes for patients who receive care. - Appropriate content: Information regarding disease progression untreated Life expectancy projections for untreated versus treated Identifying known complications caused by or associated to the disease Identifying known complications arising from treatment methodologies Quantifying life expectancy for patients who receive care Quantifying potentials for need for re-treatment - Information regarding disease progression untreated - Life expectancy projections for untreated versus treated - Identifying known complications caused by or associated to the disease - Identifying known complications arising from treatment methodologies - Quantifying life expectancy for patients who receive care - Quantifying potentials for need for re-treatment - Remember:' This is not the section for the patient history or historical record. # History and Symptoms - Goal: The purpose of this chapter is to describe the typical symptoms that a patient verbalizes. - Appropriate content: A list of symptoms organized by frequency, such as... Disorders with similar symptoms + a link to the differential diagnosis Common symptoms Less common symptoms Rapidity of symptom onset Including links to additional WikiDoc sites for further symptom explanation. (i.e. dyspnea) - A list of symptoms organized by frequency, such as... Disorders with similar symptoms + a link to the differential diagnosis Common symptoms Less common symptoms - Disorders with similar symptoms + a link to the differential diagnosis - Common symptoms - Less common symptoms - Rapidity of symptom onset - Including links to additional WikiDoc sites for further symptom explanation. (i.e. dyspnea) - Remember: It does not include findings from the physical exam (signs of the disease). # Physical Examination - Goal: To provide a comprehensive list of symptoms presenting during a physical examination by a medical professional. - Appropriate content: Appearance of the patient during examination Vital signs Compartmentalizing symptoms by: skin, eyes, ears, nose, throat, heart, lungs, abdomen, extremities, neurologic components Differentiating characteristic denoting severity of disease presence - Appearance of the patient during examination - Vital signs - Compartmentalizing symptoms by: skin, eyes, ears, nose, throat, heart, lungs, abdomen, extremities, neurologic components - Differentiating characteristic denoting severity of disease presence - There should be no information that could identify a patient on any image. - A thorough search of youtube and google for videos related to the physical examination findings is required. - A thorough search of google for copyleft images related to the physical examination findings is required. # Laboratory Findings - Goal: To summarize all appropriate laboratory tests and applicable findings related to the condition. - Appropriate content: Electrolyte (K, Na) Kidney function (Cr, Bun) Liver function (LFTs, SGOT, SGPT) Complete blood count (CBC) White blood count (WBC, hct, Hb) Biopsy Other biological markers for the disease - Electrolyte (K, Na) - Kidney function (Cr, Bun) - Liver function (LFTs, SGOT, SGPT) - Complete blood count (CBC) - White blood count (WBC, hct, Hb) - Biopsy - Other biological markers for the disease - Remember: This section does not include imaging studies such as electrocardiogram, chest x ray, CT, MRI, echocardiography, ultrasound, etc. # Electrocardiogram - Goal: To summarize all applicable electrocardiogram diagnostic tests and findings related to the condition. - Appropriate content: Indications and contraindications Advantages and disadvantages Common modalities EKG findings EKG imaging results EKG copyleft image examples Applicable EKG studies - Indications and contraindications - Advantages and disadvantages - Common modalities - EKG findings - EKG imaging results - EKG copyleft image examples - Applicable EKG studies - Remember: You cannot take copyright images and post them to WikiDoc. All images posted as examples must be from a copyleft source such as , , . If there is any doubt as to whether an image is copyleft, please consult with Dr. Gibson ]. - There should be no information that could identify a patient on any image. # Chest X Ray - Goal: To summarize all applicable chest x ray findings related to the condition. - Appropriate content: Indications and contraindications Advantages and disadvantages Characteristics of chest x rays with the condition Chest x ray copyleft image examples - Indications and contraindications - Advantages and disadvantages - Characteristics of chest x rays with the condition - Chest x ray copyleft image examples - Remember: You cannot take copyright images and post them to WikiDoc. All images posted as examples must be from a copyleft source such as , , . If there is any doubt as to whether an image is copyleft, please consult with Dr. Gibson ]. - There should be no information that could identify a patient on any image. # CT - Goal: To summarize all applicable CT tests and findings related to the condition. - Appropriate content: Indications and contraindications Advantages and disadvantages Applicable modalities/forms of CT testing CT imaging results CT copyleft image examples CT copyleft video examples Applicable CT studies - Indications and contraindications - Advantages and disadvantages - Applicable modalities/forms of CT testing - CT imaging results - CT copyleft image examples - CT copyleft video examples - Applicable CT studies - Remember: You cannot take copyright images and post them to WikiDoc. All images posted as examples must be from a copyleft source such as , , . If there is any doubt as to whether an image is copyleft, please consult with Dr. Gibson ]. - There should be no information that could identify a patient on any image. # Echocardiography or ultrasound - Goal: To summarize all applicable echocardiography or ultrasound tests and findings related to the condition. - Appropriate content: Indications and contraindications Advantages and disadvantages Applicable modalities/forms of echocardiography or ultrasound testing Echocardiography or ultrasound imaging results Echocardiography or ultrasound copyleft image examples Echocardiography or ultrasound copyleft video examples Applicable echocardiography or ultrasound studies - Indications and contraindications - Advantages and disadvantages - Applicable modalities/forms of echocardiography or ultrasound testing - Echocardiography or ultrasound imaging results - Echocardiography or ultrasound copyleft image examples - Echocardiography or ultrasound copyleft video examples - Applicable echocardiography or ultrasound studies - Remember: You cannot take copyright images and post them to WikiDoc. All images posted as examples must be from a copyleft source such as National Library of Medicine, Wikipedia, RadsWiki, Radiopedia or Wiki Echo. even though the image is copyleft, you should cite the site that was the original source. If there is any doubt as to whether an image is copyleft, please consult with Dr. Gibson . - There should be no information that could identify a patient on any image. # Other Imaging Findings - Goal: To provide a space for additional imaging results that pertain to the disease. - Appropriate content: Coronary angiography/cardiac catheterization Additional scans (i.e. Gallium scanning) Applicable coplyleft images and videos - Coronary angiography/cardiac catheterization - Additional scans (i.e. Gallium scanning) - Applicable coplyleft images and videos - Remember: You cannot take copyright images and post them to WikiDoc. All images posted as examples must be from a copyleft source such as National Library of Medicine, Wikipedia, RadsWiki, Radiopedia or Wiki Echo. even though the image is copyleft, you should cite the site that was the original source. If there is any doubt as to whether an image is copyleft, please consult with Dr. Gibson . # Treatment - Goal: When applicable, a treatment overview page serves to address things like precipitating factors, risk factor modification, treatment essentials, and a brief overview of methodologies (such as pharmacological and surgical). All treatments should be placed on microchapters relating to the type of intervention (i.e. medical therapy vs. surgical therapy vs. primary prevention). - All treatments should be placed on microchapters relating to the type of intervention (i.e. medical therapy vs. surgical therapy vs. primary prevention). - Appropriate content: As treatment is not universal from condition to condition, each disease may have different microchapters for treatment. Common microchapters include: - As treatment is not universal from condition to condition, each disease may have different microchapters for treatment. Common microchapters include: - Medical therapy - Pharmacological therapy (may even be further microchaptered into type of pharmacological therapy such as antiplatelet, anti-lipid, etc.) - Treatment/management of supporting conditions - Including guidelines for treatment: - National Guideline Clearinghouse - Cardiology resources: - ACC/AHA Guidelines - European Society of Cardiologists Guidelines - Canadian Cardiovascular Society Guidelines - Try searching Google Scholar for treatment guidelines, i.e. Searching Google Scholar for treatment of a condition like Crohn's Disease # Categories - Goal: The goal of including categories at the bottom of your WikiDoc article is to allow for the textbook to compile a comprehensive table of contents. Every category that is coded will create a new directory for WikiDoc readers to utilize to find content. For example, Category:Cardiology - Appropriate content: - The spelling of each category is case sensitive. All links must follow the convention: capitalize the first letter of the first word and every subsequent word will be lowercase (i.e. Mature chapter). If you spell Mature chapter as Mature Chapter, WikiDoc will not send it to the same place. One wrong capital will send the link elsewhere. It is crucial that the sitewide convention be applied appropriately or you will be creating dead links and the potential for unnecessarily duplicated content. Categories you may include at the bottom include: - Category:Mature chapter- All chapters must have an overview section. Once they do, and if the chapter is complete, it can be categorized as a mature chapter. This tag signifies that the chpater has been extensively vetted based upon the process above and is of high quality chapter. - Category:Microchapter candidate - If a chapter has progressed in size and sophistication to the point that it should be divided into subchapters, please include it in the category microchapter candidate. Once it is divided into microchapters, this designation should be removed. - Category:Patient information- If you are creating a patient information page, put it in the patient information category. Note that the i in information is a small i. - Category:Disease- If the chapter you are working on is a disease, make sure you include it in the disease state category. - Category:Physical examination - This category is used for those chapters that focus on the physical examination - Category:Signs and symptoms - This category is used for those chapters that focus on the signs and symptoms. An example would include the chapter on headache. - Category:Subspecialty - Examples include cardiology, emergency medicine, intensive care medicine, oncology.

Sandbox:Parul This page is for your practice! Keywords and synonyms: Cerebral herniation, cerebellar herniation, uncal herniation, central herniation, supratentorial herniation, infratentorial herniation, transtentorial herniation, tonsillar herniation, cingulate herniation, transcalvarial herniation # Overview Herniation, a deadly side effect of very high intracranial pressure, occurs when the brain shifts across structures within the skull. The brain can shift by such structures as the falx cerebri, the tentorium cerebelli, and even through the hole called the foramen magnum in the base of the skull (through which the spinal cord connects with the brain). Herniation can be caused by a number of factors that increase intracranial pressure such as traumatic brain injury. Because herniation puts extreme pressure on parts of the brain, it is often fatal. Therefore, extreme measures are taken in hospital settings to prevent the condition by reducing intracranial pressure. # Historical Perspective In 1783, a medical educator and anatomist from Scotland, Alexander Monro, first proposed the concept of Intracranial pressure in his paper 'Observations on the Structure and Functions of the Nervous System'. In this paper, he stated his observations about brain, cranial cavity, and cranial blood flow. He mentioned that the cranial cavity is rigid and it encloses the incompressible brain. He hypothesized that the blood volume is constant in the cranial cavity at all times. There is a continuous balance between outflowing venous and incoming arterial blood. This hypothesis was supported by George Kellie's (Monore's former student) experiments, and 'Monro–Kellie hypothesis' came into existence. According to this, the sum of brain volume, cerebrospinal fluid, and intrcranial blood flow is constant. # Classification There are two major classes of herniation: supratentorial and infratentorial.. Depending on which structures of the brain have been displaced, herniation is further sub-classified. Tentorium Cerebelli is one of the four duramater folds (Extention of outermost meningeal layer, duramater). It serves as a landmark and divides the cranial cavity structures into supra and infra tentorial. This dural extention has a fixed and free margin. The free margin of tentorium cerebelli is called as 'Tentorial notch". ## Central herniation In central herniation, (also called "transtentorial herniation") the diencephalon and parts of the temporal lobes of both of the cerebral hemispheres are squeezed through a notch in the tentorium cerebelli. Downward herniation can stretch branches of the basilar artery (paramedian artery), causing them to tear and bleed, known as a Duret hemorrhage. The result is usually fatal. ## Uncal herniation In uncal herniation, a common subtype of transtentorial herniation, the innermost part of the temporal lobe, the uncus, can be squeezed so much that it goes by the tentorium and puts pressure on the brainstem. The tentorium is a structure within the skull formed by the meningeal layer the dura mater. Tissue may be stripped from the cerebral cortex in a process called decortication. The uncus can squeeze the third cranial nerve, which controls parasympathetic input to the eye on the side of the affected nerve. This interrupts the parasympathetic neural transmission, causing the pupil of the affected eye to dilate and fail to constrict in response to light as it should, so a dilated unresponsive pupil is an important sign of increased intracranial pressure. Pupillary dilation often precedes a later finding of cranial nerve III compression, which is deviation of the eye to a "down and out" position due to loss of innervation to all ocular motility muscles except for the lateral rectus (innervated by cranial nerve VI) and the superior oblique (innervated by cranial nerve IV). Cranial arteries may be compressed during the herniation. Compression of the posterior cerebral artery may result in loss of the contralateral visual field. A later important finding, the false localizing sign, results from compression of the contralateral cerebral crus, which contains descending corticospinal fibers. This leads to ipsilateral (to herniating uncus) hemiparesis of the body. This type of herniation can also damage the brain stem, causing lethargy, slow heart rate, respiratory abnormalities, and pupil dilation. Uncal herniation may advance to central herniation. ## Cerebellar herniation Increased pressure in the posterior fossa can cause the cerebellum to move up through the tentorial opening in upward, or cerebellar herniation. The midbrain is pushed through the tentorial notch. This also pushes the midbrain down. ## Tonsillar herniation In tonsillar herniation, also called downward cerebellar herniation, the cerebellar tonsils move downward through the foramen magnum possibly causing compression of the lower brainstem and upper cervical spinal cord as they pass through the foramen magnum. Increased pressure on the brainstem can result in dysfunction of the centers in the brain responsible for controlling respiratory and cardiac function. Tonsillar herniation of the cerebellum is also known commonly as a Chiari Malformation (CM) which previously was called an Arnold Chiari Malformation (ACM). There are at least three types of Chiari malformation that are widely recognized, and they represent very different disease processes with different symptoms and prognosis. These conditions can be found in asymptomatic patients, as an incidental finding, or can be so severe as to be life-threatening. This condition is now being diagnosed more frequently by radiologists as more and more patients undergo MRI scans of their heads. Cerebellar ectopia is a term used by radiologists to describe cerebellar tonsils that are "low lying" but that do not meet the radiographic criteria for definition as a Chiari malformation. The currently accepted radiographic definition for a Chiari malformation are cerebellar tonsils that lay at least 5mm below the level of the foramen magnum. Some clinicians have reported that some patients appear to experience symptoms consistent with a Chiari malformation without radiographic evidence of tonsillar herniation. Sometimes these patients are described as having a 'Chiari 0'. There are many suspected causes of tonsillar herniation including (but not exclusively)- Spinal cord tethering or occult tight filum terminale (pulling down on the brainstem and surrounding structures); decreased or malformed posterior fossa (the lower, back part of the skull) not providing enough room for the cerebellum; hydrocephalus or abnormal CSF volume pushing the tonsils out; connective tissue disorders, such as Ehlers Danlos Syndrome, can be associated as well.(These may affect the ability of the brain, as well as the supporting joints, to maintain proper position/strength; in pediatric cases, ACM is often an 'incidental' finding while doing a work up for scoliosis, which is usually associated with certain connective tissue disorders). For further evaluation of tonsillar herniation, CINE flow studies are suggested. This type of MRI will look at the flow of CSF at the cranio-cervical joint. For persons experiencing symptoms with seemingly minimal herniation, especially if the symptoms are better in the suppine position and worse upon standing/upright, an upright MRI may be useful. ## Cingulate herniation In cingulate or subfalcine herniation, the most common type, the innermost part of the frontal lobe is scraped under part of the falx cerebri, the dura mater at the top of the head between the two hemispheres of the brain. Cingulate herniation can be caused when one hemisphere swells and pushes the cingulate gyrus by the falx cerebri. This does not put as much pressure on the brainstem as the other types of herniation, but it may interfere with blood vessels in the frontal lobes that are close to the site of injury (anterior cerebral artery), or it may progress to central herniation. Interference with the blood supply can cause dangerous increases in ICP that can lead to more dangerous forms of herniation. Symptoms for cingulate herniation are not well defined. Usually occurring in addition to uncal herniation, cingulate herniation may present with abnormal posturing and coma. Cingulate herniation is frequently believed to be a precursor to other types of herniation. - Subfalcine-herniation ## Transcalvarial Herniation In transcalvarial herniation, the brain squeezes through a fracture or a surgical site in the skull. # Natural History, Complications and Prognosis The patient may become paralyzed on the same side as the lesion causing the pressure, or damage to parts of the brain caused by herniation may cause paralysis on the side opposite the lesion. Damage to the midbrain, which contains the reticular activating network that regulates consciousness will result in coma. Damage to the cardio-respiratory centers in the medulla will cause respiratory and cardiac arrest. # Pathophysiology The exact pathogenesis of is not fully understood. OR It is thought that is the result of / is mediated by / is produced by / is caused by either , , or . OR is usually transmitted via the route to the human host. OR Following transmission/ingestion, the uses the to invade the cell. OR arises from s, which are cells that are normally involved in . OR The progression to usually involves the . OR The pathophysiology of depends on the histological subtype. # Causes Conditions that lead to elevation of inracranial pressure increase the risk of brain herniation. These include- Localized or generalized swelling of the brain Space-occupying lesions Increase intracranial venous blood pressure (venous sinus thrombosis, Heart failure, jugular venous obstruction) Obstruction of Cerebro-spinal Fluid flow Traumatic (bRAIN HEMORRHAGES, CONTUSION) Space-occupying lesions (eg, brain tumor, edema, or abscess; contusions; hematomas) Generalized swelling or edema of the brain (eg, due to acute liver failure or hypertensive encephalopathy) Increased venous pressure (eg, due to heart failure, obstruction of superior mediastinal or jugular veins, or venous sinus thrombosis) Obstruction of the CSF flow (eg, due to hydrocephalus or extensive meningeal disease) There are multispectral factors that can predispose to raised intracranial pressure and brain herniation syndrome such as: Hematoma (traumatic epidural and subdural hematoma, contusions, intracerebral hemorrhage) Malignant infarction Tumors Infections (abscess, empyema, hydatid cyst) Hydrocephalus Diffuse subarachnoid hemorrhage Pneumocephalus (traumatic or postoperative) CSF over drainage Metabolic-hepatic encephalopathy Disease name] may be caused by , , or . OR Common causes of include , , and . OR The most common cause of is . Less common causes of include , , and . OR The cause of has not been identified. To review risk factors for the development of , click here. # Diagnosis ## Diagnostic Study of Choice The diagnosis of is made when at least of the following diagnostic criteria are met: , , , and . OR The diagnosis of is based on the criteria, which include , , and . OR The diagnosis of is based on the definition, which includes , , and . OR There are no established criteria for the diagnosis of . ## History and Symptoms The majority of patients with are asymptomatic. OR The hallmark of is . A positive history of and is suggestive of . The most common symptoms of include , , and . Common symptoms of include , , and . Less common symptoms of include , , and . ## Physical Examination Patients with usually appear . Physical examination of patients with is usually remarkable for , , and . OR Common physical examination findings of include , , and . OR The presence of on physical examination is diagnostic of . OR The presence of on physical examination is highly suggestive of . ## Laboratory Findings An elevated/reduced concentration of serum/blood/urinary/CSF/other is diagnostic of . OR Laboratory findings consistent with the diagnosis of include , , and . OR is usually normal among patients with . OR Some patients with may have elevated/reduced concentration of , which is usually suggestive of . OR There are no diagnostic laboratory findings associated with . ## Electrocardiogram There are no ECG findings associated with . OR An ECG may be helpful in the diagnosis of . Findings on an ECG suggestive of/diagnostic of include , , and . ## X-ray There are no x-ray findings associated with . OR An x-ray may be helpful in the diagnosis of . Findings on an x-ray suggestive of/diagnostic of include , , and . OR There are no x-ray findings associated with . However, an x-ray may be helpful in the diagnosis of complications of , which include , , and . ## Echocardiography or Ultrasound There are no echocardiography/ultrasound findings associated with . OR Echocardiography/ultrasound may be helpful in the diagnosis of . Findings on an echocardiography/ultrasound suggestive of/diagnostic of include , , and . OR There are no echocardiography/ultrasound findings associated with . However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of , which include , , and . ## CT scan There are no CT scan findings associated with . OR CT scan may be helpful in the diagnosis of . Findings on CT scan suggestive of/diagnostic of include , , and . OR There are no CT scan findings associated with . However, a CT scan may be helpful in the diagnosis of complications of , which include , , and . ## MRI There are no MRI findings associated with . OR MRI may be helpful in the diagnosis of . Findings on MRI suggestive of/diagnostic of include , , and . OR There are no MRI findings associated with . However, a MRI may be helpful in the diagnosis of complications of , which include , , and . ## Other Imaging Findings There are no other imaging findings associated with . OR may be helpful in the diagnosis of . Findings on an suggestive of/diagnostic of include , , and . ## Other Diagnostic Studies There are no other diagnostic studies associated with . OR may be helpful in the diagnosis of . Findings suggestive of/diagnostic of include , , and . OR Other diagnostic studies for include , which demonstrates , , and , and , which demonstrates , , and . Treatment Medical Therapy Brain Herniation is a medical emergency and requires prompt management. Cautious adjustment of intracranial pressure should be done in all patients who develop displacement of the brain tissue. Based on Monroe-Kellie hypothesis, balance in brain volume, CSF volume and intracranial blood OR The mainstay of treatment for is . OR The optimal therapy for depends on the stage at diagnosis. OR is recommended among all patients who develop . OR Pharmacologic medical therapy is recommended among patients with , , and . OR Pharmacologic medical therapies for include (either) , , and/or . OR Empiric therapy for depends on and . OR Patients with are treated with , whereas patients with are treated with . Surgery Surgical intervention is not recommended for the management of . OR Surgery is not the first-line treatment option for patients with . Surgery is usually reserved for patients with either , , and OR The mainstay of treatment for is medical therapy. Surgery is usually reserved for patients with either , , and/or . OR The feasibility of surgery depends on the stage of at diagnosis. OR Surgery is the mainstay of treatment for . Primary Prevention There are no established measures for the primary prevention of . OR There are no available vaccines against . OR Effective measures for the primary prevention of include , , and . OR vaccine is recommended for to prevent . Other primary prevention strategies include , , and . Secondary Prevention There are no established measures for the secondary prevention of . OR Effective measures for the secondary prevention of include , , and .

Multiple endocrine neoplasia (patient information) For the WikiDoc page for this topic, click here # Overview Multiple endocrine neoplasia (MEN) encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. Multiple endocrine neoplasia may be classified according to tumor characteristics into 3 subtypes: multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2 and multiple endocrine neoplasia type 4. Symptoms vary from person to person, and depend on which gland is involved. Genetic mutation is the cause of multiple endocrine neoplasia. The most potent risk factor in the development of multiple endocrine neoplasia is family history of multiple endocrine neoplasia. Surgery to remove the diseased gland is the treatment of choice for multiple endocrine neoplasia. # What are the symptoms of multiple endocrine neoplasia? - Symptoms vary from person to person, and depend on which gland is involved. They may include: - Abdominal pain - Anxiety - Black, tarry stools - Bloated feeling after meals - Burning, aching, or hunger discomfort in the upper abdomen or lower chest that is relieved by antacids, milk, or food - Decreased sexual interest - Fatigue - Headache - Lack of menstrual periods (in women) - Loss of appetite - Loss of body or facial hair (in men) - Mental changes or confusion - Muscle pain - Nausea and vomiting - Sensitivity to the cold - Unintentional weight loss - Vision problems - Weakness # What causes multiple endocrine neoplasia? - MEN I is caused by a defect in a gene that carries the code for a protein called menin. The condition causes tumors of various glands to appear in the same person, but not necessarily at the same time. - The disorder may occur at any age, and it affects men and women equally. A family history of this disorder raises your risk. # Who is at highest risk? The most potent risk factor in the development of multiple endocrine neoplasia is family history of multiple endocrine neoplasia. # Diagnosis - The health care provider will perform a physical exam and ask questions about your medical history and symptoms. The following tests may be done: - Blood cortisol level - CT scan of the abdomen - CT scan of the head - Fasting blood sugar - Genetic testing - Insulin test - MRI of the abdomen - MRI of the head - Parathyroid biopsy - Serum adrenocorticotropic hormone - Serum calcium - Serum follicle stimulating hormone - Serum gastrin - Serum glucagon - Serum luteinizing hormone - Serum parathyroid hormone - Serum prolactin - Serum thyroid stimulating hormone - Ultrasound of the neck # When to seek urgent medical care? Call your health care provider if you notice symptoms of MEN I or have a family history of this condition. # Treatment options - Surgery to remove the diseased gland is the treatment of choice. A medication called bromocriptine may be used instead of surgery for pituitary tumors that release the hormone prolactin. - The parathyroid glands, which control calcium production, can be removed. However, because it is difficult for the body to regulate calcium levels without these glands, a total parathyroid removal is usually not done initially. - Medicine is available to decrease the excess stomach acid production caused by some tumors (gastrinomas), and to reduce the risk of ulcers. - Hormone replacement therapy is given when entire glands are removed or do not produce enough hormones. # Where to find medical care for multiple endocrine neoplasia? Directions to Hospitals Treating Multiple endocrine neoplasia # Prevention of multiple endocrine neoplasia Screening close relatives of people affected with this disorder is recommended. # What to expect (Outlook/Prognosis)? - Pituitary and parathyroid tumors are usually noncancerous (benign), but some pancreatic tumors may become cancerous (malignant) and spread to the liver. These can lower life expectancy. - The symptoms of peptic ulcer disease, low blood sugar, excess calcium in the blood, and pituitary dysfunction usually respond well to appropriate treatment. # Possible complications - The tumors can keep coming back. Symptoms and complications depend on which glands are involved. Regular check-ups by your health care provider are essential. # Sources Endocrine.gov NIH.gov Merck.com Medlineplus Medlineplus

Diffuse esophageal spasm overview # Overview Diffuse or Distal esophageal spasm (DES) is an uncommon esophageal motility disorder causing chest pain and/or dysphagia. DES was first described by Osgood, in 1889 in 6 patients presenting with chest pain and dysphagia. Creamer et al. (1958) made the first manometric descriptions of DES. Development of high resolution esophageal manometry in 2000 has led to classification of esophageal motility disorders. Diffuse esophageal spasm can be classified as primary or secondary based on presence or absence of other disease associated with it. The exact pathogenesis of DES is not fully understood. Current high-resolution manometric studies suggests impairment of inhibitory neurons. These inhibitory neurons use nitric oxide (NO) as neurotransmitter. Exact cause of diffuse esophageal spasm is unknown. However, may be caused by consequence of various diseases and secondary to conditions like compression of nerves within esophageal wall, inflammation of the esophagus, stricture, GERD, psychological conditions like anxiety or depression. Diffuse esophageal spasm must be differentiated from other diseases that cause dysphagia, chest pain and weight loss such as angina, reflux esophagitis, esophageal carcinoma, systemic sclerosis, nutcracker esophagus, hypertensive LES, esophageal web/stricture, pseudoachalasia, stroke, esophageal candidiasis, Chagas disease etc. Common risk factors in the development of Diffuse Esophageal Spasm include: Age (60-80 years), obesity, mitral valve prolapse, presence of GERD, Hypertension, anxiety or depression, and drinks (eg. red wine, very hot or cold liquid or fluid). If left untreated, most patients are symptom free over the course of time. Very few cases report of progression to achalasia and nut cracker esophagus. The diagnostic study of choice for DES is manometry. An x-ray of esophagus after barium swallow (esophagogram) is the next best test to support manometric diagnosis. The mainstay of treatment for DES is medical therapy with calcium channel blockers, and/or tricyclic antidepressants. # Historical Perspective Esophagus was described by Vasalius in 1543. Diffuse esophageal spasm was first described by Osgood in 1889 in 6 patients presenting with chest pain and dysphagia. Development of high resolution esophageal manometry in 2000 has led to classification of esophageal motility disorders. # Classification Diffuse esophageal spasm can be classified as primary or secondary based on its association with other diseases. # Pathophysiology The exact pathogenesis of DES is not fully understood. Current high-resolution manometric studies suggests impairment of inhibitory neurons. These inhibitory neurons use nitric oxide (NO) as neurotransmitter. # Causes Exact cause of diffuse esophageal spasm is unknown. However, may be caused by consequence of various diseases and secondary to conditions like compression of nerves within esophageal wall, inflammation of the esophagus, strictures, GERD, and psychological conditions like anxiety or depression. # Differentiating Diffuse esophageal spasm from Other Diseases Diffuse esophageal spasm must be differentiated from other diseases that cause dysphagia, chest pain and weight loss such as angina, reflux esophagitis, esophageal carcinoma, systemic sclerosis, nutcracker esophagus, hypertensive LES, esophageal web/stricture, pseudoachalasia, stroke, esophageal candidiasis and Chagas disease etc. # Epidemiology and Demographics Diffuse esophageal spasm is relatively uncommon disease with incidence of 1 per 100,000 in the USA. DES affects all age groups. There is no racial predilection to DES. # Risk Factors Common risk factors in the development of diffuse esophageal spasm include age (60-80 years), obesity, mitral valve prolapse, presence of GERD, hypertension, anxiety or depression, and drinks (eg. red wine, very hot or cold liquid or fluid). # Screening There is insufficient evidence to recommend routine screening for DES. # Natural History, Complications, and Prognosis If left untreated, most patients remain asymptomatic over the course of time. Very few cases report progression to Achalasia and nut cracker esophagus. # Diagnosis ## Diagnostic Study of Choice The diagnostic study of choice for DES is manometry. ## History and Symptoms The hallmark of DES is esophageal dysphagia for both solids and liquids and chest pain. Symptom onset is sudden, intermittent and non-progressive in nature. Chest pain usually retrosternal in location, which is intense and squeezing in nature and may be mistaken for Angina. Difficulty swallowing, is sometimes related to specific substances like red wine, very cold or hot liquid. ## Physical Examination Patients with primary diffuse esophageal spasm usually appear normal. Physical examination of patients with DES is usually remarkable for findings related to secondary diseases. ## Laboratory Findings There are no diagnostic laboratory findings associated with DES. ## Electrocardiogram There are no ECG findings associated with DES. ## X-ray An x-ray of esophagus after barium swallow (esophagogram) is the next best test to support manometric diagnosis. ## Ultrasound There are no echocardiography/ultrasound findings associated with DES. ## CT scan Chest CT scan may be helpful in the diagnosis of DES. Findings on CT scan suggestive of DES include esophageal wall thickening. ## MRI There are no MRI findings associated with diffuse esophageal spasm. ## Other Imaging Findings Endoscopy may be helpful in the diagnosis of DES to exclude other esophageal lesion causing chest pain. ## Other Diagnostic Studies 24-hour esophageal pH monitoring may be helpful in the diagnosis of secondary DES. # Treatment ## Medical Therapy The mainstay of treatment for DES is medical therapy with calcium channel blockers, and/or tricyclic antidepressants. ## Surgery The mainstay of treatment for DES is medical therapy. Surgery is usually reserved for patients with manometrically proven, symptomatic and those cases refractory to medical therapy. ## Primary Prevention There are no established measures for the primary prevention of diffuse esophageal spasm. ## Secondary Prevention There are no secondary preventive measures available for insulinoma.

Metallic hydrogen Metallic hydrogen results when hydrogen is sufficiently compressed and undergoes a phase change; it is an example of degenerate matter. Solid metallic hydrogen consists of a crystal lattice of atomic nuclei (namely, protons), with a spacing which is significantly smaller than a Bohr radius. Indeed, the spacing is more comparable with an electron wavelength (see De Broglie wavelength). The electrons are unbound and behave like the conduction electrons in a metal. As is the dihydrogen molecule H2, metallic hydrogen is an allotrope. In liquid metallic hydrogen protons do not have lattice ordering i.e. the system is a liquid of protons and electrons. # History ## Theoretical Predictions ### Metalization of hydrogen under pressure Though topping the Periodic Table's alkali metal column, hydrogen is not, under ordinary conditions, an alkali metal. In 1935, however, physicists Eugene Wigner and H.B. Huntington predicted that under an immense pressure of two hundred and fifty thousand atmospheres (~ 25 GPa), hydrogen atoms would display metallic properties, losing hold over their electrons.. Since then metallic hydrogen was the holy grail of high-pressure physics. The initial prediction about the amount of pressure needed was proven to be too low. Since the first work by Wigner and Huntington the more modern theoretical calculations were pointing toward higher but nonetheless potentially experimentally accessible metalization pressures. Professor Malcolm McMahon (Centre for Science and Extreme Conditions at Edinburgh University) states that they are currently developing techniques for creating pressures of up to five million atmospheres (ie, higher than the pressure at the center of the earth) in hopes of creating metallic hydrogen. ### Liquid metallic hydrogen The proton has one fourth the mass of 4He, which at normal conditions is a liquid even at lowest temperatures, a consequence of high zero-point energy. Similarly, zero-point energies of protons in a dense state are also high, and at elevated compressions there is expected to be a decline in the ordering energies from interactions relative to protonic zero-point energies. Arguments have been advanced by N.W. Ashcroft and others that there is a melting point maximum in compressed hydrogen, but also that there may be a range of densities (at pressures around 400 GPa) where hydrogen may be a liquid metal even at lowest temperatures. ### Superconductivity Theory has been put forward by Neil Ashcroft that metallic hydrogen may be a superconductor as high as room temperature (290 K), far higher than any other known candidate material. This stems from its extremely high speed of sound and the expected strong coupling between the conduction electrons and the lattice vibrations. ### Possibility of novel types of quantum fluid Presently known "super" states of matter are superconductors, superfluid liquids and gases, and supersolids. It was predicted by Egor Babaev that if hydrogen and deuterium have liquid metallic states, they may have ordered states in quantum domain which cannot be classified as superconducting or superfluid in usual sense but represent two possible novel types of quantum fluids: “superconducting superfluid” and “metallic superfluid”. These were shown to have highly unusual reactions to external magnetic field and rotation which might represent a route for experimental verification of these possible new states of matter. It has also been suggested that under the influence of magnetic field the hydrogen may exhibit phase transitions from superconductivity to superfluidity and vice versa. ## Experimental pursuit ### Metalization of hydrogen in shock-wave compression In March 1996, a group of scientists at Lawrence Livermore National Laboratory reported that they had serendipitously produced, for about a microsecond and at temperatures of thousands of kelvin and pressures of over a million atmospheres (>100 GPa), the first identifiably metallic hydrogen. The Lawrence Livermore team did not expect to produce metallic hydrogen, as they were not using solid hydrogen, thought to be necessary, and were working at temperatures above those specified by metallization theory. Furthermore, previous studies in which solid hydrogen was compressed inside diamond anvils to pressures of up to 2.5 million atmospheres (~253 GPa), did not confirm detectable metallization. The team had sought simply to measure the less extreme electrical conductivity changes which were expected to occur. The researchers used a 1960s-era light gas gun, originally used in guided missile studies, to shoot an impactor-plate into a sealed container containing a half-millimetre thick sample of liquid hydrogen. The liquid hydrogen was in contact with wires leading to a device capable of measuring electrical resistance. The scientists were surprised to find that, as pressure rose to 1.4 million atmospheres (142 GPa), the electronic energy band gap, a measure of electrical resistance, fell to almost zero. The band-gap of hydrogen in its uncompressed state is about 15 eV, making it an insulator but, as the pressure increases significantly, the band-gap gradually falls to 0.3 eV and because the 0.3 eV is provided by the thermal energy of the fluid (the temperature became about 3000 K due to compression of the sample), the hydrogen may, at this point, effectively be considered metallic. ### Other experimental research since 1996 Many experiments are continuing in the production of metallic hydrogen in laboratory conditions at static compression and low temperature. Arthur Ruoff and Chandrabhas Narayana from Cornell University in 1998, and later Paul Loubeyre and René LeToullec from Commissariat à l'Énergie Atomique, France in 2002, have shown that at pressures close to those at the center of the Earth (3.2 to 3.4 million atmospheres or 324 to 345 GPa) and temperatures of 100 K–300 K, hydrogen is still not a true alkali metal, because of the non-zero band gap. The quest to see metallic hydrogen in laboratory at low temperature and static compression continues. Studies are also undergoing on deuterium.. Shahriar Badiei and Leif Holmlid from the University of Goteborg have shown in 2004 that condensed metallic states made of excited hydrogen atoms (H Rydberg matter) are effective promoters to metallic hydrogen. ### Experimental breakthroughs in 2008 The theoretically predicted maximum of the melting curve (the prerequisite for the liquid metallic hydrogen) was discovered by Shanti Deemyad and Isaac F. Silvera by using innovative technique of pulsed laser heating. Hydrogen-rich alloy Template:SiliconTemplate:Hydrogen was metalized in 2008 and found to be superconducting (by M.I. Eremets et al), confirming earlier theoretical prediction by N. W. Ashcroft. In this hydrogen rich alloy, even at moderate pressures (because of chemical precompression) the hydrogen forms a sublattice with density corresponding to metallic hydrogen. # Metallic hydrogen in other contexts ## Astrophysics Metallic hydrogen is thought to be present in tremendous amounts in the gravitationally compressed interiors of Jupiter, Saturn, and some of the newly discovered extrasolar planets. Because previous predictions of the nature of those interiors had taken for granted metallization at a higher pressure than the one at which we now know it to happen, those predictions must now be adjusted. The new data indicates much more metallic hydrogen must exist inside Jupiter than previously thought, that it comes closer to the surface, and that therefore, Jupiter's tremendous magnetic field, the strongest of any planet in the solar system is, in turn, produced closer to the surface. # Applications ## Nuclear power One method of producing nuclear fusion, called inertial confinement fusion, involves aiming laser beams at pellets of hydrogen isotopes. The increased understanding of the behavior of hydrogen in extreme conditions could help to increase energy yields. ## Fuel It may be possible to produce substantial quantities of metallic hydrogen for practical purposes. The existence has been theorized of a form called 'Metastable Metallic Hydrogen', (abbreviated MSMH) which would not immediately revert to ordinary hydrogen upon the release of pressure. In addition, 'MSMH' would make an efficient fuel itself and also a clean one, with only water as an end product. Nine times as dense as standard hydrogen, it would give off considerable energy when reverting to standard hydrogen. Burned more quickly, it could be a propellant with five times the efficiency of liquid H2/O2, the current Space Shuttle fuel. Unfortunately, the 'Lawrence Livermore' experiments produced metallic hydrogen too briefly to determine whether or not metastability is possible.

Siponimod for treating secondary progressive multiple sclerosis Evidence-based recommendations on siponimod (Mayzent) for treating secondary progressive multiple sclerosis in adults. # Recommendations Siponimod is recommended, within its marketing authorisation, as an option for treating secondary progressive multiple sclerosis with evidence of active disease (that is, relapses or imaging features of inflammatory activity) in adults. It is recommended only if the company provides siponimod according to the commercial arrangement. Why the committee made these recommendations Interferon beta‑1b is the only disease-modifying treatment available for people with active secondary progressive multiple sclerosis. However, few people have it. Most people do not have any disease-modifying treatments. Effective treatment options are therefore very limited. Clinical trial results show that siponimod reduces the number of relapses and slows disability progression compared with placebo. It is uncertain how effective siponimod is compared with interferon beta‑1b because there is no evidence directly comparing them. The most plausible cost-effectiveness estimates for siponimod compared with no disease-modifying treatment and with interferon beta‑1b (Extavia) are in the range that NICE normally considers an acceptable use of NHS resources. Therefore, siponimod is recommended.# Information about siponimod # Marketing authorisation indication Siponimod (Mayzent, Novartis) is indicated for 'the treatment of adult patients with secondary progressive multiple sclerosis with active disease evidenced by relapses or imaging features of inflammatory activity'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics. # Price The list price for siponimod is £1,643.72 per pack of 28×2‑mg tablets (excluding VAT; BNF online, September 2020). The company has a commercial arrangement with the NHS. This makes siponimod available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee (section 5) considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence. # Treatment pathway ## Secondary progressive multiple sclerosis is a continuum of relapsing–remitting multiple sclerosis Relapsing–remitting multiple sclerosis progresses to secondary progressive multiple sclerosis in many people. The patient and clinical experts, company and ERG all indicated that there is a period of transition in which people with relapsing–remitting multiple sclerosis may be suspected of having secondary progressive disease but are not formally diagnosed. This is especially the case for the population in this appraisal (that is, people with active secondary progressive disease) because they may still have relapses. The clinical experts confirmed that multiple sclerosis is a spectrum and does not consist of distinct phenotypic subtypes. The patient and clinical experts acknowledged that, historically, there has been reluctance to diagnose secondary progressive multiple sclerosis. This is because there is only 1 licensed treatment, interferon beta‑1b, which people may have already had. Also, disease-modifying treatments for relapsing–remitting multiple sclerosis are no longer indicated once someone is diagnosed with secondary progressive multiple sclerosis, so treatment usually stops. The clinical experts explained that many factors influence disease progression in multiple sclerosis, including inflammation and age. However, there is a lack of clinical understanding in this area. The committee concluded that secondary progressive multiple sclerosis is a continuum of relapsing–remitting multiple sclerosis, and that various factors contribute to the progression of disease. ## Siponimod could change the timing of diagnosis of secondary progressive multiple sclerosis and involve doing an MRI scan In its submission, the company explained that the availability of a new treatment option for active secondary progressive multiple sclerosis could lead to diagnosing secondary progressive multiple sclerosis earlier. This is because neurologists are reluctant to make the diagnosis without an effective treatment being available (see section 3.1). The clinical experts explained that, if siponimod becomes available, somebody who would usually be diagnosed with secondary progressive multiple sclerosis at an Expanded Disability Status Scale (EDSS) score of 6 may instead be diagnosed at EDSS 4. They explained that diagnosis is currently based on signs and symptoms rather than biochemical or radiological testing. The committee was aware that siponimod's marketing authorisation limits its use to people with 'active' disease, and that the company defined active disease by either relapses or imaging features of inflammatory activity. The clinical experts explained that, if siponimod becomes available, more people would have an MRI scan to assess whether they have secondary progressive disease and identify whether they are eligible for siponimod. They explained that people already diagnosed with secondary progressive disease would have to have MRI scans and visit a neurologist to assess if siponimod is a suitable treatment option. The committee was aware that this additional activity could have a substantial resource impact for the NHS. It concluded that people may be formally diagnosed earlier with secondary progressive multiple sclerosis if siponimod becomes available, and that diagnosis would involve an MRI scan. # Comparators ## Interferon beta‑1b and best supportive care are the relevant comparators Interferon beta‑1b is the only treatment licensed for secondary progressive multiple sclerosis with active disease evidenced by relapses. One brand, Extavia, is recommended in NICE's technology appraisal guidance on beta interferons for multiple sclerosis. The patient and clinical experts explained that many people have difficulty tolerating interferon beta‑1b because it can cause adverse effects such as flu-like symptoms, and involves having subcutaneous injections every other day. Also, the clinical experts reported that healthcare professionals query the efficacy of interferon beta‑1b, so few people with secondary progressive multiple sclerosis have it. An NHS commissioning expert estimated that only about 75 people with secondary progressive multiple sclerosis in England have interferon beta‑1b. So, most people do not have any disease-modifying treatment. In its original base-case analysis, the company compared siponimod with interferon beta‑1b. It also provided scenario analyses comparing siponimod with a range of disease-modifying treatments licensed for relapsing–remitting multiple sclerosis. In its updated base case, the company compared siponimod with best supportive care and with interferon beta‑1b, but not with other disease-modifying treatments. This was in line with the committee conclusions from its first meeting. The company also presented a scenario using a weighted comparator. This included some people who were assumed to be having disease-modifying treatments licensed for relapsing–remitting multiple sclerosis and others who were not. The clinical experts explained that disease-modifying treatments are sometimes used outside of their licensed indications in people with secondary progressive multiple sclerosis during the transition period from relapsing–remitting disease. However, the NHS commissioning expert clarified that the NHS does not commission these drugs for secondary progressive multiple sclerosis, so they should not be considered relevant comparators. The committee concluded that some people diagnosed with active secondary progressive multiple sclerosis have interferon beta‑1b, but that most people have no disease-modifying treatment. This means that patients and their clinicians have limited treatment options, and best supportive care or interferon beta‑1b are the only relevant comparators. The committee further concluded not to consider the weighted comparator in its decision making. # EXPAND clinical trial ## Characteristics of people in the subgroup with active disease from EXPAND reflect the population with active disease in NHS clinical practice The main clinical evidence for siponimod came from EXPAND, a double-blind, randomised, placebo-controlled trial in adults with secondary progressive multiple sclerosis. The randomised part of the trial was followed by an observational period in which everyone was switched to open-label (unblinded) siponimod and followed for up to 10 years. This part of the trial is ongoing. The committee was aware that the marketing authorisation, being limited to active disease, reflected only a portion of the overall trial population. EXPAND enrolled people in 31 countries, including the UK. The primary outcome was the percentage of people with sustained disability lasting at least 3 months, defined as a 1‑point increase in EDSS if the baseline score was 3.0 to 5.0 or a 0.5‑point increase if the baseline score was 5.5 to 6.5. Health-related quality of life data were collected using EQ‑5D. The company suggested that EXPAND was generalisable to the secondary progressive multiple sclerosis population seen in NHS clinical practice because the study had UK sites. However, the committee noted that most sites were not in the UK. The ERG was concerned that outcomes and clinical practice may vary across the countries in the trial. The clinical experts advised that the baseline characteristics reflected people with the condition seen in the NHS. The committee concluded that the baseline characteristics of the subgroup with active disease in EXPAND were similar to the NHS population with active secondary progressive multiple sclerosis, and that the trial results are likely to be generalisable to the NHS population. ## Siponimod is an effective treatment compared with placebo for active secondary progressive multiple sclerosis In the subgroup of people with active disease in EXPAND, both time to 3‑month (the primary endpoint) and 6‑month confirmed disability progression (defined by the same EDSS changes as for the primary endpoint, but lasting at least 6 months) were longer with siponimod than with placebo. The annualised relapse rate was lower with siponimod than with placebo. The full results cannot be reported here because the company considers them confidential. The patient experts explained that the endpoints of 6‑month confirmed disability progression and annualised relapse rate are important to patients, and the clinical experts considered the improvements seen in these endpoints to be clinically meaningful. The committee concluded that siponimod is an effective treatment for active secondary progressive multiple sclerosis compared with placebo. ## It is uncertain whether siponimod has the same effect in disease with and without imaging features of inflammatory activity Based on the possibility that it could not recommend siponimod for use in all patients covered in the marketing authorisation, in its first meeting, the committee was interested in whether siponimod is of more benefit in disease with imaging features of inflammatory activity than without. The clinical experts advised that it is possible to have active disease without any changes in imaging features, and that it is possible to progress in terms of changes on MRI without evidence of clinical progression. For the committee's second meeting, the company provided results for subgroups of the EXPAND active population according to whether the disease was relapsing and whether there were imaging features of inflammatory activity. Based on these results, the company considered siponimod to be an effective treatment regardless of whether or not people have imaging features of inflammatory activity. However, it did not provide a test for interaction. The committee concluded that it remains uncertain whether siponimod compared with placebo has the same effect on disease with and without imaging features of inflammatory activity. # Indirect treatment comparisons ## All of the company's and ERG's indirect treatment comparisons have limitations There is no trial comparing siponimod with interferon beta‑1b. Therefore, the company did an indirect comparison using data from EXPAND and 2 trials of interferon beta‑1b, which reported relevant efficacy outcomes. One trial by the European Study Group, known as the 'European trial', reported annualised relapse rate and 3‑month confirmed disability progression. The other, a North American trial, reported annualised relapse rate and 6‑month confirmed disability progression. The company chose a matching-adjusted indirect comparison as its base case because it considered that differences between EXPAND and the 2 interferon beta‑1b trials made a network meta-analysis unfeasible. The company stated that its analysis used the full trial populations because the trials did not report relevant results separately for people with active disease. The company highlighted differences in the inclusion and exclusion criteria, placebo regimens and response in the placebo arms. The ERG stated that the company did not match for all relevant confounders and effect modifiers in its matching-adjusted indirect comparison. It noted that matching to the data for interferon beta‑1b reduced the EXPAND effective sample size, which increased uncertainty. The ERG did its own network meta-analysis because it did not consider the company's reasons for doing a matching-adjusted indirect comparison instead of a network meta-analysis reasonable. Both the company's and the ERG's analyses favoured siponimod over interferon beta‑1b for the outcome of 6‑month confirmed disability progression, but the wide confidence interval around the ERG's estimate included the possibility of no effect. For annualised relapse rate, both the company's and the ERG's analyses favoured siponimod over interferon beta‑1b, but the confidence intervals for both analyses included the possibility of no effect. The company considered that any network meta-analysis should be based on the population in the marketing authorisation (that is, people with active disease), whereas the ERG used the full EXPAND population. At technical engagement, the company provided an additional network meta-analysis based on the active-disease population from EXPAND. The point estimate of effectiveness for 6‑month confirmed disability progression favoured siponimod compared with interferon beta‑1b, but the confidence interval included the possibility of no benefit. The results cannot be reported here because they are considered confidential by the company. The committee was concerned that, although this network meta-analysis used the active-disease population from EXPAND, it used the full trial populations for the trials of interferon beta‑1b. The committee noted that, in the European trial, about 70% of people had relapses, indicating probable active disease. It questioned whether a matching-adjusted indirect comparison using only this trial data may provide a more reliable result than any of the indirect comparisons it had been presented with so far. However, the committee was aware that the European trial collected only 3‑month rather than 6‑month confirmed disability progression data, which it would normally prefer. In response to consultation, the company explained that the point estimate of effectiveness for 3‑month confirmed disability progression favoured siponimod compared with interferon beta‑1b, but the confidence interval included the possibility of no benefit. The company also expressed concerns that the population in the European trial was younger than in the EXPAND and North American trials, and the effective sample size was lower when using European trial data. The committee concluded that there were substantial uncertainties associated with all of the indirect comparisons. # The company's economic model ## Data from the placebo arm of EXPAND and the London Ontario registry should be used to model untreated secondary progressive multiple sclerosis The company modelled disease progression using 11 health states, 10 defined by EDSS scores ranging from 0 to 9 (with a higher score indicating worse disease) and a death state. It assumed that an effective treatment for secondary progressive multiple sclerosis improves quality of life by delaying the progression of disease to higher EDSS states, and by reducing the frequency of relapses. The company also assumed that treatment improves a carer's quality of life, and that an effective treatment prolongs life by delaying progression to higher EDSS states that are associated with higher rates of death. To model untreated disease (best supportive care), the company used the placebo group from EXPAND supplemented with data from the London Ontario registry. In each cycle, people could move to a higher or lower EDSS state (that is, their disability could worsen or improve) or remain in the same state. The ERG, in discussion with its clinical adviser, highlighted that, over the long term, people with secondary progressive multiple sclerosis will progress to (or sometimes plateau at) higher EDSS states. But, in the short term, if people have a relapse from which they recover, they could improve before they worsen again. The ERG assumed that this short timeframe may be about 2 to 3 months and pointed out that transitions in the model were yearly, so improvements were likely to be very rare. Because the London Ontario data do not allow improvements in the EDSS, the ERG considered it to be more appropriate than the trial data. It also highlighted that these data were collected over 25 years compared with the 2‑year duration of EXPAND. The committee was aware that previous appraisals for relapsing–remitting multiple sclerosis had used both the London Ontario data alone and the trial placebo data supplemented by registry data. The committee considered that, because improvements in EDSS had been seen in the trial, it was reasonable for the model to capture them. The committee concluded that it was appropriate for the company to model untreated disease using data from the placebo arm of EXPAND supplemented by the London Ontario registry. ## The modelled population should have active disease to reflect the marketing authorisation In its base case, the company used baseline characteristics reflecting the subgroup of people with active disease in EXPAND. The ERG considered that the characteristics from the full (intention-to-treat) population should have been used instead because this is the population in whom the treatment effect estimates were derived in both the company's and the ERG's preferred indirect comparison (see section 3.7). The committee was aware that it could appraise treatments only within the marketing authorisation. It considered that the modelled population should match the marketing authorisation for siponimod, which covers people with active secondary progressive multiple sclerosis. The committee concluded that the modelled population should have active disease at baseline. ## Treatment discontinuation rather than study discontinuation provides a better estimate of the number of people stopping siponimod in clinical practice The committee noted that it was unclear whether the company had used study discontinuation or treatment discontinuation from EXPAND to model stopping treatment with siponimod for any reason in its original model. The committee considered that treatment discontinuation rather than study discontinuation would provide a better estimate of the number of people stopping siponimod in clinical practice. The company clarified that its original model used study discontinuation. It agreed with the committee's suggested change and in response to consultation used treatment discontinuation instead in its updated base case. # Utility values in the economic model ## The model should include utility values from the active subgroup of EXPAND supplemented by Orme et al. (2007) To estimate health-related quality of life, the company used EQ‑5D‑3L utility values from EXPAND. It supplemented these with values from a published paper, Orme et al. (2007), for EDSS states 0, 1, 2, 8 and 9 because there were few people with these EDSS values in the EXPAND trial. The ERG considered that there was uncertainty about the EQ‑5D values from EXPAND and that they might not be generalisable to people in the NHS. The ERG preferred to use the data from Orme et al. because they were based on more people than EXPAND. The committee noted that the utility value for EDSS 3 (0.529) from Orme et al. was lower than the value for EDSS 4 (0.565), which the committee considered to lack face validity. The clinical experts explained that the EXPAND data were more recent than the Orme data, so may better reflect advances in supportive care. The committee considered that the model should have included utility values from the subgroup of people with active disease, rather than the full EXPAND population. The company updated its base case in response to consultation to reflect the committee's preferences. # Costs in the economic model ## Costs associated with starting siponimod are appropriately included in the company's model The committee was aware that the company estimated costs for each EDSS state using data from the UK Multiple Sclerosis Survey, which was used in NICE's technology appraisal guidance on dimethyl fumarate for relapsing–remitting multiple sclerosis. The company inflated the prices to 2017/2018 values. The patient and clinical experts explained that many people with secondary progressive multiple sclerosis do not regularly attend a specialist service, especially if they are not having disease-modifying treatments. The clinical and commissioning experts agreed that, if siponimod was offered in the NHS, it would be prescribed by healthcare professionals in a specialist service. Before starting treatment, people being considered for siponimod would attend a neurology clinic and have an MRI scan that they may not previously have been offered (see section 3.2). The clinical experts highlighted that these costs would apply only to people who had already been diagnosed with secondary progressive multiple sclerosis. It would not apply to people who are transitioning from relapsing–remitting to secondary progressive disease, who would generally have regular MRI scans. The company clarified that its original model already included 2 neurology appointments for siponimod each year, including a higher cost of a first appointment as well as a follow-up appointment in the first year. In response to consultation, it also presented a scenario in which it included a third annual neurology appointment and explained that its updated base case included the cost of an additional MRI scan for people starting siponimod. The committee concluded that the company had appropriately modelled costs associated with additional neurology visits and scans in its updated base case. # Waning of siponimod treatment effect ## It is appropriate to model waning of the effect of treatment with siponimod The company presented an analysis of 6‑year data from the open-label extension of EXPAND. It argued that this shows the effect of siponimod treatment does not diminish over time. The committee considered this analysis to be highly uncertain because everyone in the open-label extension had siponimod. Also, there was no comparator arm that could be used to confidently estimate siponimod's relative treatment effect. In its original analysis, the company considered the rate at which people stop treatment for any reason to be a suitable proxy for the waning of treatment effect with siponimod in the model. This was because, if siponimod stops working, people are likely to stop taking it. The committee considered that the company's original approach may have overestimated the benefits of siponimod if people remain on treatment even if its efficacy decreases over time. Including a waning of the treatment effect in the model would help to address this possibility. The clinical experts explained that it is difficult to comment on whether the effect of treatment with siponimod is likely to wane over time. The committee noted NICE's technology appraisal guidance for fingolimod, which has a related mechanism of action to siponimod. In that appraisal, the committee concluded that the treatment effect was likely to wane. In response to consultation, the company updated its base case to include a 50% decrease in siponimod's effectiveness from year 11 of treatment onwards. It also presented a scenario with a 25% decrease in effectiveness from year 7 to year 10 of treatment, then a 50% decrease from year 10 onwards. The committee concluded that the company appropriately included waning of siponimod's treatment effect in its updated model. # Innovation ## The company's model may not capture all the benefits of treatment with siponimod The company explained that it considered siponimod to be innovative because it is taken orally, whereas interferon beta‑1b is a powder that must be mixed with solvent and injected subcutaneously. Therefore, people are likely to find siponimod easier to take. Consultees noted that people with impaired motor function are likely to find it particularly difficult to self-administer interferon beta‑1b, so this is a potential equality issue. The company also suggested that the beneficial effects of siponimod on cognitive processing have not been captured in the modelling. It presented results from EXPAND showing improvements in the symbol digit modalities test score (a test for assessing cognitive processing in multiple sclerosis) with siponimod compared with placebo. The ERG agreed with the company that there was some evidence suggesting that siponimod benefits cognitive processing speed and that the EQ‑5D may not have fully captured this. The committee agreed that such benefits could be important. However, the symbol digit modalities test score was only 1 exploratory endpoint of the EXPAND trial, and the committee did not see the other exploratory endpoints, so it was difficult to draw conclusions using this score alone. However, the committee concluded that the benefits related to ease of administration had likely not been captured in the model. # Cost-effectiveness estimate ## The company's updated base case reflects the committee's preferred assumptions Following changes made in response to consultation, the company's updated analysis reflected the committee's preferences as follows: a comparison of siponimod with interferon beta‑1b and best supportive care in a probabilistic fully incremental analysis treatment discontinuation rather than study discontinuation used to estimate the numbers stopping siponimod in clinical practice utility values from the subgroup of people with active disease from EXPAND supplemented by Orme et al. (2007) costs of neurology appointments and MRI scans for people starting siponimod a waning of the effect of treatment for siponimod.Because of confidential commercial arrangements for siponimod and interferon beta‑1b, the cost-effectiveness results cannot be reported here. ## Siponimod is likely to be a cost-effective use of NHS resources The committee considered the company's base-case cost-effectiveness results based on its matching-adjusted indirect treatment comparison, and a scenario analysis based on its network meta-analysis using the active population from EXPAND. For the comparison with best supportive care, the committee noted that the EXPAND trial compared siponimod with placebo directly. Therefore, the company could have used the trial results as a source of effectiveness evidence in the model without the need for an indirect comparison. This analysis was not available. However, the committee noted that the hazard ratio for 6‑month confirmed disability progression was more favourable for siponimod in EXPAND than in the company's network meta-analysis. It was therefore satisfied that the incremental cost-effectiveness ratio would decrease if the EXPAND results were used instead of the network meta-analysis. The committee noted that some uncertainty remained about the cost-effectiveness results because of uncertainties associated with the indirect comparisons. However, the committee appreciated the steps taken by the company to resolve some of this uncertainty, including presenting an updated analysis that was in line with its preferences. The committee also noted that there were limited alternative treatment options for this population (see section 3.3). Taking this into account, the committee was satisfied that the cost-effectiveness estimates were within the range that NICE normally considers an acceptable use of NHS resources.

INSIDE: Continuing Education Examination depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction Improving preconception health can result in improved reproductive health outcomes, with potential for reducing societal costs as well (1)(2)(3)(4). Preconception care aims to promote the health of women of reproductive age before conception and thereby improve pregnancy-related outcomes (5)(6)(7). Therefore, the goals of the 10 recommendations in this report are to improve a woman's health before conception, whether before a first or a subsequent pregnancy. The recommendations are 1) individual responsibility across the lifespan, 2) consumer awareness, 3) preventive visits 4) interventions for identified risks, 5) interconception care, 6) prepregnancy checkup, 7) health insurance coverage for women with low incomes, 8) public health programs and strategies, 9) research, and 10) monitoring improvements. Since 1996, progress in the United States to improve pregnancy outcomes, including low birthweight, premature birth, and infant mortality has slowed, in part, because of inconsistent delivery and implementation of interventions before pregnancy to detect, treat, and help women modify behaviors, health conditions, and risk factors that contribute to adverse maternal and infant outcomes (8). This report discusses several interventions that, if implemented before pregnancy, can improve pregnancy outcomes for women and infants. However, millions of women and couples do not receive such interventions and services (8). Childbearing is a common experience among women in the United States. In 2000, an estimated 62 million U.S. women were of childbearing age (aged 15-44 years), distributed in approximately equal segments across the age groups of 15-24, 25-34, and 35-44 years (9). By age 25 years, approximately half of all women in the United States have experienced at least one birth, and approximately 85% of all women in the United States have given birth by age 44 years. In 2003, the fertility rate was 66 live births per 1,000 women aged 15-44 years, with highest rates among women aged 25-29 years (114 per 1,000) and lowest rates among women aged >44 years (0.5 per 1,000). A similar age pattern has been observed within racial/ethnic populations, although women aged <25 years who are non-Hispanic black and Native American had higher fertility rates than non-Hispanic whites and Asian/ Pacific Islanders. Hispanic women have the highest fertility rates overall and within each age group (10). In a 2004 survey of women aged 18-44 years, 84% had a health-care visit during the previous year, and slightly more than half (55%) of women of reproductive age obtained preventive health services in any given year, which are opportunities to deliver preconception care (11). Because approximately one third to half of women have more than one primary care provider (i.e., generally a family physician or internal medicine physician and an obstetrician/ gynecologist) (12), all providers who routinely treat women for well-woman examinations or other routine visits play an important role in improving preconception health. However, only approximately one of six obstetrician/gynecologists or family physicians had provided preconception care to the majority of the women for whom they provided prenatal care (13). Another study reported that mothers frequently interacted with pediatricians after the birth of one child and before conception of another, which affords another opportunity to promote preconception health care (14). Community health centers and other Federally Qualified Health Centers (FQHC), including primary care and prenatal care, deliver services to approximately 4.5 million women of childbearing age each year (15). These centers can be used to provide preconception care to women with low incomes (income <200% of the federal poverty level) and with no health insurance. This report provides recommendations to improve both preconception health and preconception health care. Several of the medical conditions, personal behaviors, psychosocial risks, and environmental exposures associated with negative pregnancy outcomes can be identified and modified before conception through clinical interventions. For certain conditions, opportunities for preventive interventions occur only before conception. Establishing preconception health screening as part of routine care for women of reproductive age has been discussed in previously published reports (2,5,6,7,13,14). However better health care alone will not achieve optimal improvements in women's preconception health and reproductive outcomes. Health promotion activities to modify personal knowledge and attitudes and behaviors related to reproductive risk factors and the use of a reproductive life plan for women and couples also have been proposed (16,17). A reproductive health plan reflects a person's intentions regarding the number and timing of pregnancies in the context of their personal values and life goals. This health plan might increase the number of planned pregnancies and encourage persons to address risk behaviors before conception, reducing the risk for adverse outcomes for both the mother and the infant. The recommendations should be used by consumers, clinical care providers, public health professionals, researchers, policy makers, and others concerned with the health of women, children, and families. Federal, state, and local public health agencies can play a vital role in translating these recommendations into projects, educational materials, and programs designed to improve preconception health. Primary care providers serving women of reproductive age, including obstetrician/gynecologists, family physicians, nurse midwives, nurse practitioners, and others working in various clinical settings, have an equally critical role to play in implementing these recommendations. CDC developed these recommendations by 1) reviewing published research; 2) convening the CDC/ASTDR Preconception Care Work Group, representing 22 programs; 3) evaluating presentations of best and emerging practice models at the National Summit on Preconception Care in 2005; and 4) convening the Select Panel on Preconception Care (SPPC), comprised of subject matter specialists on obstetrics and gynecology, nursing, public health, midwifery, epidemiology, dentistry, family practice, pediatrics, and other disciplines. Various databases (e.g., PubMed ® ) were searched to iden-tify published studies for review. Search parameters included preconception care, birth outcomes, reproductive health, and women's health. The reports were reviewed by the SPPC of specialists. These recommendations reflect the research, professional opinion, practice in medicine, public health, and related fields, which are sufficient to guide changes in program, practice, and policy. SPPC reviewed evidence to determine the effectiveness of certain interventions of preconception care (e.g., folic acid to prevent neural tube defects and cessation of alcohol use) and identified missed opportunities for dissemination of preconception information. Implementation of these effective interventions can contribute to the health of thousands of women each year. These recommendations are a strategic plan to improve preconception health through clinical care, individual behavior change, community-based public health programs, and social marketing campaigns to change consumer knowledge and attitudes and practices. In addition, they are designed to increase research knowledge related to preconception health and care and to improve reproductive health outcomes for all women and couples. Policy changes at the local, state, and federal levels will be necessary to support several of these recommendations. These policies will address changes in access, payment, and types of services available. Four goals were established for achieving these recommendations: 1) improve the knowledge and attitudes and behaviors of men and women related to preconception health; 2) assure that all women of childbearing age in the United States receive preconception care services (i.e., evidence-based risk screening, health promotion, and interventions) that will enable them to enter pregnancy in optimal health; 3) reduce risks indicated by a previous adverse pregnancy outcome through interventions during the interconception period, which can prevent or minimize health problems for a mother and her future children; and 4) reduce the disparities in adverse pregnancy outcomes. # Preconception Health and Care Preconception care is recognized as a critical component of health care for women of reproductive age (1)(2)(3)(4)(5)7,16,17,(19)(20)(21)(22)(23)(24)(25). The main goal of preconception care is to provide health promotion, screening, and interventions for women of reproductive age to reduce risk factors that might affect future pregnancies (7,16,(22)(23)(24)(25). Preconception care is part of a larger health-care model that results in healthier women, infants, and families (7,16,(26)(27)(28)(29). A substantial number of definitions for preconception care have been used (2)(3)(4)(5)16,19,(30)(31)(32)(33). On the basis of previous guidelines and recommendations, SPPC developed a refined definition for preconception care. Preconception care is de-fined as a set of interventions that aim to identify and modify biomedical, behavioral, and social risks to a woman's health or pregnancy outcome through prevention and management. Certain steps should be taken before conception or early in pregnancy to have a maximal effect on health outcomes. Preconception care is more than a single visit to a health-care provider and less than all well-woman care, as defined by including the full scope of preventive and primary care services for women before a first pregnancy or between pregnancies (i.e., commonly known as interconception care). Improving preconception health and pregnancy outcomes will require more than effective clinical care for women. Changes in the knowledge and attitudes and behaviors related to reproductive health among both men and women need to be made to improve preconception health. Despite several health promotion campaigns aimed at reducing smoking, misuse of alcohol, intimate partner violence, obesity, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), reduction of vaccine-preventable diseases, and exposure to occupational hazards, the majority of U.S. adults are not aware of how these and other health and lifestyle factors influence reproductive health and childbearing (34,35). Preconception health promotion, therefore, should focus on a general awareness among men and women regarding reproductive health and risks to childbearing (26). # Healthy People 2000/2010 Objectives for Improving Preconception Health and Guidelines for Preconception Care A Healthy People 2000 objective (objective 14.3) is for 60% of primary care physicians to provide age-appropriate preconception care (36). This objective was deleted from Healthy People 2010 because it was not being measured. Although no specific objective for preconception exists, several of those specified in Healthy People 2010 are relevant to preconception health (37,38). The Institute of Medicine, several national committees, and a substantial number of professional organizations have established guidelines and recommendations regarding the importance and content of preconception health care (1,3,4,(30)(31)(32)(33). The primary objective of these reports is to improve the health of women, children, and families. The previously issued evidence-based guidelines for preconception care have been summarized and are the foundation for the recommendations developed by SPPC. The American Academy of Pediatrics (AAP) and the American College of Obstetricians and Gynecologists (ACOG) have classified the main components of preconception care into four categories of interventions: physical assessment, risk screening, vaccinations, and counseling. Eight areas of risk screening are 1) reproductive awareness; 2) environmental toxins and teratogens; 3) nutrition and folic acid; 4) genetics; 5) substance use, including tobacco and alcohol; 6) medical conditions and medications; 7) infectious diseases and vaccination; and 8) psychosocial concerns (e.g., depression or violence) (3,24,(26)(27)(28)(29)(30)(31)33). Preconception care should be an essential part of primary and preventive care, rather than an isolated visit (4,5,(21)(22)(23)(24)(25)(26)32,39,40). Whereas a prepregnancy planning visit in the months before conception has been recommended (3,19,31), improving preconception health will require changes in the process of care, including the types of screening and riskreduction interventions offered to women of childbearing age. Guidelines for Perinatal Care, jointly issued by AAP and ACOG, has recommended that all health encounters during a woman's reproductive years, particularly those that are a part of preconception care, should include counseling on appropriate medical care and behavior to optimize pregnancy outcomes (41). Recommendations from these organizations are analogous to the risk screening recommended by the American Heart Association for cardiovascular disease (42). Several national organizations have recommended the routine delivery of preconception care. For example, the March of Dimes has recommended that the key physician/primary care provider and the obstetrician/gynecologist take advantage of every health encounter to provide preconception care and risk reduction before and between conceptions, the time when health encounters can improve health status (39). # Preconception Risks Associated with Adverse Pregnancy Outcomes Risk factors for adverse outcomes among women and infants occur during the preconception period and are characterized by the need to start, and sometimes finish, intervention(s) before conception occurs. In a systematic review, researchers (43) discussed published reports that identified a list of risk factors for which preconception care (i.e., risk assessment, health promotion, and interventions) can be effective. Women of childbearing age suffer from various chronic conditions and are exposed to (or consume) substances that can have an adverse effect on pregnancy outcomes, leading to pregnancy loss, infant death, birth defects, or other complications for mothers and infants. For example, in 2002, approximately 6% of adult women aged 18-44 years had asthma, 50% were overweight or obese, 3% had cardiac disease, 3% were hypertensive, 9% had diabetes, and 1% had thyroid disorder (44). Dental caries and other oral diseases also are common (>80% of women aged 20-39 years) and associated with complications for women and infants. In addition to having chronic diseases, a substantial proportion of women who become pregnant engage in high-risk behaviors and contribute to adverse pregnancy outcomes. In 2003, a total of 11% of pregnant women smoked during pregnancy, a risk factor for low birthweight (10), and 10% of pregnant women and 55% of women at risk for getting pregnant (i.e., those not using contraception or using ineffective contraceptive methods or using effective contraceptive methods inconsistently) consumed alcohol, a risk for fetal alcohol syndrome (45). Certain women also continued to engage in high-risk sexual behavior, potentially exposing themselves to sexually transmitted diseases (STDs), including HIV (46). Although a smaller proportion of women used illicit drugs, this high-risk behavior has been associated with adverse outcomes. These behaviors often co-occur, therefore, compounding the risk for adverse outcomes for certain groups. Immunization for adults and infants is critical for preventing infectious diseases (e.g., influenza and pertussis). Data from the Pregnancy Risk Assessment and Monitoring System (PRAMS) in four states (i.e., Maine, Michigan, Oklahoma, and West Virginia) indicated that 38% of mothers who planned pregnancies and an additional 30% who did not plan pregnancies had one or more indications for preconception counseling, including use of tobacco or alcohol, being underweight, or delayed initiation of prenatal care (47). In Minnesota and Washington, data from a telephone survey of women revealed that pregnancy intention was associated with health behaviors before pregnancy that might influence pregnancy outcome, with the most marked differences in smoking and vitamin use (48). Preconception health care is critical because several risk behaviors and exposures affect fetal development and subsequent outcomes. The greatest effect occurs early in pregnancy, often before women enter prenatal care or even know that they are pregnant (4,(23)(24)(25)49). For example, for optimal effect on reducing the risk for neural tube defects, folic acid supplementation should start at least 3 months before conception (50)(51)(52). During the first weeks (before 52 days' gestation) of pregnancy, exposure to alcohol, tobacco, and other drugs; lack of essential vitamins (e.g., folic acid); and workplace hazards can adversely affect fetal development and results in pregnancy complications and poor outcomes for both the mother and infant (45,(53)(54)(55)(56)(57)(58). This evidence demonstrates the potential impact of preconception care on the health of women and their infants. Social determinants of women's health also play a role in pregnancy outcomes. The health status of minority women with low incomes contributes to persistent, and sometimes increasing, disparities in birth outcomes. In one study, the reduced overall health status (including poorer physical and emotional health) of women with low income during the month before pregnancy was associated with an increased risk for preterm labor (59). Socioeconomic status directly and indirectly influences three major determinants of health: healthcare access, environmental exposure, and health behavior (60,61). Racial inequalities in access to effective treatment also influence these determinants of pregnancy outcomes for women and infants (62)(63)(64). The following selected preconception risk factors for adverse pregnancy outcomes and evidence for the effectiveness of preconception care have been used to develop clinical practice guidelines (e.g., AAP and ACOG). - (105)(106)(107)(108)(109). Appropriate weight loss and nutritional intake before pregnancy reduces these risks. - Oral anticoagulant. Warfarin, which is used for the control of blood clotting, has been demonstrated to be a teratogen. To avoid exposure to warfarin during early pregnancy, medications can be changed to a nonteratogenic anticoagulant before the onset of pregnancy (110-112). - STD. Chlamydia trachomatis and Neisseria gonorrhoeae have been strongly associated with ectopic pregnancy, infertility, and chronic pelvic pain. STDs during pregnancy might result in fetal death or substantial physical and developmental disabilities, including mental retardation and blindness (113,114). Early screening and treatment prevents these adverse outcomes. - Smoking. Preterm birth, low birthweight, and other adverse perinatal outcomes associated with maternal smoking in pregnancy can be prevented if women stop smoking before or during early pregnancy. Because only 20% of women successfully control tobacco dependence during pregnancy, cessation of smoking is recommended before pregnancy (115)(116)(117)(118). Several providers and maternal and child health researchers have recommended that health risks and behaviors be addressed during any encounter with the health-care system because approximately half of pregnancies in the United States are unintended (20,22,27,119,120). One clinical trial has indicated that provision of preconception care can increase pregnancy planning and intention (121). This finding is vital because studies have consistently demonstrated that planned pregnancies typically have improved outcomes for both women and infants. # Preconception Prevention and Intervention Since 1987, several reviews of published reports have assessed the evidence and documented the effectiveness for specific preconception interventions (2,5,33,43). A systematic review of 21 research trials published during the 1990s have strengthened the evidence base for preconception care in particular areas (e.g., folic acid deficiency, maternal PKU, and oral anticoagulant; 43). The effectiveness of several interventions that address the risk factors for adverse outcomes (19,33,43) have been documented, including folic acid supplementation (51,52,(122)(123)(124)(125); appropriate management of hyperglycemia (126)(127)(128)(129)(130)(131); rubella, influenza, and hepatitis vaccination; low phenylalanine diet (132)(133)(134); and provision of antiretroviral medications to reduce the risk for mother-to-child HIV transmission (97). Interventions for smoking and alcohol cessation (135)(136)(137)(138)(139) have been demonstrated to be effective in certain populations; however, they have been less effective with persons at highest risk (e.g., injection-drug users and polysubstance users). A list of core interventions exist that are part of preconception care services. These interventions are risk-specific; providers can screen and provide appropriate interventions for persons who need them. However, the best evidence for the effectiveness of these specific components of preconception care has been documented when the focus of delivery was on a single risk behavior and accompanying intervention, rather than delivery of multiple interventions. Because of the direct links between a mother's oral health and her offspring's risk for dental caries, dental interventions can reduce the risk for prematurity and low birthweight (140)(141)(142)(143). Evidence supporting interventions to reduce motherto-child transmission of cariogenic bacteria supports recommendations for the appropriate use of fluorides and dietary control to reduce maternal salivary reservoirs of cariogenic bacteria, particularly for women who have experienced high rates of dental caries (140). Interventions that address multiple pregnancy-related risk behaviors simultaneously have not been systematically evaluated and are less commonly delivered. The U.S. Preventive Services Task Force (USPSTF) evaluated the effectiveness of interventions related to smoking, alcohol misuse, and obesity, based on studies of interventions delivered in primary care settings that were not complicated by the additional delivery of multiple components of preconception care (69,70,(144)(145)(146)(147). These effective methods for intervention (e.g., the Five As ) for smoking cessation and brief counseling interventions to reduce alcohol misuse, as identified by USPSTF, provide models for the delivery of multiple interventions that can be adapted and tested (69,70). One study has reported the effectiveness of comprehensive preconception care; however, the findings have limited applicability for the implementation of preconception health-care services in the United States because the study was conducted in Hungary (147). One priority for preconception care activities is to ensure that evidence-based interventions are implemented to further improve infant and maternal pregnancy outcomes among women living with chronic conditions. Clinical practice guidelines (CPGs) for preconception care for specific maternal chronic health conditions have been developed by several national health professional groups (25)(26)(27)(28). For example, the American Diabetes Association has developed CPGs that should be followed before pregnancy for women with diabetes (81). The American Association of Clinical Endocrinologists has developed CPGs for women with hypothyroidism who are attempting to conceive (100). CPGs have also been developed for women being treated with teratogenic medications to guide the transition to safer medications. CPGs for women considering pregnancy and who are using antiepileptic drugs or oral anticoagulants have been developed by the American Academy of Neurology ( 77) and the American Heart Association/American College of Cardiologists (78), respectively. Whereas the evidence supporting specific interventions and the importance of intervening before pregnancy are definitive, limited evidence is available to determine effective methods for delivering preconception care and improving preconception health. Only a limited number of studies regarding effectiveness of interventions have been tested for increasing preconception screening, counseling, and intervention in primary care settings (121,148,149). In one randomized clinical trial, preconception risk factors were identified among women who sought care at a hospital primary care clinic for a pregnancy test. In this trial, an average of nine risk factors per woman was identified at the time of a negative pregnancy test. However, notifying women and their clinicians of identified preconception risks did not improve intervention rates (148). In another study in which didactic lectures and chart cues were used, significant increases occurred in risk screening for medical risk factors (15%-44%), medications (10%-30%), domestic violence (10%-57%), and nutrition (9%-50%) among nonpregnant women who attended an innercity hospital gynecologic clinic. However, intervention rates and provider attitudes toward preconception care did not change substantially (149). A prospective study of the effect of preconception health promotion on intendedness of pregnancy revealed that women in a family planning clinic who had received the intervention (22%) during routine visits were more likely to report intended pregnancies than those patients in the same clinic who were not exposed to the intervention (15) (121). A limited number of studies have assessed the best methods for integrating interventions to achieve maximum impact and optimize the use of limited resources. As with other types of preventive care services, time constraints limit physicians' ability to deliver health promotion interventions (144). Preconception care interventions can potentially be integrated into a limited number of model visits to focus on specific content at different visits, as is done for well-child care (150). Integrated and coordinated care services might also provide additional support to improve health outcomes. For example, an evaluation of the quality of care in the National Centers of Excellence in Women's Health indicated that women served in these centers, compared with community samples, received more clinical preventive services and had higher satisfaction levels (151). Another approach (e.g., self-management) to integrated service of delivery has been illustrated in CDC's recommendations in Strategies for Reducing Morbidity and Mortality from Diabetes Through Health-Care System Interventions and Diabetes Self-Management Education in Community Settings: A Report on Recommendations of the Task Force on Community Preventive Services (152). HIV intervention efforts also have suggested that integrated interventions address substance use and reduce sexual risk behaviors simultaneously. The purpose of preconception care is to deliver risk screening, health promotion, and effective interventions as a part of routine health care. In the United States, this approach is the standard used to achieve prevention of vaccine-preventable disease, heart disease, diabetes, and other chronic conditions. This approach is similar to well-child care, prenatal care, and adult wellness care in which studies have demonstrated the effectiveness of individual components rather than the effectiveness of combined interventions. However, effectiveness depends on ongoing monitoring of health status with interventions. Preconception care should be tailored to meet the needs of the individual woman. Because preconception care needs to be provided across the lifespan and not during only one visit, certain recommendations will be more relevant to women at different life stages and with varying levels of risk. Health promotion, risk screening, and interventions are different for a young woman who has never experienced pregnancy than for a woman aged 35 years who has had three children. Women with chronic diseases, previous pregnancy complications, or behavioral risk factors might need more intensive interventions. Such variations also place constraints on how interventions can and should be integrated. # Context and Frame Work for Recommendations The recommendations are designed to promote optimal health throughout the lifespan for women, children, and families by using both clinical care and population-focused public health strategies. In this report, the approach to promoting preconception health is not a single clinical visit but a process of care and interventions designed to address the needs of women during the different stages of reproductive life. SPPC has encouraged the use of a broad definition of prenatal care that includes ongoing preconception interventions, the addition of a prepregnancy visit, multiple postpartum visits, and the currently recommended prenatal care visits. Preconception care offers health services that allow women to maintain optimal health for themselves, choose the number and spacing of their pregnancies and, when desired, prepare for a healthy baby. Interventions and health care that occur before and between pregnancies are included in this report. This review identified areas for which further research is needed (43). Increasing evidence-based research of clinical and public health interventions by using both qualitative and quantitative methods is essential to the fulfillment of these recommendations. Each of the 10 recommendations has specific action steps that can be implemented in the next 2-5 years. Increasing access to and use of preconception care will not occur immediately; diffusion of innovation theory demonstrates how slowly concepts and best practices are typically disseminated (153,154). The action steps recommend revision of professional standards of care, modification of provider behaviors, development of effective health promotion messages, changes in consumer behavior, and adjustments to payment mechanisms. In addition, the recommendations emphasize individual behavior and responsibility for improving preconception health and identify specific evidence-based strategies for modifying individual knowledge and attitudes and behaviors across the lifespan. The recommendations promote changes in clinical care, public health programs at the federal, state, and local levels, and other community-based programs. For example, quality improvement strategies, commonly used today in clinical practice, might be used to modify provider knowledge and attitudes and behaviors. In addition to participation among traditional partners in public health interventions, improving preconception health will require increased involvement from partners in various sectors (e.g., education, housing, urban planning, and environmental health). These partners should be included as part of the comprehensive solution to improve women's health and the health of families. Approaches to improve surveillance, performance monitoring, and results accountability have been recom-mended along with strategies to integrate care, develop complementary approaches, and reduce duplication of activities among different professional and programmatic stakeholders. The risk and the burden of disease is unequally distributed, and a small number of women experience the majority of the pregnancy-related morbidity and mortality, which suggests that a two-step approach to implementing interventions would be beneficial. The first step would target women at highest risk (whether the risks are biologic or social) to reduce morbidity and mortality. The second step would aim to improve preconception health for all women of reproductive age, regardless of risk status. The recommendations emphasize targeting interventions for groups of women with known risks and conditions (e.g., those with previous poor pregnancy outcomes or chronic conditions). Culturally and linguistically appropriate systems of care are needed to ensure maximal use and impact of preconception health-care services. By increasing the acceptability, effectiveness, and impact of the health-care system through these changes, persons involved in improving preconception health care have the opportunity to address and reduce health disparities. The recommendations are a starting point to make comprehensive preconception care a standard of care in the United States and to provide a more universal, comprehensive, evidence-based model of preconception care. The recommendations will promote the development and practice of preconception care that will be flexible to meet persons' changing reproductive care needs and address risks throughout their lifespan. # How the Recommendations were Developed The recommendations were developed through the collaborative efforts of CDC and external partners to 1) target life stages in reproductive-aged women; 2) encourage special interest groups to collaborate to achieve common goals; 3) encourage scientific and public health collaboration; and 4) address health impact, public health systems, efficiency, and effectiveness. During 2003, a review of studies published regarding maternal and child health and preconception care was conducted by CDC to assess preconception care. The CDC work group also discussed opportunities for collaboration across programs. Several CDC programs in the work group had previously identified specific interventions with scientific evidence which, if delivered before conception, would promote preconception health and improve pregnancy-related outcomes. These programs recognized the need to integrate these interventions with similar services to improve coverage, effectiveness, access, efficiency, and ultimately maternal and infant pregnancy outcomes. The need for preconception health promotion and care was identified as a critical public health topic by CDC and partners. As a result, a broader working group of national organizations involved in preconception health issues were established (Appendix). In November 2004, the CDC work group and representatives of 16 external organizations discussed the evidence supporting preconception care to determine the steps that can be taken to develop national recommendations. The consensus of the participants was that a larger meeting on preconception care and an interdisciplinary panel of specialists should be convened in 2005. A steering committee and planning committee were established (including representatives from CDC and external partners) to plan for a national summit and to bring together a group of specialists with experience in data, practice, and policy issues related to preconception health. In June 2005, a national summit on preconception care was convened to gather information concerning promising practice models. The summit agenda was developed based on 68 submitted abstracts and reflected various preconception project models, finance approaches, and research questions (CDC, unpublished data, 2005). In conjunction with the summit, CDC convened SPPC, which included various subject matter specialists and representatives from national organizations concerned about the health of women, infants, and families. A Delphi technique was used to identify subject matter specialists to serve on SPPC. SPPC discussed recommendations regarding clinical practice, public health/community programs, research/data, and policy/finance. Initial recommendations were sent to the CDC work group, panel members, and additional subject matter specialists from academic and professional backgrounds for comment and review. Reviewers shared their comments in writing or as part of a series of conference calls convened by the SPPC steering committee. # Recommendations to Improve Preconception Health Ten recommendations were developed for improving preconception health through changes in consumer knowledge, clinical practice, public health programs, health-care financing, and data and research activities. Each recommendation has specific action steps. If each action step is implemented, benefits might be observed within 2-5 years, which would help achieve the Healthy People 2010 objectives to improve maternal and child health outcomes. The recommendations are aimed at achieving four goals, based on personal health outcomes. Goal 1. Improve the knowledge and attitudes and behaviors of men and women related to preconception health. Goal 2. Assure that all women of childbearing age in the United States receive preconception care services (i.e., evidence-based risk screening, health promotion, and interventions) that will enable them to enter pregnancy in optimal health. Goal 3. Reduce risks indicated by a previous adverse pregnancy outcome through interventions during the interconception period, which can prevent or minimize health problems for a mother and her future children. Goal 4. Reduce the disparities in adverse pregnancy outcomes. The recommendations are a strategic plan for improving the health of women, their children, and their families and are based on existing knowledge and evidence-based practice. Improving preconception health among the estimated 62 million women of childbearing age (9) will require a multistrategy, action-oriented initiative. The recommendations, which are not prioritized, should be used by consumers, public health and clinical providers, researchers, and policy makers. Therefore, the recommendations should be implemented simultaneously. In the action steps, persons, public health and clinical providers, communities, governments (i.e., local, state, and federal), and professional organizations all have roles. Finally, these recommendations are designed to reduce disparities in maternal and infant health by improving the preconception health of women and men. # Recommendations Recommendation 1. Individual Responsibility Across the Lifespan. Each woman, man, and couple should be encouraged to have a reproductive life plan. The target population for preconception health promotion is women, from menarche to menopause, who are capable of having children, even if they do not intend to conceive. To reach such a broad group, a lifespan perspective is needed (3,17,20), which is commonly used in efforts to reduce chronic diseases, particularly cardiovascular disease. For example, persons are encouraged to consider the role of genetic and dietary factors in determining their risk for high cholesterol and to modify their behaviors according to cumulative individual risks (e.g., changes in diet, exercise, or medications) (155). Similarly, a lifespan approach can be used to focus in-dividual attention on reproductive health to reduce unintended pregnancies, age-related infertility, fetal exposures to teratogens, and to improve women's health and pregnancy outcomes (20). Certain researchers, providers, and health-care advocates have suggested developing a reproductive health life plan for young women and couples as they enter their reproductive years. However, reproductive health life plans have not been systematically implemented and evaluated (23,26,29,33). Implementing such a reproductive health life plan will require a change in provision of health services and health promotion (Box 1). Recommendation 2. Consumer Awareness. Increase public awareness of the importance of preconception health behaviors and preconception care services by using information and tools appropriate across various ages; literacy, including health literacy; and cultural/linguistic contexts. Consumers should be more involved in improving preconception care services. Knowledge and attitudes and behaviors related to reproductive health are influenced by childhood experiences and prevailing social norms among adults. Certain U.S. adults are not aware of the factors that influence reproductive health and childbearing (34,35). The preconception guidelines from Canada state that preconception care is 1) physical preparation for pregnancy and parenting and 2) the social, psychological, and spiritual components of pregnancy. The factors that influence attitudes regarding preconception care include a person's age and life stage, their childbearing history, and their life priorities (156). Activities specifically designed to improve school general health education are an essential step in improving reproductive awareness. Efforts to inform adults regarding the risks and opportunities to improve their health are equally important. Several health promotion campaigns provide opportunities to change adult knowledge and attitudes and behaviors, - Develop, evaluate, and disseminate age-appropriate educational curricula and modules for use in school health education programs. - Integrate reproductive health messages into existing health promotion campaigns (e.g., campaigns to reduce obesity and smoking). - Conduct consumer-focused research to identify terms that the public understands and to develop messages for promoting preconception health and reproductive awareness. - Design and conduct social marketing campaigns necessary to develop messages for promoting preconception health knowledge and attitudes, and behaviors among men and women of childbearing age. - Engage media partners to assist in depicting positive role models for lifestyles that promote reproductive health (e.g., delaying initiation of sexual activity, abstaining from unprotected sexual intercourse, and avoiding use of alcohol and drugs). # Box 2. Recommendation 2 preconception health action steps including campaigns designed to reduce tobacco use, promote responsible use of alcohol, and encourage healthy diet and optimal weight. Campaigns can include messages concerning reproductive health and childbearing. Such campaigns typically focus on the effect of adverse behaviors on children and do not include parallel messages regarding the potential impact on childbearing. New social marketing and health promotion campaigns that focus on how to prepare for childbearing and parenting can influence the behavior of men and women. For example, folic acid intake has been promoted among women of childbearing age (123). Similar to efforts to reduce teenage childbearing or increase use of prenatal care, the media can play a vital role in promoting reproductive awareness (157). Success in improving preconception health will require changes in public attitudes and has been achieved in other areas (e.g., attitudes changed during the previous 10 years regarding tobacco use, infant sleep position, or vaccinations for infants and toddlers instead of preschoolers) (158). A critical tool for stimulating these changes is social marketing, which is designed to influence the voluntary behavior of targeted audiences to improve their well-being (159,160). Consumer-friendly tools can help women self-assess risks, make plans, and take actions that will improve their health and that of their children. More consumer-focused research is needed to determine which messages and tools might be effective to encourage reproductive life planning. The SPPC members have suggested that such research explore which terms the public best understands, what messages might increase demand for services, and how touch-screen kiosks or other technology might be used to promote knowledge of preconception health topics (Box 2). Recommendation 3. Preventive Visits. As a part of primary care visits, provide risk assessment and educational and health promotion counseling to all women of childbearing age to reduce reproductive risks and improve pregnancy outcomes. Integration of preconception components into primary care can better serve women across their lifespan and at various levels of risk. Primary care integrates various health promotion, prevention, and acute care services to address the majority of personal health-care needs and common health problems in a community setting. Primary care also might include screening for and ongoing management of chronic conditions in a primary care setting. Elements of preconception care can be integrated into every primary care visit. Professional guidelines for clinicians (i.e., obstetrician/gynecologists, family practice physicians, certified nurse midwives, and nurse practitioners) who provide the majority of primary care to women in the United States should include routine risk assessment through screening (14,24,28,29,33). Different guidelines recommend eight to 10 specific areas for preconception risk assessment, including: 1) reproductive history; 2) environmental hazards and toxins; 3) medications that are known teratogens; 4) nutrition, folic acid intake, and weight management; 5) genetic conditions and family history; 6) substance use, including tobacco and alcohol; 7) chronic diseases (e.g., diabetes, hypertension, and oral health); 8) infectious diseases and vaccinations; 9) family planning; and 10) social and mental health concerns (e.g., depression, social support, domestic violence, and housing) (5)(6)(7)30,31,33,40,41). In addition to risk assessment or screening, professional guidelines include health promotion education and counseling related to reproductive health risks. Such activities should routinely include promotion of healthy behaviors; discussion of child spacing, family planning, and unintended pregnancy prevention; counseling concerning healthy diet, folic acid supplementation, and optimal weight; immunization for infectious disease; information regarding the importance of early prenatal care; and counseling concerning the availability of social and financial support programs. For women with identified risks, additional counseling, testing, and brief interventions (e.g., for smoking, alcohol, or changes in prescription medications) can be conducted in the primary care setting (68)(69)(70)(116)(117)(118) (e.g., a limited number of model visits), as is done for wellchild care. Clinical practice can be influenced by evidence-based guidelines, but additional strategies are needed to promote widespread adoption of professional guidelines (25,(30)(31)(32)(33)(151)(152)(153)(154). In the recommended action steps (Box 3), additional activities should be provided to support changes in primary care provider knowledge and attitudes and practices. Consolidation of existing guidelines, better tools, and use of quality improvement techniques have fostered changes in knowledge and practices (161)(162)(163)(164). For example, the Bright Futures Program has consolidated guidelines for child health, and the Bright Futures for Women's Health and Wellness offers models and opportunities for links to preconception care (165). Community health centers and other FQHC can be a key point of dissemination for strategies to improve preconception health. FQHC are a critical source of primary care for millions of women with low incomes and no insurance. Perinatal care for 332,000 women account for one of every 10 U.S. births (166). Among FQHC, the Health Disparities Collaboratives (HDC) Initiative is designed to improve the quality of primary care delivered, and approximately 600 FQHCs have participated (167). The HDC model relies on partnerships among community clinics, federal agencies, and national organizations. HDC started with a chronic disease care model for quality improvement, and a primary healthcare model integrated with the perinatal care collaboratives and other efforts has been developed. # Recommendation 4. Interventions for Identified Risks. Increase the proportion of women who receive interventions as follow-up to preconception risk screening, focusing on high priority interventions (i.e., those with evidence of effectiveness and greatest potential impact). Timely preconception interventions for certain conditions can substantially improve maternal health and birth outcomes (4,43). Separating childbearing from the management of chronic health problems and infectious diseases places women, their future pregnancies, and their future children at unnecessary risk (7,20,24,149). Conditions and risk factors have been identified for which the following exist 1) evidence of potential harm to mother or baby, 2) high prevalence of adverse pregnancy outcome or effective interventions for reducing adverse pregnancy outcomes, and 3) one or more effective interventions that have been evaluated. Certain women and men need additional counseling and interventions. For example, women who have conditions treated with medications that are known teratogens (e.g., anticonvulsant or anticoagulant medications and isotretinoins) might need to change prescriptions. Women with medical conditions associated with increased risks for morbidity and mortality to mother and fetus (e.g., diabetes, hypertension, heart disease, rubella sero-negativity, thrombophilias, dental disease, or obesity) need to control these conditions. Women with behaviors associated with increased health risks for the fetus (e.g., smoking and alcohol and illicit drug use) also need targeted interventions. Another group with specific counseling needs includes prospective parents with a family history of inherited (i.e., genetic) disorders. The preparers of this report analyzed the National Ambulatory Medical Care Survey (168) and demonstrated that diabetes affects approximately 1.85 million (21 per 1,000) women in the United States aged 18-44 years, and that preconceptional diabetes management has the potential to reduce the risk for pregnancy loss and congenital malformation for approximately 113,000 births per year. Anti-epileptic/ - Increase health provider (including primary and specialty care providers) awareness concerning the importance of ongoing care for chronic conditions and intervention for identified risk factors. (168). Women with chronic medical conditions and their specialty providers should take advantage of every opportunity to discuss preconception health and risks. These conditions and risk factors affect substantial proportions of the approximately 4 million pregnancies that occur in the United States each year. Studies of preconception care have indicated that providers do not routinely provide interventions for identified preconception risks (23,147,148,164,169). Dissemination of professional guidelines and evidence-based interventions are two vital ways to encourage changes in practice. However, quality improvement tools and techniques offer increased potential, particularly for specific interventions for women with identified conditions (162,170). Research has increasingly indicated that providers and health-care organizations are more likely to engage in evidence-based or best clinical practices, after participation in quality improvement projects (e.g., rapid improvement cycles using the plan/do/study/act approach, collaborative groups, or the model of improvement process that involves an aim/change/measure cycle) (162,170). Incorporation of preconception care modules into the curricula of medical graduate, postgraduate, and continuing medical education might be another method of disseminating messages regarding the importance and content of preconception care for women (Box 4). Recommendation 5. Interconception Care. Use the interconception period to provide additional intensive interventions to women who have had a previous pregnancy that ended in an adverse outcome (i.e., infant death, fetal loss, birth defects, low birthweight, or preterm birth). Experiencing an adverse outcome in a previous pregnancy is an important predictor of future reproductive risk (171)(172)(173). However, many women with adverse pregnancy outcomes do not receive targeted interventions to reduce risks during future pregnancies. Each year, approximately 28,000 infants die during the first year of life (171). Approximately 12% of all births are preterm (i.e., <37 weeks' gestation) (10), and an estimated 3% of infants are born with birth defects (174). Whereas a preterm birth is identified on birth certificates and a woman's primary care provider typically knows this information, professional guidelines do not include systematic follow-up and intervention for women with this critical predictor of risk. Postpartum visits are an opportunity to link women to interventions designed to reduce risks to them and their future chil-dren, and promising strategies focus on the postpartum period (170). The Health Employer Data and Information Set (HEDIS), used by public and private health plans, has measures for postpartum visits. HEDIS data indicate that 80% of women with private (i.e., commercial) insurance coverage and 55% of those covered by Medicaid receive postpartum checkups. However, for the majority of health plans, strategies to encourage compliance or address low rates of return for postpartum care have not been implemented (44). Measures for monitoring postpartum visits also are used by a limited number of state Title V Maternal Child Health Block Grant agencies (175). Data collected during postpartum visits typically have not been used to guide health-care system planning. Approaches to interconception care, which are part of preconception care, have been proposed (176,177), and certain approaches have been tested. For example, in the Interpregnancy Care Program of Grady Memorial Hospital in Atlanta, Georgia, researchers have been studying the effectiveness of interconception care in improving subsequent reproductive outcomes for women who have delivered a baby born at very low birthweight (<1,500 grams). This model focuses on reducing identified medical, dental, and psychosocial risks and assisting women in developing and - Consolidate existing professional guidelines to develop the recommended content and approach for such a visit. - Modify third party payer rules to permit payment for one prepregnancy visit per pregnancy, including development of billing and payment mechanisms. - Educate women and couples regarding the value and availability of prepregnancy planning visits. # Box 6. Recommendation 6 preconception health action steps achieving their reproductive goals for the future. During the pilot phase, the program identified and treated various medical conditions and reported substantial positive impact on the length of birth intervals (177). The federal Healthy Start program requires that a grantee follow a woman and her child for 2 years postpartum, providing interconception care. In addition, certain Healthy Start grantees provide more in-depth interconception services to women at high risk to reduce future adverse pregnancy outcomes (175). Across the United States, Healthy Start grantees (e.g., the Magnolia Project in northeastern Florida) are providing intensive postpartum case management for women at high risk for adverse pregnancy outcomes (178)(179). Opportunities are available to identify, refer, and serve women at high risk in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) nutrition sites, family planning clinics, and home visiting programs (175). Federal and state agencies can support such efforts with funding for demonstration, evaluation, and replication projects (Box 5). Recommendation 6. Prepregnancy Checkup. Offer, as a component of maternity care, one prepregnancy visit for couples and persons planning pregnancy. SPPC encourages the use of a broad definition of maternity care that includes the addition of a prepregnancy visit and the recommended prenatal and postpartum visits. The addition of this prepregnancy visit is an essential step toward improving pregnancy outcomes, particularly for those planning pregnancy. The Institute of Medicine Panel on Preventing Low Birthweight, the U.S. Public Health Service Expert Panel on the Content of Prenatal Care, and the national Committee on Perinatal Health have recommended that women have a prepregnancy visit (i.e., sometimes called a preconception visit) in the months before conception (1,3,4). Such visits would include preconception care content, providing women an opportunity to benefit from risk assessment, health promotion, and specific interventions related to circumstances when couples are trying to conceive. Adoption of the prepregnancy visit as a standard of care also can help to reinforce the importance of pregnancy planning and preparedness among women and men (Box 6). # Recommendation 7. Health Insurance Coverage for Women with Low Incomes. Increase public and private health insurance coverage for women with low incomes to improve access to preventive women's health and preconception and interconception care. Affordability of care is a major concern for multiple women (11,180,181), and improved access to preconception care is needed. Approximately 17 million women do not have health insurance, and they are more likely to postpone or forgo care (180). During 2003, one third of women with low incomes, half of women with disabilities, and 18% of all nonelderly (aged <65 years) women did not have health insurance (180). Younger women aged 18-34 years were more likely than older women not to have health insurance during 2003. Reflecting their income and employment status patterns (i.e., more likely to have incomes <200% of poverty level and less likely to be employed in jobs that offer health insurance), non-Hispanic white, Asian, and non-Hispanic black women were more likely than non-Hispanic white women not to have health insurance (11,180,181 # Box 7. Recommendation 7 preconception health action steps Medicaid is the primary mechanism for extending health coverage to women with low incomes and who do not have health insurance. During 2003, a total of 12% of all women of childbearing age and 37% of women with low incomes in that age group relied on Medicaid for health-care coverage (181,182). Medicaid has been demonstrated to be effective in improving access to health care for women with low incomes (179). Because nearly two thirds (63%) of women covered by Medicaid are of childbearing age, the program's performance is related to preconception care access and to the outcomes of pregnancy (183). Many women with low incomes, however, do not qualify for Medicaid because they do not have children aged <18 years or do not have documentation of legal residence in the United States. As states seek to expand Medicaid coverage to persons with low incomes and adults who do not have health insurance, women of childbearing age should receive priority for qualifying for Medicaid coverage. Since 1995, a total of 22 states have used their federal waiver authority to expand family planning services to women who do not otherwise qualify for Medicaid, known as family planning waivers. Certain states offer coverage to women who lose coverage after the birth of a baby or starting a job, whereas other states offer family planning coverage based on the income status of men and women (182). An evaluation of these family planning waiver projects prepared for the federal Center for Medicare and Medicaid Services indicated that the projects resulted in substantial savings to both the federal and state governments (184). Increased potential savings and prevention, however, can result if states provided coverage for more comprehensive risk screening, health promotion, and interventions, resulting in higher levels of preconception wellness (Box 7). # Recommendation 8. Public Health Programs and Strategies. Integrate components of preconception health into existing local public health and related programs, including emphasis on interconception interventions for women with previous adverse outcomes. Public health programs serve millions of women each year. Preconception interventions can be incorporated into these programs to target women at highest risk. Title X family planning programs provide approximately 4.6 million women with family planning education and contraceptives and pregnancy tests. However, a limited number of programs offer more comprehensive risk screening, reproductive health promotion, and reproductive life planning (185). Each year, WIC provides nutrition screening and counseling, supplemental food, and referrals to health services for approximately 8 million women during pregnancy and the postpartum period (186). These services provide an opportunity to promote preconception health and refer women at risk to clinicians. Federal and state public health programs funded by the Title V Maternal and Child Health Services Block Grant and CDC can give greater priority to preconception health and offer support for demonstration projects and evaluations of prevention programs. Whereas federally funded Healthy Start projects are required to have interconception health activities, these projects, located in communities with high infant mortality, provide opportunities to offer more systematic preconception screening, health promotion, and interventions. Publicly funded programs that offer screening and related services for STDs and HIV/AIDS also might provide risk assessment and health promotion interventions. Title X, WIC, Title V, Healthy Start, and other public health programs also provide a setting to test and evaluate new approaches to improve preconception health (44,187). Strategies to promote dialogue and action among community members for a geographically defined community or a community of professionals can help advance these recommendations and action steps (Box 8). Local task force groups that involve consumer, community leaders, and health professionals can help implement preconception strategies that are similar to strategies used previously for other topics (e.g., adolescent pregnancy prevention and childhood vaccinations). Functioning parallel to clinical practice collaboratives, public health practice collaboratives that link local public health programs can promote development and dissemination of community-based best practices. Recommendation 9. Research. Increase the evidence base and promote the use of the evidence to improve preconception health. At the state and local levels, PRAMS, Perinatal Periods of Risk, Fetal-Infant Mortality Review, and youth risk behavior surveys provide additional opportunities for the data collection, analysis, and interpretation that comprise public health surveillance (190,(192)(193)(194). The Maternal and Child Health Bureau, in cooperation with states, operates the Title V data and information system, which provides an opportunity to strengthen public health surveillance and performance monitoring. A review of stateselected performance measures and priority needs for 2006-2010 indicated that a limited number of states are monitoring trends for access to components of preconception and interconception care, access to primary care for women of childbearing age, unintended pregnancy, and other related topics (175). Since 1990, indicators and monitoring systems have been used not only to assess programs at the population level but also to measure the quality of health-care services. HEDIS is an example of a set of measures commonly used by purchasers of health-care coverage, including state Medicaid agencies and employers. HEDIS includes indicators on prenatal and postpartum care and family planning (195). New HEDIS measures are needed to monitor access to, use of, and outcomes of preconception care services as well as improved maternal and infant health. The recommendations in this report can be used as a frame work for developing or modifying # Box 9. Recommendation 9 preconception health action steps Additional evidence is needed regarding the effectiveness of interventions, the value of better service integration, and the potential cost benefit of preconception care for the general population and for women at high risk for poor pregnancy outcomes. Evaluations of preconception health programs and projects can help advance understanding of the potential impact of selected approaches. For certain clinical interventions (e.g., interventions to address multiple risk factors simultaneously or single risk factor interventions), randomized clinical trials are warranted, although not all preconception health interventions can be ethically tested in this manner. Economic studies, particularly of clinical intervention strategies, can support the case for wider dissemination of preconception care practices (188; Box 9). # Recommendation 10. Monitoring Improvements. Maximize public health surveillance and related research mechanisms to monitor preconception health. Community health data are used systematically to conduct public health surveillance to evaluate and improve health, health programs, and health policy (187). Surveillance includes monitoring the frequency of conditions, risk factors, services, and outcomes. CDC and other public health agencies conduct surveillance and maintain data collection and surveillance systems, and the field of maternal and child health benefits from several of these systems. For example, PRAMS, the Behavioral Risk Factor Surveillance System, and the National Survey of Family Growth (NSFG) can be modified to provide more data concerning preconception health (189- # Conclusion The 10 recommendations for improving preconception care services and the health of women and infants were developed through a process of consultation with a select panel of specialists from the relevant disciplines. Implementation of the recommendations will help achieve the SPPC vision of preconception health and pregnancy outcomes in which 1) women and men of childbearing age have high reproductive awareness (i.e., understand risk factors related to childbearing); 2) women and men have a reproductive life plan (e.g., whether or when they want to have children and how they will maintain their reproductive health); 3) pregnancies are intended and planned; 4) women and men of childbearing age have health-care coverage; 5) women of childbearing age are screened before pregnancy for risks related to the outcomes of pregnancy; and 6) women with a previous adverse preg-nancy outcome (e.g., infant death, very low birthweight or preterm birth) have access to interconception care aimed at reducing their risks. Improving preconception health will require changes in the knowledge and attitudes and behaviors of persons, families, communities, and institutions (e.g., government and healthcare settings). The purpose of preconception care is to improve the health of each woman before any pregnancy and thereby affect the future health of the woman, her child, and her family. The recommendations and specific action steps were developed as a result of SPPC meeting and implementation of CDC's preconception health programs. The frame work has incorporated both an ecological model and a lifespan perspective on health and recognized the unique contributions and challenges encountered by women, their families, communities, and institutions. Improving the health of women can increase the quality of health for families and the community. Several preconception care interventions have reduced risk and improved health outcomes. By increasing support for provision of preconception care, policy makers have the opportunity to promote broad-based programs and services aimed at improving the health of women, children, and families. The recommendations present a conceptual frame work for innovative service delivery models so that women are afforded the benefit of risk-appropriate preconception services during every encounter with the health-care system. - Apply public health surveillance strategies to monitor selected preconception health indicators (e.g., folic acid supplementation, smoking cessation, alcohol misuse, diabetes, and obesity). - Expand data systems and surveys (e.g., the Pregnancy Risk Assessment and Monitoring System and the National Survey of Family Growth) to monitor individual experiences related to preconception care. - Use geographic information system techniques to target preconception health programs and interventions to areas where high rates of poor health outcomes exist for women of reproductive age and their infants. - Use analytic tools (e.g., Perinatal Periods of Risk) to measure and monitor the proportion of risk attributable to the health of women before pregnancy. - Include preconception, interconception, and health status measures in population-based performance monitoring systems (e.g., in national and state Title V programs). - Include a measure of the delivery of preconception care services in the Healthy People 2020 objectives. - Develop and implement indicator quality improvement measures for all aspects of preconception care. For example, use the Health Employer Data and Information Set measures to monitor the percentage of women who complete preconception care and postpartum visits or pay for performance measures. # CDC/ATSDR Preconception Care Work Group Agency for Toxic Substances and Disease Registry: Robert H. Johnson, MD, Division of Health Education and Promotion. # Appendix # Continuing Nursing Education (CNE). This activity for 2.0 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. You must complete and return the response form electronically or by mail by April 21, 2009, to receive continuing education credit. If you answer all of the questions, you will receive an award letter for 1. 75 # Goals and Objectives This report provides an updated review of the evidence for interventions to improve the health of women before pregnancy. The goal of this report is to present 10 recommendations to improve preconception care, focusing on specific activities at the individual, clinical, public health, community, and research levels. Upon completion of this educational activity, the reader should be able to 1) describe the need for preconception health for families, 2) define preconception care, 3) list the 10 recommendations for improving preconception care, 4) list specific action steps for each recommendation, 5) describe the interventions for improving preconception health that are supported by professional guidelines, 6) describe the responsibilities of persons concerned with preconception health, and 7) describe areas of preconception health care that need further research. To receive continuing education credit, please answer all of the following questions.

The Living Guidelines: Prevention of thromboembolism in patients with atrial fibrillation undergoing cardioversion: Polling Results for CLASS IIa Guidelines # Class IIa Guidelines 1. During the first 48 h after onset of AF, the need for anticoagulation before and after cardioversion may be based on the patient’s risk of thromboembolism. (Level of Evidence: C) ACC / AHA 2008 guidelines for diagnosis and management of atrial fibrillation: Class IIa Recommendation 1 for pharmacological cardioversion of atrial fibrillation should be: 2. As an alternative to anticoagulation prior to cardioversion of AF, it is reasonable to perform TEE in search of thrombus in the LA or LAA. (Level of Evidence: B) < ACC / AHA 2008 guidelines for diagnosis and management of atrial fibrillation: Class IIa Recommendation 2 for pharmacological cardioversion of atrial fibrillation should be: 2a. For patients with no identifiable thrombus, cardioversion is reasonable immediately after anticoagulation with unfractionated heparin (e.g., initiate by intravenous bolus injection and an infusion continued at a dose adjusted to prolong the activated partial thromboplastin time to 1.5 to 2 times the control value until oral anticoagulation has been established with a vitamin K antagonist (e.g., warfarin), as evidenced by an INR equal to or greater than 2.0.). (Level of Evidence: B) ACC / AHA 2008 guidelines for diagnosis and management of atrial fibrillation: Class IIa Recommendation 2a for pharmacological cardioversion of atrial fibrillation should be: 2a 1. Thereafter, oral anticoagulation (INR 2.0 to 3.0) is reasonable for a total anticoagulation period of at least 4 wk, as for patients undergoing elective cardioversion. (Level of Evidence: B) ACC / AHA 2008 guidelines for diagnosis and management of atrial fibrillation: Class IIa Recommendation 2a-1 for pharmacological cardioversion of atrial fibrillation should be: 2a-2. Limited data are available to support the subcutaneous administration of a low molecular weight heparin in this indication. (Level of Evidence: C) ACC / AHA 2008 guidelines for diagnosis and management of atrial fibrillation: Class IIa Recommendation 2a-2 for pharmacological cardioversion of atrial fibrillation should be: 2b. For patients in whom thrombus is identified by TEE, oral anticoagulation (INR 2.0 to 3.0) is reasonable for at least 3 week prior to and 4 week after restoration of sinus rhythm, and a longer period of anticoagulation may be appropriate even after apparently successful cardioversion, because the risk of thromboembolism often remains elevated in such cases. (Level of Evidence: C) ACC / AHA 2008 guidelines for diagnosis and management of atrial fibrillation: Class IIa Recommendation 2b for pharmacological cardioversion of atrial fibrillation should be: 3. For patients with atrial flutter undergoing cardioversion, anticoagulation can be beneficial according to the recommendations as for patients with AF. (Level of Evidence: C) ACC / AHA 2008 guidelines for diagnosis and management of atrial fibrillation: Class IIa Recommendation 3 for pharmacological cardioversion of atrial fibrillation should be:

Eutherian fetoembryonic defense system (eu-FEDS) hypothesis The Eutherian Fetoembryonic Defense System (eu-FEDS) is a hypothetical model describing a method by which immune systems are capable of recognizing additional states of relatedness like "own species" such as is observed in maternal tolerance of a related fetus. The model includes descriptions of the proposed signaling mechanism and several proposed examples of exploitation of this signaling in disease states. # Background The concept of immunity refers to an organism's ability to respond to various foreign intrusions (as occurs in infection). A basic requirement in such a system is the ability to avoid self harm through some mechanism of recognizing "self". In classic immunity several types of molecules label the organism's own cells as "self". Cells lableled in this manner are tolerated and not damaged by the various defense mechanisms employed to protect against infection. Dysregulation of this system is responsible for several types of disease states known collectively as autoimmune disorders. The term Eutheria is a taxon describing placental organisms such as mammals. The sister group of Eutheria is Metatheria, which includes marsupials and their extinct relatives. The term eu-FEDS was first described in 1997 by Gary F. Clark et al. as "the human fetoembryonic defense system", and later renamed to apply more broadly to all members of the taxon Eutheria. In 1949 Frank Burnet, and later in 1953 Peter Medawar, observed that the developing fetus was, in fact, similar to a transplanted "foreign" organ, because of the father's contribution to its genome.In 1960, Medawar and Burnet were awarded the Nobel Prize in part for their early contributions and discoveries related to understanding the necessity for the development of tolerance to the developing eutherian. It is now apparent that a human fetus is tolerated by its birth mother, even when it is completely unrelated. These observations were made following the introduction of modern assisted reproduction technologies involving unrelated donor eggs and the use of in vitro fertilization (IVF). The eu-FEDS hypothesis was itself proposed to describe the precise immunological mechanisms that mediate protection of the developing eutherian fetus from the immune responses of its mother. # Hypothesis The basic premise of the eu-FEDS hypothesis is that both soluble and cell surface associated glycoproteins, present in the reproductive system and expressed on gametes, suppress any potential immune responses, and inhibit rejection of the fetus. The eu-FEDS model further suggests that specific carbohydrate sequences (oligosaccharides) are covalently linked to these immunosuppressive glycoproteins and act as “functional groups” that suppress the immune response. The major uterine and fetal glycoproteins that are associated with the eu-FEDS model in the human include alpha-fetoprotein,CA125, and glycodelin-A (also known as placental protein 14 (PP14)). Normally, a low level of these glycoproteins is detected in the maternal serum during the early stages of pregnancy. It appears that the effects of these eu-FEDS associated glycoproteins are manifested only during implantation and the very early development of the embryo. In humans, the expression of such glycoproteins greatly decreases toward the end of the first trimester. Therefore, more highly targeted mechanisms of immune suppression (such as the expression of the enzyme indoleamine dioxygenase (IDO)) are likely employed by the fetus during the subsequent stages of development. One potential reason for early inactivation of the system is that the immunosuppressive effect of these glycoproteins may be so complete that their continued leakage into the circulatory system could lead to a global suppression of the maternal immune response, compromising the mother's ability to carry the fetus to term. # Implications of the hypothesis Human sperm and eggs also lack molecules for the immune recognition of "self". These immune markers are also known as major histocompatibility (MHC) antigens or more specifically in humans as human leukocyte antigens (HLA)),. Therefore a major question is how are human gametes recognized by immune effector cells. Specifically, their lack of MHC recognition markers should trigger the immune system, resulting in lysis of both sperm and eggs by leukocytes known as natural killer, or NK cells. These cells target and kill other cells lacking such MHC markers, a concept known as “missing self”. One distinct possibility is that sperm and eggs are recognized via oligosaccharides expressed on their surfaces. For example, human gametes are coated with carbohydrate sequences that have been implicated in the suppression of NK cell mediated responses. One of the major corollaries of the eu-FEDS hypothesis is that persistent pathogens and aggressive tumor cells are able to either mimic or acquire the same carbohydrate functional groups used to suppress any immune response that could interfere with the reproductive imperative, thus enabling them to similarly resist the human immune response. These pathogens include HIV-1, helminthic parasites such as schistosomes, and Helicobacter pylori, the bacteria that causes stomach ulcers. There are some notable examples of this mimicry or acquisition of the same carbohydrate sequences implicated in this protective system by pathogens and aggressive tumor cells. The major carbohydrate sequence linked to glycodelin-A also profusely coats the surface of schistosomes . The profile of the major oligosaccharides linked to CA125 and the major surface glycoprotein of HIV-1 (gp120) almost perfectly overlap. More persistent pathogens linked to the eu-FEDS model may be identified as mass spectrometry methods for sequencing oligosaccharides become more sensitive. # Other experimental models Several other models have been developed that seek to address this hypothetical system for immune tolerance, including the depletion of tryptophan via the enzyme indoleamine dioxygenase (IDO) and the expression of the nonclassical MHC class I molecule designated HLA-G. However, genetic deletion of IDO in female mice does not lead to the rejection of their foreign fetal offsrping, indicating that a redundant system for the suppression of the mother's immune response exists in the uterus during pregnancy. In addition, HLA-G expresses oligosaccharides that are very different from those linked to other HLA class I molecules, so the possibility exists that HLA-G at the fetomaternal interface is itself employing its unusual carbohydrate sequences as functional groups to suppress the mother's immune response.

Valsartan - When pregnancy is detected, discontinue valsartan as soon as possible. - Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. ## Hypertension - Dosing information - Recommended starting dosage: 80 mg or 160 mg PO qd when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions may be started at the higher dose. - Dosage range: 80 mg to 320 mg PO qd - The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks. - Maximum: 320 mg - Addition of a diuretic has a greater effect than dose increases beyond ‘’‘80 mg’‘’. - No initial dosage adjustment is required for elderly patients, for patients with mild or moderate renal impairment, or for patients with mild or moderate liver insufficiency. Care should be exercised with dosing of valsartan tablets in patients with hepatic or severe renal impairment. - Valsartan tablets may be administered with other antihypertensive agents. - Valsartan tablets may be administered with or without food. ## Heart Failure - Dosing information - Recommended starting dose 40 mg PO bid. - Uptitration to 80 mg -160 mg PO bid should be done to the highest dose, as tolerated by the patient. - Consideration should be given to reducing the dose of concomitant diuretics. - Maximum dosage: 320 mg/day ## Prophylaxis of Diabetes mellitus type 2 - Dosing information - Initial dosage: 80 mg PO qd with an increase to 160 mg PO qd after 2 weeks. ## Diabetic nephropathy - Dosing information - 40 mg/day - 80 mg/day ## Erectile dysfunction - Dosing information - 80- 160 mg PO qd ## Impaired cognition - Dosing information - 160 PO qd ## Left ventricular hypertrophy - Dosing information - 40 mg PO qd - 80 mg/day ## Prophylaxis of Newly detected atrial fibrillation - Dosing information - 80 mg/day ## Prophylaxis of Restenotic lesion of coronary artery - Dosing information - 80 mg/day ## Hypertension - Dosing information - For children who can swallow tablets - Recommended starting dosage: ’‘’1.3 mg/kg PO qd (up to 40 mg total)‘’‘. - The dosage should be adjusted according to blood pressure response. - Doses higher than 2.7 mg/kg (up to 160 mg) once daily have not been studied in pediatric patients 6 to 16 years old. - For children who can't swallow tablets,or children for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths of valsartan, the use of a suspension is recommended. - The dosage should be adjusted according to blood pressure response. - Doses higher than 2.7 mg/kg (up to 160 mg) once daily have not been studied in pediatric patients 6 to 16 years old. - Do not coadminister aliskiren with Diovan in patients with diabetes Pregnancy Category D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Diovan as soon as possible. # Hypotension - Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with Diovan alone. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of Diovan, or the treatment should start under close medical supervision. - Caution should be observed when initiating therapy in patients with heart failure or post-myocardial infarction patients. Patients with heart failure or post-myocardial infarction patients given Diovan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients. - If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. # Impaired Renal Function - Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g. patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on Diovan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Diovan. # Hyperkalemia - Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of Diovan may be required. - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. ## Adult Hypertension - Diovan (valsartan) has been evaluated for safety in more than 4,000 patients, including over 400 treated for over 6 months, and more than 160 for over 1 year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with Diovan was similar to placebo. - The overall frequency of adverse reactions was neither dose-related nor related to gender, age, race, or regimen. Discontinuation of therapy due to side effects was required in 2.3% of valsartan patients and 2.0% of placebo patients. The most common reasons for discontinuation of therapy with Diovan were headache and dizziness. - The adverse reactions that occurred in placebo-controlled clinical trials in at least 1% of patients treated with Diovan and at a higher incidence in valsartan (n=2,316) than placebo (n=888) patients included viral infection (3% vs. 2%), fatigue (2% vs. 1%), and abdominal pain (2% vs. 1%). - Headache, dizziness, upper respiratory infection, cough, diarrhea, rhinitis, sinusitis, nausea, pharyngitis, edema, and arthralgia occurred at a more than 1% rate but at about the same incidence in placebo and valsartan patients. - In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE-inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129-patient trial limited to patients who had had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p <0.001). - Dose-related orthostatic effects were seen in less than 1% of patients. An increase in the incidence of dizziness was observed in patients treated with Diovan 320 mg (8%) compared to 10 to 160 mg (2% to 4%). - Diovan has been used concomitantly with hydrochlorothiazide without evidence of clinically important adverse interactions. - Other adverse reactions that occurred in controlled clinical trials of patients treated with Diovan (>0.2% of valsartan patients) are listed below. It cannot be determined whether these events were causally related to Diovan. Body as a Whole: Allergic reaction and asthenia Cardiovascular: Palpitations Dermatologic: Pruritus and rash Digestive: Constipation, dry mouth, dyspepsia, and flatulence Musculoskeletal: Back pain, muscle cramps, and myalgia Neurologic and Psychiatric: Anxiety, insomnia, paresthesia, and somnolence Respiratory: Dyspnea Special Senses: Vertigo Urogenital: Impotence - Other reported events seen less frequently in clinical trials included chest pain, syncope, anorexia, vomiting, and angioedema. ## Pediatric Hypertension - Diovan has been evaluated for safety in over 400 pediatric patients aged 6 to 17 years and more than 160 pediatric patients aged 6 months to 5 years. No relevant differences were identified between the adverse experience profile for pediatric patients aged 6-16 years and that previously reported for adult patients. Headache and hyperkalemia were the most common adverse events suspected to be study drug-related in older children (6 to 17 years old) and younger children (6 months to 5 years old), respectively. Hyperkalemia was mainly observed in children with underlying renal disease. Neurocognitive and developmental assessment of pediatric patients aged 6 to 16 years revealed no overall clinically relevant adverse impact after treatment with Diovan for up to 1 year. - Diovan is not recommended for pediatric patients under 6 years of age. In a study (n=90) of pediatric patients (1-5 years), two deaths and three cases of on-treatment transaminase elevations were seen in the one-year open-label extension phase. These 5 events occurred in a study population in which patients frequently had significant co-morbidities. A causal relationship to Diovan has not been established. In a second study in which 75 children aged 1 to 6 years were randomized, no deaths and one case of marked liver transaminase elevations occurred during a 1 year open-label extension. ## Heart Failure - The adverse experience profile of Diovan in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the Valsartan Heart Failure Trial, comparing valsartan in total daily doses up to 320 mg (n=2,506) to placebo (n=2,494), 10% of valsartan patients discontinued for adverse reactions vs. 7% of placebo patients. - The table shows adverse reactions in double-blind short-term heart failure trials, including the first 4 months of the Valsartan Heart Failure Trial, with an incidence of at least 2% that were more frequent in valsartan-treated patients than in placebo-treated patients. All patients received standard drug therapy for heart failure, frequently as multiple medications, which could include diuretics, digitalis, beta-blockers. About 93% of patients received concomitant ACE inhibitors. - Discontinuations occurred in 0.5% of valsartan-treated patients and 0.1% of placebo patients for each of the following: elevations in creatinine and elevations in potassium. - Other adverse reactions with an incidence greater than 1% and greater than placebo included headache NOS, nausea, renal impairment NOS, syncope, blurred vision, upper abdominal pain and vertigo. (NOS = not otherwise specified). - From the long-term data in the Valsartan Heart Failure Trial, there did not appear to be any significant adverse reactions not previously identified. ## Post-Myocardial Infarction - The safety profile of Diovan was consistent with the pharmacology of the drug and the background diseases, cardiovascular risk factors, and clinical course of patients treated in the post-myocardial infarction setting. The table shows the percent of patients discontinued in the valsartan and captopril-treated groups in the Valsartan in Acute Myocardial Infarction Trial (VALIANT) with a rate of at least 0.5% in either of the treatment groups. - Discontinuations due to renal dysfunction occurred in 1.1% of valsartan-treated patients and 0.8% of captopril-treated patients. - Hypersensitivity: There are rare reports of angioedema. Some of these patients previously experienced angioedemawith other drugs including ACE inhibitors. Diovan should not be re-administered to patients who have had angioedema. Digestive: Elevated liver enzymes and very rare reports of hepatitis Renal: Impaired renal function, renal failure Clinical Laboratory Tests: Hyperkalemia Dermatologic: Alopecia Blood and Lymphatic: There are very rare reports of thrombocytopenia Vascular: Vasculitis - Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. - Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin. CYP 450 Interactions: In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin,cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan. Potassium: Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium sparing diuretics(e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, monitoring of serum potassium is advisable. - Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan and NSAID therapy. - The antihypertensive effect of angiotensin II receptor antagonists, including valsartan may be attenuated by NSAIDs including selective COX-2 inhibitors. - Dual Blockade of the renin-angiotensin system (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Diovan and other agents that affect the RAS. - Do not coadminister aliskiren with Diovan in patients with diabetes. Avoid use of aliskiren with Diovan in patients with renal impairment (GFR <60 mL/min). # Clinical Laboratory Test Findings - In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Diovan. Creatinine: Minor elevations in creatinine occurred in 0.8% of patients taking Diovan and 0.6% given placebo in controlled clinical trials of hypertensive patients. In heart failure trials, greater than 50% increases in creatinine were observed in 3.9% of Diovan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients. Hemoglobin and Hematocrit: Greater than 20% decreases in hemoglobin and hematocrit were observed in 0.4% and 0.8%, respectively, of Diovan patients, compared with 0.1% and 0.1% in placebo-treated patients. One valsartan patient discontinued treatment for microcytic anemia. Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in Diovan-treated patients. Three patients (< 0.1%) treated with valsartan discontinued treatment for elevated liver chemistries. Neutropenia: Neutropenia was observed in 1.9% of patients treated with Diovan and 0.8% of patients treated with placebo. Serum Potassium: In hypertensive patients, greater than 20% increases in serum potassium were observed in 4.4% of Diovan-treated patients compared to 2.9% of placebo-treated patients. In heart failure patients, greater than 20% increases in serum potassium were observed in 10.0% of Diovan-treated patients compared to 5.1% of placebo-treated patients. Blood Urea Nitrogen (BUN): In heart failure trials, greater than 50% increases in BUN were observed in 16.6% of Diovan-treated patients compared to 6.3% of placebo-treated patients. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramniosis observed, discontinue Diovan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramniosmay not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Diovan for hypotension, oliguria, and hyperkalemia. - In children and adolescents with hypertension where underlying renal abnormalities may be more common, renal function and serum potassium should be closely monitored as clinically indicated. - Diovan is not recommended for pediatric patients under 6 years of age due to safety findings for which a relationship to treatment could not be excluded. - No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate <30 mL/min/1.73 m2. - There is limited clinical experience with Diovan in pediatric patients with mild to moderate hepatic impairment. - Daily oral dosing of neonatal/juvenile rats with valsartan at doses as low as 1 mg/kg/day (about 10% of the maximum recommended pediatric dose on a mg/m2 basis) from postnatal day 7 to postnatal day 70 produced persistent, irreversible kidney damage. These kidney effects in neonatal rats represent expected exaggerated pharmacological effects that are observed if rats are treated during the first 13 days of life. Since this period coincides with up to 44 weeks after conception in humans, it is not considered to point toward an increased safety concern in 6 to 16 year old children. - If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. - Of the 2,511 patients with heart failure randomized to valsartan in the Valsartan Heart Failure Trial, 45% (1,141) were 65 years of age or older. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), 53% (2,596) of the 4,909 patients treated with valsartan and 51% (2,515) of the 4,885 patients treated with valsartan + captopril were 65 years of age or older. There were no notable differences in efficacy or safety between older and younger patients in either trial. - There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one-200th that of valsartan itself. - Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. - Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensinII on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure. - Valsartan is chemically described as N-(1-oxopentyl)-N--4-yl]methyl]-L-valine. Its empirical formula is C24H29N5O3, its molecular weight is 435.5, and its structural formula is - Valsartan is a white to practically white fine powder. It is soluble in ethanol and methanol and slightly soluble in water. - Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed. - In multiple-dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow. - In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid. Metabolism and Elimination: Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. - Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance). Distribution: The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin. ## Special Populations Pediatric: In a study of pediatric hypertensive patients (n=26, 1-16 years of age) given single doses of a suspension of Diovan (mean: 0.9 to 2 mg/kg), the clearance (L/h/kg) of valsartan for children was similar to that of adults receiving the same formulation. Geriatric: Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary. Gender: Pharmacokinetics of valsartan does not differ significantly between males and females. Heart Failure: The average time to peak concentration and elimination half-life of valsartan in heart failure patients are similar to those observed in healthy volunteers. AUC and Cmax values of valsartan increase linearly and are almost proportional with increasing dose over the clinical dosing range (40 to 160 mg twice a day). The average accumulation factor is about 1.7. The apparent clearance of valsartan following oral administration is approximately 4.5 L/h. Age does not affect the apparent clearance in heart failure patients. Renal Insufficiency: There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan. Hepatic Insufficiency: On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease - There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at doses up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.6 and 6 times, respectively, the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.) - Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella (Ames) and E coli; a gene mutation test with Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells; and a rat micronucleus test. - Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.) # Animal Toxicology and/or Pharmacology ## Reproductive Toxicology Studies - No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits represent 9, 6, and 0.1 times, respectively, the maximum recommended human dose on a mg/m2 basis. Calculations assume an oral dose of 320 mg/day and a 60-kg patient. ## Adult Hypertension - The antihypertensive effects of Diovan (valsartan) were demonstrated principally in 7 placebo-controlled, 4- to 12-week trials (one in patients over 65) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95-115. The studies allowed comparison of once-daily and twice-daily regimens of 160 mg/day; comparison of peak and trough effects; comparison (in pooled data) of response by gender, age, and race; and evaluation of incremental effects of hydrochlorothiazide. - Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change. - In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower doses (40 mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160 mg), there is little difference in peak and trough effect. During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long-term follow-up studies (without placebo control), the effect of valsartan appeared to be maintained for up to 2 years. The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin-II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in high-renin hypertensives (frequently whites). In pooled, randomized, controlled trials of Diovan that included a total of 140 blacks and 830 whites, valsartan and an ACE-inhibitor control were generally at least as effective in blacks as whites. The explanation for this difference from previous findings is unclear. - Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure. - The blood pressure lowering effect of valsartan and thiazide-type diuretics are approximately additive. - The 7 studies of valsartan monotherapy included over 2,000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo. Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6-9/3-5 mmHg at 80-160 mg and 9/6 mmHg at 320 mg. In a controlled trial the addition of HCTZ to valsartan 80 mg resulted in additional lowering of systolic and diastolic blood pressure by approximately 6/3 and 12/5 mmHg for 12.5 and 25 mg of HCTZ, respectively, compared to valsartan 80 mg alone. - Patients with an inadequate response to 80 mg once daily were titrated to either 160 mg once daily or 80 mg twice daily, which resulted in a comparable response in both groups. - In controlled trials, the antihypertensive effect of once-daily valsartan 80 mg was similar to that of once-daily enalapril 20 mg or once-daily lisinopril 10 mg. - There are no trials of Diovan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits. - There was essentially no change in heart rate in valsartan-treated patients in controlled trials. ## Pediatric Hypertension - The antihypertensive effects of Diovan were evaluated in two randomized, double-blind clinical studies. - In a clinical study involving 261 hypertensive pediatric patients 6 to 16 years of age, patients who weighed < 35 kg received 10, 40 or 80 mg of valsartan daily (low, medium and high doses), and patients who weighed ≥ 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium and high doses). Renal and urinary disorders, and essential hypertension with or without obesity were the most common underlying causes of hypertension in children enrolled in this study. At the end of 2 weeks, valsartan reduced both systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium and high) significantly reduced systolic blood pressure by -8, -10, -12 mm Hg from the baseline, respectively. Patients were re-randomized to either continue receiving the same dose of valsartan or were switched to placebo. In patients who continued to receive the medium and high doses of valsartan, systolic blood pressure at trough was -4 and -7 mm Hg lower than patients who received the placebo treatment. In patients receiving the low dose of valsartan, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose-dependent antihypertensive effect of valsartan was consistent across all the demographic subgroups. - In a clinical study involving 90 hypertensive pediatric patients 1 to 5 years of age with a similar study design, there was some evidence of effectiveness, but safety findings for which a relationship to treatment could not be excluded mitigate against recommending use in this age group. # Heart Failure - The Valsartan Heart Failure Trial (Val-HeFT) was a multinational, double-blind study in which 5,010 patients with NYHA class II (62%) to IV (2%) heart failure and LVEF <40%, on baseline therapy chosen by their physicians, were randomized to placebo or valsartan (titrated from 40 mg twice daily to the highest tolerated dose or 160 mg twice daily) and followed for a mean of about 2 years. Although Val-HeFT’s primary goal was to examine the effect of valsartan when added to an ACE inhibitor, about 7% were not receiving an ACE inhibitor. Other background therapy included diuretics (86%), digoxin (67%), and beta-blockers (36%). The population studied was 80% male, 46% 65 years or older and 89% Caucasian. At the end of the trial, patients in the valsartan group had a blood pressure that was 4 mmHg systolic and 2 mmHg diastolic lower than the placebo group. There were two primary end points, both assessed as time to first event: all-cause mortality and heart failure morbidity, the latter defined as all-cause mortality, sudden death with resuscitation, hospitalization for heart failure, and the need for intravenous inotropic or vasodilatory drugs for at least 4 hours. These results are summarized in the table below. - Although the overall morbidity result favored valsartan, this result was largely driven by the 7% of patients not receiving an ACE inhibitor, as shown in the following table. - The modest favorable trend in the group receiving an ACE inhibitor was largely driven by the patients receiving less than the recommended dose of ACE inhibitor. Thus, there is little evidence of further clinical benefit when valsartan is added to an adequate dose of ACE inhibitor. - Secondary end points in the subgroup not receiving ACE inhibitors were as follows. - In patients not receiving an ACE inhibitor, valsartan-treated patients had an increase in ejection fraction and reduction in left ventricular internal diastolic diameter (LVIDD). - Effects were generally consistent across subgroups defined by age and gender for the population of patients not receiving an ACE inhibitor. The number of black patients was small and does not permit a meaningful assessment in this subset of patients. # Post-Myocardial Infarction - The VALsartan In Acute myocardial infarction trial (VALIANT) was a randomized, controlled, multinational, double-blind study in 14,703 patients with acute myocardial infarction and either heart failure (signs, symptoms or radiological evidence) or left ventricular systolic dysfunction (ejection fraction ≤40% by radionuclide ventriculography or ≤35% by echocardiography or ventricular contrast angiography). Patients were randomized within 12 hours to 10 days after the onset of myocardial infarction symptoms to one of three treatment groups: valsartan (titrated from 20 or 40 mg twice daily to the highest tolerated dose up to a maximum of 160 mg twice daily), the ACE inhibitor, captopril (titrated from 6.25 mg three times daily to the highest tolerated dose up to a maximum of 50 mg three times daily), or the combination of valsartan plus captopril. In the combination group, the dose of valsartan was titrated from 20 mg twice daily to the highest tolerated dose up to a maximum of 80 mg twice daily; the dose of captopril was the same as for monotherapy. The population studied was 69% male, 94% Caucasian, and 53% were 65 years of age or older. Baseline therapy included aspirin (91%), beta-blockers (70%), ACE inhibitors (40%), thrombolytics (35%) and statins (34%). The mean treatment duration was 2 years. The mean daily dose of Diovan in the monotherapy group was 217 mg. - The primary endpoint was time to all-cause mortality. Secondary endpoints included (1) time to cardiovascular (CV) mortality, and (2) time to the first event of cardiovascular mortality, reinfarction, or hospitalization for heart failure. The results are summarized in the table below: - There was no difference in overall mortality among the three treatment groups. There was thus no evidence that combining the ACE inhibitor captopril and the angiotensin II blocker valsartan was of value. - The data were assessed to see whether the effectiveness of valsartan could be demonstrated by showing in a non-inferiority analysis that it preserved a fraction of the effect of captopril, a drug with a demonstrated survival effect in this setting. A conservative estimate of the effect of captopril(based on a pooled analysis of 3 post-infarction studies of captopril and 2 other ACE inhibitors) was a 14-16% reduction in mortality compared to placebo. Valsartan would be considered effective if it preserved a meaningful fraction of that effect and unequivocally preserved some of that effect. As shown in the table, the upper bound of the CI for the hazard ratio (valsartan/captopril) for overall or CV mortality is 1.09-1.11, a difference of about 9-11%, thus making it unlikely that valsartan has less than about half of the estimated effect of captopril and clearly demonstrating an effect of valsartan. The other secondary endpoints were consistent with this conclusion. 40 mg tablets are yellow colored, film-coated, oval-shaped tablets debossed with ' RX121' on one side and break line on the other side NDC 51660-140-03 Bottles of 10 NDC 51660-140-30 Bottles of 30 NDC 51660-140-05 Bottles of 500 80 mg tablets are yellowish brown colored, film-coated, oval-shaped tablets debossed with ' RX124' on one side and plain on the other side NDC 51660-141-03 Bottles of 10 NDC 51660-141-90 Bottles of 90 NDC 51660-141-05 Bottles of 500 160 mg tablets are pink colored, film-coated, oval-shaped tablets debossed with ' RX125' on one side and plain on the other side NDC 51660-142-03 Bottles of 10 NDC 51660-142-90 Bottles of 90 NDC 51660-142-05 Bottles of 500 320 mg tablets are brown colored, film-coated, oval-shaped tablets debossed with ' RX126' on one side and plain on the other side NDC 51660-143-03 Bottles of 10 NDC 51660-143-90 Bottles of 90 NDC 51660-143-05 Bottles of 500 Protect from moisture. Dispense in tight container (USP). Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to valsartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. Distributed by: Ohm Laboratories Inc. North Brunswick, NJ 08902 USA March 2014 FDA-02 CROSPOVIDONE HYPROMELLOSES MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE STARCH, CORN TALC TITANIUM DIOXIDE POLYETHYLENE GLYCOLS FERRIC OXIDE YELLOW|+sep=; CROSPOVIDONE HYPROMELLOSES MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE STARCH, CORN TALC TITANIUM DIOXIDE POLYETHYLENE GLYCOLS FERRIC OXIDE YELLOW|+sep=; CROSPOVIDONE HYPROMELLOSES MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE STARCH, CORN TALC TITANIUM DIOXIDE POLYETHYLENE GLYCOLS FERRIC OXIDE YELLOW|+sep=; CROSPOVIDONE HYPROMELLOSES MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE STARCH, CORN TALC TITANIUM DIOXIDE POLYETHYLENE GLYCOLS FERRIC OXIDE YELLOW|+sep=; - ↑ NAVIGATOR Study Group. McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B; et al. (2010). "Effect of valsartan on the incidence of diabetes and cardiovascular events". N Engl J Med. 362 (16): 1477–90. doi:10.1056/NEJMoa1001121. PMID 20228403.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} Review in: Ann Intern Med. 2010 Jun 15;152(12):JC6-9 Review in: Evid Based Med. 2011 Aug;16(4):122-3 - ↑ Suzuki K, Souda S, Ikarashi T, Kaneko S, Nakagawa O, Aizawa Y (2002). "Renoprotective effects of low-dose valsartan in type 2 diabetic patients with diabetic nephropathy". Diabetes Res Clin Pract. 57 (3): 179–83. PMID 12126767.CS1 maint: Multiple names: authors list (link) - ↑ Jacobsen P, Andersen S, Jensen BR, Parving HH (2003). "Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy". J Am Soc Nephrol. 14 (4): 992–9. PMID 12660333.CS1 maint: Multiple names: authors list (link) - ↑ Düsing R (2003). "Effect of the angiotensin II antagonist valsartan on sexual function in hypertensive men". Blood Press Suppl. 2: 29–34. PMID 14761074. - ↑ Fogari R, Mugellini A, Zoppi A, Marasi G, Pasotti C, Poletti L; et al. (2004). "Effects of valsartan compared with enalapril on blood pressure and cognitive function in elderly patients with essential hypertension". Eur J Clin Pharmacol. 59 (12): 863–8. doi:10.1007/s00228-003-0717-9. PMID 14747881.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Suzuki K, Kato K, Soda S, Kamimura T, Aizawa Y (2004). "The effect of valsartan on regression of left ventricular hypertrophy in type 2 diabetic patients". Diabetes Obes Metab. 6 (3): 195–9. doi:10.1111/j.1462-8902.2004.00331.x. PMID 15056127.CS1 maint: Multiple names: authors list (link) - ↑ Mutlu H, Ozhan H, Okçün B, Okuyan E, Yigit Z, Erbaş C; et al. (2002). "The efficacy of valsartan in essential hypertension and its effects on left ventricular hypertrophy". Blood Press. 11 (1): 53–5. PMID 11926352.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Schmieder RE, Kjeldsen SE, Julius S, McInnes GT, Zanchetti A, Hua TA; et al. (2008). "Reduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: the VALUE trial". J Hypertens. 26 (3): 403–11. doi:10.1097/HJH.0b013e3282f35c67. PMID 18300848.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Peters S, Götting B, Trümmel M, Rust H, Brattström A (2001). "Valsartan for prevention of restenosis after stenting of type B2/C lesions: the VAL-PREST trial". J Invasive Cardiol. 13 (2): 93–7. PMID 11176015.CS1 maint: Multiple names: authors list (link)

Blunt trauma Synonyms and keywords: Blunt injury; non-penetrating trauma; blunt force trauma. # Overview In medical terminology, blunt trauma refers to a type of physical trauma caused to a body part, either by impact, injury or physical attack; the latter usually being referred to as blunt force trauma. The term itself is used to refer to the precursory trauma, from which there is further development of more specific types of trauma, such as contusions, abrasions, lacerations, and/or bone fracturing. # Variations ## Abdominal Trauma (BAT) Blunt abdominal trauma is often referred to as the most common type of trauma, representing around 50 to 75 percent of blunt trauma. The majority of BAT is often attributed to car-to-car collisions, in which rapid deceleration often propels the driver forwards into the steering wheel or dashboard, causing contusions in less serious cases or rupturing of internal organs due to briefly increased intraluminal pressure in more serious cases where speed or forward force is greater. Abdominal trauma caused by deceleration and impact shows a similar effect to trauma to any other part of the body; namely the rupturing or damage of free and relatively fixed objects, a classic example of such an injury would be a hepatic tear along the ligamentum teres followed with injuries to the renal arteries. As with most trauma, blunt abdominal trauma is often the case of further injury, depending upon the severity of the accident. In the majority of cases, the liver and spleen (see Blunt splenic trauma) are most severely affected, followed by damage to the small intestine. Recent studies utilizing CT scanning have suggested that hepatic and other concomitant injuries may develop from blunt abdominal trauma. In rare cases, BAT has been attributed to several medical techniques such as the heimlich maneuver, attempts at cardiopulmonary resuscitation, and manual thrusts to a clear an airway. Although these are rare causes of blunt abdominal trauma, it is often thought that they are caused by applying unnecessary pressure when administering such techniques. # Diagnosis Although blunt trauma is a condition in itself, the main emphasis on the diagnosis of blunt trauma is to ascertain the cause of the accident, any further injury and its correlation with the medical, dietary, and physiological history of the patient gathered from various sources, such as family and friends, or previous physicians, in order to establish the most swift path to recovery. This method is given the mnemonic "SITEMAP"; - Social history and/or evidence of substance abuse - Immunization history - Time of last meal or sign of nutrient intake - Events leading to the accident or incident - Medication status, history - Allergies - Past surgical and medical treatment history Usually, in the case of examination, areas such as the head or those linked with the respiratory system have a higher priority, and are examined before the abdomen, so as to administer, if necessary, medical treatments which will immediately limit the amount of progressive damage which could be caused from such injuries. The amount of time spent on diagnosing abdominal injury should be minimal, and expedited by using relatively quick methods of determining the extent of such injury, such as by identifying free intra-abdominal fluid through diagnostic peritoneal lavage (DPL) before recommending a laparotomy if the situation requires one. # Treatment Whenever any blunt trauma is sustained to the body, it is normal to ensure first that there is no bleeding, internal or back injury, or breathing problems before administering any type of rehabilitative care to the patient. In cases of car accidents, or where a patient has had some form of accelerated impact, the likelihood is that there will be progressive damage to internal organs, as well as the fracturing of bones, both of which are dealt with by splinting fractures and controlling external hemorrhaging. Most cases require IV therapy along with other methods of stabilization such as securing the airway or providing a respirator. # Related Chapters - Penetrating trauma - Blunt splenic trauma

Genetic fingerprinting # Overview Genetic Fingerprinting (also called DNA testing, DNA typing, or DNA profiling) is a technique used to distinguish between individuals of the same species using only samples of their DNA. Although two individuals will have the vast majority of their DNA sequence in common, DNA profiling exploits highly variable repeat sequences called VNTRs. These loci are variable enough that two unrelated humans are unlikely to have the same alleles. The technique was first reported in 1984 by Dr. Alec Jeffreys at the University of Leicester, and is now the basis of several national DNA identification databases. # Reference samples DNA identification must be done by an extraction of DNA from substances such as: - Personal items (e.g. toothbrush, razor, ...) - Banked samples (e.g. banked sperm or biopsy tissue) - Blood kin (biological relative) - Human remains previously identified Reference samples are often collected using buccal swab. # DNA fingerprinting methods DNA fingerprinting begins by extracting DNA from the cells in a sample of blood, saliva, semen, or other appropriate fluid or tissue. ## RFLP analysis The first methods used for DNA fingerprinting involved restriction enzyme digestion, followed by Southern blot analysis. Although polymorphisms can exist in the restriction enzyme cleavage sites, more commonly the enzymes and DNA probes were used to analyze VNTR loci. However, the Southern blot technique is laborious, and requires large amounts of undegraded sample DNA. Also, Jeffreys' original technique looked at many minisatellite loci at the same time, increasing the observed variablitiy, but making it hard to discern individual alleles (and thereby precluding parental testing). These early techniques have been supplanted by PCR-based assays. ## PCR analysis With the invention of the polymerase chain reaction (PCR) technique, DNA fingerprinting took huge strides forward in both discriminating power and the ability to recover information from very small (or degraded) starting samples. PCR greatly amplifies the amounts of a specific region of DNA, using oligonucleotide primers and a thermostable DNA polymerase. Early assays such as the HLA-DQ alpha reverse dot blot strips grew to be very popular due to their ease of use, and the speed with which a result could be obtained. However they were not as discriminating as RFLP. It was also difficult to determine a DNA profile for mixed samples, such as a vaginal swab from a sexual assault victim. Fortunately, the PCR method is readily adaptable for analyzing VNTR loci. In the United States the FBI has standardized a set of 13 VNTR assays for DNA typing, and has organized the CODIS database for forensic identification in criminal cases. Similar assays and databases have been set up in other countries. Also, commercial kits are available that analyze Single Nucleotide Polymorphisms (SNPs). These kits use PCR to amplify specific regions with known variations and hybridize them to probes anchored on cards, which results in a colored spot corresponding to the particular sequence variation. ## STR analysis The most prevalent method of DNA fingerprinting used today is based on PCR and uses short tandem repeats (STR). This method uses highly polymorphic regions that have short repeated sequences of DNA (the most common is 4 bases repeated, but there are other lengths in use, including 3 and 5 bases). Because different people have different numbers of repeat units, these regions of DNA can be used to discriminate between individuals. These STR loci (locations) are targeted with sequence-specific primers and are amplified using PCR. The DNA fragments that result are then separated and detected using electrophoresis. There are two common methods of separation and detection, capillary electrophoresis (CE) and gel electrophoresis. The polymorphisms displayed at each STR region are by themselves very common, typically each polymorphism will be shared by around 5 - 20% of individuals. When looking at multiple loci, it is the unique combination of these polymorphisms to an individual that makes this method discriminating as an identification tool. The more STR regions that are tested in an individual the more discriminating the test becomes. From country to country, different STR-based DNA-profiling systems are in use. In North America systems which amplify the CODIS 13 core loci are almost universal, while in the UK the SGM+ system, which is compatible with The National DNA Database in use. Whichever system is used, many of the STR regions under test are the same. These DNA-profiling systems are based around multiplex reactions, whereby many STR regions will be under test at the same time. Capillary electrophoresis works by electrokinetically (movement through the application of an electric field) injecting the DNA fragments into a thin glass tube (the capillary) filled with polymer. The DNA is pulled through the tube by the application of an electric field, separating the fragments such that the smaller fragments travel faster through the capillary. The fragments are then detected using fluorescent dyes that were attached to the primers used in PCR. This allows multiple fragments to be amplified and run simultaneously, something known as multiplexing. Sizes are assigned using labeled DNA size standards that are added to each sample, and the number of repeats are determined by comparing the size to an allelic ladder, a sample that contains all of the common possible repeat sizes. Although this method is expensive, larger capacity machines with higher throughput are being used to lower the cost/sample and reduce backlogs that exist in many government crime facilities. Gel electrophoresis acts using similar principles as CE, but instead of using a capillary, a large polyacrylamide gel is used to separate the DNA fragments. An electric field is applied, as in CE, but instead of running all of the samples by a detector, the smallest fragments are run close to the bottom of the gel and the entire gel is scanned into a computer. This produces an image showing all of the bands corresponding to different repeat sizes and the allelic ladder. This approach does not require the use of size standards, since the allelic ladder is run alongside the samples and serves this purpose. Visualization can either be through the use of fluorescently tagged dyes in the primers or by silver staining the gel prior to scanning. Although it is cost-effective and can be rather high throughput, silver staining kits for STRs are being discontinued. In addition, many labs are phasing out gels in favor of CE as the cost of machines becomes more manageable. The true power of STR analysis is in its statistical power of discrimination. In the US, there are 13 core loci (DNA locations) that are currently used for discrimination in CODIS. Because these loci are independently assorted (having a certain number of repeats at one locus doesn't change the likelihood of having any number of repeats at any other locus), the product rule for probabilities can be applied. This means that if someone has the DNA type of ABC, where the three loci were independent, we can say that the probability of having that DNA type is the probability of having type A times the probability of having type B times the probability of having type C. This has resulted in the ability to generate match probabilities of 1 in a quintillion (1 with 18 zeros after it) or more. ## AmpFLP Another technique, AmpFLP, or amplified fragment length polymorphism was also put into practice during the early 1990s. This technique was also faster than RFLP analysis and used PCR to amplify DNA samples. It relied on variable number tandem repeat (VNTR) polymorphisms to distinguish various alleles, which were separated on a polyacrylamide gel using an allelic ladder (as opposed to a molecular weight ladder). Bands could be visualized by silver staining the gel. One popular locus for fingerprinting was the D1S80 locus. As with all PCR based methods, highly degraded DNA or very small amounts of DNA may cause allelic dropout (causing a mistake in thinking a heterozygote is a homozygote) or other stochastic effects. In addition, because the analysis is done on a gel, very high number repeats may bunch together at the top of the gel, making it difficult to resolve. AmpFLP analysis can be highly automated, and allows for easy creation of phylogenetic trees based on comparing individual samples of DNA. Due to its relatively low cost and ease of set-up and operation, AmpFLP remains popular in lower income countries. ## Y-chromosome analysis Recent innovations have included the creation of primers targeting polymorphic regions on the Y-chromosome (Y-STR), which allows resolution of a mixed DNA sample from a male and female and/or cases in which a differential extraction is not possible. Y-chromosomes are paternally inherited, so Y-STR analysis can help in the identification of paternally related males. Y-STR analysis was performed in the Sally Hemings controversy to determine if Thomas Jefferson had sired a son with one of his slaves. It turns out that he did. ## Mitochondrial analysis For highly degraded samples, it is sometimes impossible to get a complete profile of the 13 CODIS STRs. In these situations, mitochondrial DNA (mtDNA) is sometimes typed due to there being many copies of mtDNA in a cell, while there may only be 1-2 copies of the nuclear DNA. Forensic scientists amplify the HV1 and HV2 regions of the mtDNA, then sequence each region and compare single nucleotide differences to a reference. Because mtDNA is maternally inherited, directly linked maternal relatives can be used as match references, such as one's maternal grandmother's sister's son. A difference of two or more nucleotides is generally considered to be an exclusion. Heteroplasmy and poly-C differences may throw off straight sequence comparisons, so some expertise on the part of the analyst is required. mtDNA is useful in determining unclear identities, such as those of missing persons when a maternally linked relative can be found. mtDNA testing was used in determining that Anna Anderson was not the Russian princess she had claimed to be, Anastasia Romanov. mtDNA can be obtained from such material as hair shafts and old bones/teeth. # National DNA databases The United States maintains the largest DNA database in the world: The Combined DNA Index System, with over 5 million records as of 2007. The United Kingdom maintains the National DNA Database (NDNAD), which is of similar size. The size of this database, and its rate of growth, is giving concern to civil liberties groups in the UK, where police have wide-ranging powers to take samples and retain them even in the event of acquittal. The U.S. Patriot Act of the United States provides a means for the U.S. government to get DNA samples from other countries if they are either a division of, or head office of, a company operating in the U.S. Under the act, the American offices of the company can't divulge to their subsidiaries/offices in other countries the reasons that these DNA samples are sought or by whom. # Considerations when evaluating DNA evidence In the early days of the use of genetic fingerprinting as criminal evidence, juries were often swayed by spurious statistical arguments by defense lawyers along these lines: given a match that had a 1 in 5 million probability of occurring by chance, the lawyer would argue that this meant that in a country of say 60 million people there were 12 people who would also match the profile. This was then translated to a 1 in 12 chance of the suspect being the guilty one. This argument is not sound unless the suspect was drawn at random from the population of the country. In fact, a jury should consider how likely it is that an individual matching the genetic profile would also have been a suspect in the case for other reasons. Another spurious statistical argument is based on the false assumption that a 1 in 5 million probability of a match automatically translates into a 1 in 5 million probability of guilt and is known as the prosecutor's fallacy. When using RFLP, the theoretical risk of a coincidental match is 1 in 100 billion (100,000,000,000). However, the rate of laboratory error is almost certainly higher than this, and often actual laboratory procedures do not reflect the theory under which the coincidence probabilities were computed. For example, the coincidence probabilities may be calculated based on the probabilities that markers in two samples have bands in precisely the same location, but a laboratory worker may conclude that similar—but not precisely identical—band patterns result from identical genetic samples with some imperfection in the agarose gel. However, in this case, the laboratory worker increases the coincidence risk by expanding the criteria for declaring a match. Recent studies have quoted relatively high error rates which may be cause for concern . In the early days of genetic fingerprinting, the necessary population data to accurately compute a match probability was sometimes unavailable. Between 1992 and 1996, arbitrary low ceilings were controversially put on match probabilities used in RFLP analysis rather than the higher theoretically computed ones . Today, RFLP has become widely disused due to the advent of more discriminating, sensitive and easier technologies. STRs do not suffer from such subjectivity and provide similar power of discrimination (1 in 10^13 for unrelated individuals if using a full SGM+ profile) It should be noted that figures of this magnitude are not considered to be statistically supportable by scientists in the UK, for unrelated individuals with full matching DNA profiles a match probability of 1 in a billion (one thousand million) is considered statistically supportable (Since 1998 the DNA profiling system supported by The National DNA Database in the UK is the SGM+ DNA profiling system which includes 10 STR regions and a sex indicating test. However, with any DNA technique, the cautious juror should not convict on genetic fingerprint evidence alone if other factors raise doubt. Contamination with other evidence (secondary transfer) is a key source of incorrect DNA profiles and raising doubts as to whether a sample has been adulterated is a favorite defense technique. More rarely, Chimerism is one such instance where the lack of a genetic match may unfairly exclude a suspect. # Fake DNA evidence The value of DNA evidence has to be seen in light of recent cases where criminals planted fake DNA samples at crime scenes. In one case, a criminal even planted fake DNA evidence in his own body: Dr. John Schneeberger of Canada raped one of his sedated patients in 1992 and left semen on her underwear. Police drew Schneeberger's blood and compared its DNA against the crime scene semen DNA on three occasions, never showing a match. It turned out that he had surgically inserted a Penrose drain into his arm and filled it with foreign blood and anticoagulants. # DNA Evidence as Evidence in Criminal Trials ## England Evidence from an expert who has compared DNA samples must be accompanied by evidence as to the sources of the samples and the procedures for obtaining the DNA profiles.The judge must ensure that the jury understand the significance of matches and mismatches in the profiles. The judge must also ensure that the jury do not confuse the 'match probability' (the probability that a person picked at random has a matching DNA profile to the sample from the scene) with the 'likelihood ratio' (the probability that a person with matching DNA committed the crime). In Template:Cite court Phillips LJ gave this example of a summing up, which should be carefully tailored to the particular facts in each case: Members of the Jury, if you accept the scientific evidence called by the Crown, this indicates that there are probably only four or five white males in the United Kingdom from whom that semen stain could have come. The Defendant is one of them. If that is the position, the decision you have to reach, on all the evidence, is whether you are sure that it was the Defendant who left that stain or whether it is possible that it was one of that other small group of men who share the same DNA characteristics. Juries should weigh up conflicting and corroborative evidence, using their own common sense and not by using mathematical formulae, such as Bayes' theorem, so as to avoid "confusion, misunderstanding and misjudgment". R v Bates (2006) EWCA Crim 1395 Moore-Bick LJ said: ## Familial searching Familial searching is the use of family members' DNA to identify a closely related suspect in jurisdictions where large DNA databases exist, but no exact match has been found. The first successful use of the practice was in a UK case where a man was convicted of manslaughter when he threw a brick stained with his own blood into a moving car. Police could not get an exact match to the UK's DNA databased because the man had no criminal convictions, but police implicated him using a close relative's DNA. The practice, which is slated for expansion in the American state of California, has proved controversial because of civil liberties concerns regarding the disproportionate representation of blacks in DNA databases.

Hydrolysis constant A hydrolysis constant is an equilibrium constant for a hydrolysis reaction. For example, if a metal salt such as AlCl3 dissolves in an aqueous solution, the metal cation behaves as a Lewis acid and hydrolyzes the water molecules in the solvent. The hydrolysis constant for this reaction is: In a more generalized form, the hydrolysis constant can be described as: where A- represents any base, and HA represents any acid.

Parvalbumin Parvalbumin is a calcium-binding albumin protein with low molecular weight (typically 9-11 kDa). It has three EF hand motifs and is structurally related to calmodulin and troponin C. Parvalbumin is found in fast-contracting muscles, where its levels are highest, as well as in the brain and some endocrine tissues. Parvalbumin is a small, stable protein containing EF-hand type calcium binding sites. It is involved in calcium signaling. Typically, this protein is broken into three domains, domains AB, CD and EF, each individually containing a helix-loop-helix motif. The AB domain houses a two amino-acid deletion in the loop region, whereas domains CD and EF contain the N-terminal and C-terminal, respectively. Calcium binding proteins like parvalbumin play a role in many physiological processes, namely cell-cycle regulation, second messenger production, muscle contraction, organization of microtubules and phototransduction. Therefore, calcium-binding proteins must distinguish calcium in the presence of high concentrations of other metal ions. The mechanism for the calcium selectivity has been extensively studied. Alterations in the function of parvalbumin-expressing neurons have been implicated in various areas of clinical interest such as Alzheimer's disease, age-related cognitive defects and some forms of cancer. # Location and function Parvalbumin (PV) is present in GABAergic interneurons in the nervous system, especially the reticular thalamus, and expressed predominantly by chandelier and basket cells in the cortex. In the cerebellum, PV is expressed in Purkinje cells and molecular layer interneurons. In the hippocampus, PV+ interneurons are subdivided into basket, axo-axonic, bistratified, and oriens-lacunosum moleculare (O-LM) cells, each subtype targeting distinct domains of pyramidal cells. PV interneurons' connections are mostly perisomatic (around the cell body of neurons). Most of the PV interneurons are fast-spiking. They are also thought to give rise to gamma waves recorded in EEG. PV-expressing interneurons represent approximately 25% of GABAergic cells in the primate DLPFC. Other calcium-binding protein markers are calretinin (most abundant subtype in DLPFC, about 50%) and calbindin. Interneurons are also divided into subgroups by the expression of neuropeptides such as somatostatin, neuropeptide Y, cholecystokinin. # Role in pathology Decreased PV and GAD67 expression was found in PV+ GABAergic interneurons in schizophrenia. PV has been identified as an allergen causing fish allergy.

Gero-Informatics Gero-informatics (sometimes termed Geroinformatics) is the development, application, and study of health informatics in geriatrics. Whereas gerontechnology refers to "matching technological environments to health, housing, mobility, communication, leisure and work of older people", gero-informatics concerns the role of information, information systems, and information technology in geriatric medicine and geriatrics care. It includes aspects of electronic health records, personal health records, and telehealth. Gero-informatics is part of health informatics but focuses on areas of informatics that are specific to geriatrics. This is necessary, because implementation of clinical informatics at many medical institutions has often excluded, or insufficiently addressed, information about older patients. For example, electronic health records infrequently have comprehensive ways to represent the following kinds of data. - Advance directives - Physical functional status - Cognitive status - Patients' preferences for care - Key information about caregivers In addition, better clinical decision support is needed to address routine preventive and medical care of older adults. # History # Current trends In 2006, commercial developments in gero-informatics focused on tools for remote monitoring, such as for older adults living alone with distant caregivers.

Division of ankyloglossia (tongue-tie) for breastfeeding # Guidance Current evidence suggests that there are no major safety concerns about division of ankyloglossia (tongue-tie) and limited evidence suggests that this procedure can improve breastfeeding. This evidence is adequate to support the use of the procedure provided that normal arrangements are in place for consent, audit and clinical governance. Division of ankyloglossia (tongue-tie) for breastfeeding should only be performed by registered healthcare professionals who are properly trained. Publication of further controlled trials on the effect of the procedure on successful long-term breastfeeding will be useful.# The procedure # Indications Ankyloglossia, also known as tongue-tie, is a congenital anomaly characterised by an abnormally short lingual frenulum, which may restrict mobility of the tongue. It varies from a mild form in which the tongue is bound only by a thin mucous membrane, to a severe form in which the tongue is completely fused to the floor of the mouth. Breastfeeding difficulties may arise, such as problems with latching (getting the mother and baby appropriately positioned to breastfeed successfully), sore nipples and poor infant weight gain. Many tongue-ties are asymptomatic and cause no problems. Some babies with tongue-tie have breastfeeding difficulties. Conservative management includes breastfeeding advice, and careful assessment is important to determine whether the frenulum is interfering with feeding and whether its division is appropriate. Some practitioners believe that if division is required, this should be undertaken as early as possible. This may enable the mother to continue to breastfeed, rather than having to feed artificially. # Outline of the procedure In early infancy, division of the tongue-tie is usually performed without anaesthesia, although local anaesthetic is sometimes used. The baby's head is stabilised, and sharp, blunt-ended scissors are used to divide the lingual frenulum. There should be little or no blood loss and feeding may be resumed immediately. After the early months of life, general anaesthesia is usually required. # Efficacy One randomised controlled trial compared division of tongue-tie with 48 hours of intensive support from a lactation consultant. Mothers reported that 95% (19/20) of babies had improved breastfeeding 48 hours after tongue-tie division, compared with 5% (1/20) of babies in the control group (p < 0.001). In one case series of 215 babies, 80% (173/215) of mothers reported improved breastfeeding 24 hours after the procedure. In another case series of 123 babies, 100% (70/70) of mothers reported improved latch after the procedure, and the 53 mothers with nipple pain noted significant improvement immediately after the procedure. In a third case series, 100% (36/36) of babies were reported to have normal tongue motion at 3 months. For more details, refer to the Sources of evidence. There were conflicting opinions among the Specialist Advisors and some stated that it is difficult to be certain whether any perceived improvement in breastfeeding is due to division of the tongue-tie. # Safety Few adverse effects were reported. One case series reported that, after the procedure, 2% (4/215) of babies had an ulcer under the tongue for more than 48 hours. Two studies, including a total of 159 babies, stated that there were no complications. Two studies reported that 8% (3/36) and 18% (39/215) of babies slept through the procedure. For more details, refer to the Sources of evidence. The Specialist Advisors stated that adverse effects were likely to be rare. Potential adverse events include bleeding, infection, ulceration, pain, damage to the tongue and submandibular ducts, and recurrence of the tongue-tie. # Other comments It was recognised that breastfeeding is a complex interaction between mother and child, and that many factors can affect the ability to feed. Skilled breastfeeding support is an integral part of the management of breastfeeding difficulties. Public consultation highlighted that this procedure may also be relevant for bottle feeding, but it was noted that this was not included in the scope or in the literature search for this guidance.# Further information The Institute has developed a clinical guideline on postnatal care. The Health Development Agency has also published a systematic review on breastfeeding. Andrew DillonChief ExecutiveDecember 2005 # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of division of ankyloglossia (tongue-tie) for breastfeeding', February 2005. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It has been incorporated into the NICE pathway on postnatal care, along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2005. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk

Cannabinoids # Overview Cannabinoids are a group of terpenophenolic compounds present in Cannabis (Cannabis sativa L). The broader definition of cannabinoids refer to a group of substances that are structurally related to tetrahydrocannabinol (THC) or that bind to cannabinoid receptors. The chemical definition encompasses a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids, the aminoalkylindoles, the eicosanoids related to the endocannabinoids, 1,5-diarylpyrazoles, quinolines and arylsulphonamides and additional compounds that do not fall into these standard classes but bind to cannabinoid receptors. The term cannabinoids also refers to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological effects. Currently, there are three general types of cannabinoids: herbal cannabinoids occur uniquely in the cannabis plant; endogenous cannabinoids are produced in the bodies of humans and other animals; and synthetic cannabinoids are similar compounds produced in a laboratory. # Cannabinoid receptors Before the 1980's, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate. These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles. There are currently two known types of cannabinoid receptors, termed CB1 and CB2. - CB1 receptors are found primarily in the brain, specifically in the basal ganglia and in the limbic system, including the hippocampus. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are essentially absent in the medulla oblongata, the part of the brain stem that is responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis. - CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis. # Natural cannabinoids Natural cannabinoids, also called herbal cannabinoids and classical cannabinoids, are nearly insoluble in water but soluble in lipids, alcohols, and other non-polar organic solvents. However, as phenols they form more water-soluble phenolate salts under strongly alkaline conditions. All natural cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation; that is, catalyzed by heat, light, or alkaline conditions. Natural cannabinoids are only known to occur naturally in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes. In addition to cannabinoids, the resin is rich in terpenes, which are largely responsible for the odour of the cannabis plant. There are today seventy known herbal cannabinoids. To the right the main classes of natural cannabinoids are shown. All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized. Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) are the most prevalent natural cannabinoids and have received the most study. Other common ones are listed below: - CBG Cannabigerol - CBC Cannabichromene - CBL Cannabicyclol - CBV Cannabivarin - THCV Tetrahydrocannabivarin - CBDV Cannabidivarin - CBCV Cannabichromevarin - CBGV Cannabigerovarin - CBGM Cannabigerol Monoethyl Ether THC is the primary psychoactive component of the plant. Medically, it appears to ease moderate pain and to be neuroprotective. THC has approximately equal affinity for the CB1 and CB2 receptors. Its effects are perceived to be more cerebral. CBD is not psychoactive, and appears to moderate the euphoric effects of THC. It may decrease the rate of THC clearance from the body, perhaps by interfering with the metabolism of THC in the liver. Medically, it appears to relieve convulsion, inflammation, anxiety, and nausea. CBD has a greater affinity for the CB2 receptor than for the CB1 receptor. It is perceived to have more effect on the body. CBN is the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive, and is perceived to be sedative or stupefying. These compounds may be in different forms depending on the position of the double bond in the alicyclic carbon ring. There is potential for confusion because there are different numbering systems used to describe the position of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called delta-9-THC, while the minor form is called delta-8-THC. Under the alternate terpene numbering system, these same compounds are called delta-1-THC and delta-6-THC, respectively. Most herbal cannabinoid compounds are 21 carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the side chain attached to the aromatic ring. In THC, CBD, and CBN, this side chain is a pentyl (5 carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3 carbon) chain. Cannabinoids with the propyl side chain are named using the suffix "varin", and are designated, for example, THCV, CBDV, or CBNV. It appears that shorter chains increase the intensity and decrease the duration of the activity of the chemicals. Cannabinoids were first discovered in the 1940s, when CBD and CBN were identified. The structure of THC was first determined in 1964. Due to molecular similarity and ease of synthetic conversion, it was originally believed that CBD was a natural precursor to THC. However, it is now known that CBD and THC are produced independently in the cannabis plant. Cannabinoid production starts when an enzyme causes geranyl pyrophosphate and olivetolic acid to combine and form CBG. Next, CBG is independently converted to either CBD or CBC by two separate synthase enzymes. CBC is then enzymatically cyclized to THC. For the propyl homologues (THCV, CBDV and CBNV), there is a similar pathway that is based on CBGV. Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of cannabinoids produced by a plant is known as the plant's cannabinoid profile. Selective breeding has been used to control the genetics of plants and modify the cannabinoid profile. For example, strains which are used as fiber (commonly called hemp), are bred such that they are low in psychoactive chemicals like THC. Strains used in medicine are often bred for high CBD content, and strains used for recreational purposes are usually bred for high THC content, or for a specific chemical balance. Some strains of more than 20% THC have been created. Quantitative analysis of a plant's cannabinoid profile is usually determined by gas chromatography (GC), or more reliably by gas chromatography combined with mass spectrometry (GC/MS). Liquid chromatography (LC) techniques are also possible, although these are often only semi-quantitative or qualitative. There have been systematic attempts to monitor the cannabinoid profile of cannabis over time, but their accuracy is impeded by the illegal status of the plant in many countries. Cannabinoids can be administered by smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the liver, although some is stored in fat. Delta-9-THC is metabolized to 11-hydroxy-delta-9-THC, which is then metabolized to 9-carboxy-THC. Some cannabis metabolites can be detected in the body after several weeks. Cannabinoids can be separated from the plant by extraction with organic solvents. Hydrocarbons and alcohols are often used as solvents. However, these solvents are flammable and many are toxic. Supercritical solvent extraction with carbon dioxide is an alternative technique. Although this process requires high pressures, there is minimal risk of fire or toxicity, solvent removal is simple and efficient, and extract quality can be well-controlled. Once extracted, cannabinoid blends can be separated into individual components using wiped film vacuum distillation or other distillation techniques. However, to produce high purity cannabinoids, chemical synthesis or semisynthesis is generally required. # Endogenous cannabinoids Endocannabinoids are naturally produced in the bodies of animals. After the first cannabinoid receptor was discovered in 1988, scientists began searching for natural compounds that activate these receptors. In 1992, the first such compound was identified as arachidonoyl ethanolamide and named anandamide, a name derived from the Sanskrit word for bliss and amide. Anandamide is derived from the essential fatty acid arachidonic acid. It has a pharmacology similar to THC, although its chemical structure is different. Anandamide binds to both the central (CB1) and peripheral (CB2) cannabinoid receptors, and is found in nearly all tissues in a wide range of animals. It is about as potent as THC. Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and homo-γ-linolenoylethanolamide, have similar pharmacology. All of these are members of a family of signalling lipids called N-acylethanolamides which also include the noncannabimimetic palmitoylethanolamide and oleoylethanolamide which have anti-inflammatory and orexigenic effects, respectively. Another endocannabinoid, 2-arachidonoyl glycerol, binds to both the CB1 and CB2 receptors, and is more abundant and a full efficacy agonist, clearly more potent than anandamide, in mediating CB, receptor-dependent G-protein activity in native membranes. Many N-acylethanolamides have also been identified in plant seeds and in molluscs. In 2001 was reported a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. It binds to the CB1 cannabinoid receptor (Ki = 21.2 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB2 receptor. Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activate the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine, GABA or dopamine, endocannabinoids differ in numerous ways from them. Neurotransmitters are commonly small, water-soluble molecules that are contained within, and released from, tiny membrane-bound vesicles inside cells. Vesicles are often found in the tips, ‘terminals’, of long cellular branches called axons, and complex morphological and biochemical specializations mark the location from which vesicular release occurs. Endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized 'on-demand' rather than made and stored for later use. The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research. Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on a ‘postsynaptic’ cell, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively. Endocannabinoids are described as ‘retrograde’ transmitters because they most commonly travel ‘backwards’ against the usual synaptic transmitter flow. They are in effect released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid releasing cell depends on the nature of the conventional transmitter that is being controlled. When the release of the inhibitory transmitter, GABA, is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. Conversely, when release of the excitatory neurotransmitter, glutamate, is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell. Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body. Endocannabinoids constitute a versatile system for affecting neuronal network properties in the nervous system. Scientific American published an article in December of 2004, entitled "The Brain's Own Marijuana" discussing the endogenous cannabinoid system. The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body. Cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited as treatments for many diseases and ailments in anecdotal reports and scientific literature. Some of these ailments include: pain, arthritic conditions, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, GERD (chronic heartburn), nausea, glaucoma, AIDS wasting syndrome, depression, bipolar disorder (particularly depression-manic-normal), multiple sclerosis, menstrual cramps, Parkinson's, trigeminal neuralgia (tic douloureux), high blood pressure, irritable bowel syndrome, and bladder incontinence. # Synthetic & Patented Cannabinoids Historically, laboratory synthesis of cannabinoids were often based on the structure of herbal cannabinoids and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam. Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids. Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules. Medications containing natural, synthetic, or cannabinoids analogs: - Dronabinol (Marinol), an analog of Δ9-tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic and analgesic. - Nabilone (Cesamet), a synthetic cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol which is Schedule III. - Sativex, a cannabinoid extract oral spray containing both THC and CBD used for neuropathic pain and spasticity in Canada and Spain. - Rimonabant (SR141716), a selective cannabinoid (CB1) receptor antagonist used as an anti-obesity drug under the proprietary name, Acomplia. It is also used for smoking cessation. Other notable synthetic cannabinoids include: - CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC - HU-210, about 100 times as potent as THC. - SR144528, a CB2 receptor antagonists - WIN 55,212-2, a potent cannabinoid receptor agonist - JWH-133, a potent selective CB2 receptor agonist. - Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine. # Miscellaneous - delta-9-Tetrahydrocannabinol (Δ9-THC, THC) and delta-8-tetrahydrocannabinol (Δ8-THC), mimic the action of anandamide, a neurotransmitter produced naturally in the body. The THCs produce the high associated with cannabis by binding to the CB1 cannabinoid receptors in the brain. - Tetrahydrocannabivarin (THCV), prevalent in certain South African and Southeast Asian strains of Cannabis. It is an antagonist of THC at CB1 receptors and attenuates the psychoactive effects of THC. - Cannabidiol (CBD), non-psychoactive and not affecting psychoactivity of THC. CBD has anti-inflammatory effects. CBD shares a precursor with THC and is the main cannabinoid in low-THC Cannabis strains. - Cannabinol (CBN), a degradation product of THC, produces a depressant effect - Cannabichromene (CBC), non-psychoactive and not affecting psychoactivity of THC, a precursor of CBD and THC - Cannabigerol (CBG), non-psychoactive - Cannabinoids are good substrates for cytochrome P450 mixed-function oxidases, mainly CYP 2C9. Thus suplementing with CYP 2C9 inhibitors leads to extended intoxication. # Table of natural cannabinoids

The World Health Organization (WHO) convened a Guideline Development Group (GDG) meeting from to 31 July 2019 to review global guidance on contraceptive eligibility for women at high risk of HIV acquisition to and determine whether revisions to the fifth edition of the Medical eligibility criteria for contraceptive use (MEC) were needed. The issue was deemed critical, particularly for sub-Saharan Africa, given the high lifetime risk of acquiring HIV alongside the importance of hormonal contraception in offering women and adolescent girls' choice and in reducing their risk of unintended pregnancy, a common threat to the health, well-being and lives of women and adolescent girls. The GDG consisted of 28 participants from 19 countries, including experts in family planning and HIV, representatives from affected populations, clinicians, epidemiologists, researchers, programme managers, policy-makers and guideline methodologists. The GDG considered the following factors when formulating recommendations for each contraceptive method: quality of the evidence (i.e. GRADE profile) 1 values and preferences of contraceptive users balance of benefits and harms priority of the problem equity and human rights feasibility. In formulating these recommendations, the GDG kept at the centre of their deliberations the individuals most affected by the recommendations -that is, those women wanting to prevent pregnancy who are at a high risk of HIV acquisition. Through consensus, the GDG agreed to the following new recommendations. These revisions mean that women at a high risk of HIV can use all methods of contraception without restriction. Women at a high risk of HIV infection are eligible to use all progestogen-only contraceptive methods without restriction (MEC Category 1), including progestogen-only pill (POPs), intramuscular and subcutaneous depot medroxyprogesterone acetate (DMPA-IM and DMPA-SC), norethisterone enanthate (NET-EN), levonorgestrel (LNG) implants and etonogestrel (ETG) implants. Women at a high risk of HIV infection are eligible to use copper-bearing intrauterine devices (Cu-IUDs) and LNG-IUDs without restriction (MEC Category 1). In considering the 1 GRADE = Grading of Recommendations Assessment, Development and Evaluation (for further information, see: ). use of IUDs, many women at a high risk of HIV are also at risk of other sexually transmitted infections (STIs); for these women, providers should refer to the MEC recommendation on women at an increased risk of STIs, and the Selected practice recommendations for contraceptive use: third edition on STI screening before IUD insertion. Women at a high risk of HIV infection are eligible to use all combined hormonal contraceptive methods without restriction (MEC Category 1), including combined oral contraceptives (COCs), combined injectable contraceptives (CICs), combined contraceptive patches and combined vaginal rings. These recommendations were strongly informed by new epidemiological evidence, particularly from one high-quality randomized clinical trial (the ECHO trial), which did not demonstrate a statistically significant difference in HIV acquisition among women using the three contraceptive methods studied: DMPA-IM, Cu-IUDs and LNG implants. This high-quality evidence superseded the previously available observational evidence of low and low-to-moderate quality. For COCs and NET-EN injectables, evidence of low and low-tomoderate quality from observational studies indicated no increased risk of HIV infection. While no direct evidence was available for DMPA-SC, LNG-IUDs or ETG implants, there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism or different progestogen would modify HIV risk. A consideration of women's values, preferences, views and concerns regarding contraceptive methods provided support for optimizing informed contraceptive choice and the availability of a wide range of contraceptive options. There are several key messages from this guidance for policymakers, programme managers and health-care providers. A woman's risk of HIV does not restrict her contraceptive choice. Efforts to expand contraceptive method options and ensure full and equitable access to family planning services must continue. A renewed emphasis on HIV/STI testing and prevention services is urgently needed, including the integration of family planning and HIV/STI services as appropriate, along with sexual and reproductive health packages. # PROGESTOGEN-ONLY CONTRACEPTIVES Progestogen-only contraceptives (POCs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protection against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. # Condition MEC category Clarification/evidence POP DMPA/ NET-EN # LNG/ ETG High risk of HIV 1 1 1 EVIDENCE: High-quality evidence from one randomized clinical trial observed no statistically significant differences in HIV acquisition between: DMPA-IM versus Cu-IUD, DMPA-IM versus LNG implant, and Cu-IUD versus LNG implant. Of the low-to-moderate-quality evidence from 14 observational studies, some studies suggested a possible increased risk of HIV with progestogen-only injectable use, which was most likely due to unmeasured confounding. Low-quality evidence from 3 observational studies did not suggest an increased HIV risk for implant users. No studies of sufficient quality were identified for POPs. Cu-IUD: copper-bearing intrauterine device; DMPA: depot medroxyprogesterone acetate (injectable); IM: intramuscular; LNG/ETG: levonorgestrel and etonogestrel (implants); MEC: Medical eligibility criteria for contraceptive use; NET-EN: norethisterone enanthate (injectable); POP: progestogen-only pill # INTRAUTERINE DEVICES Intrauterine devices (IUDs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protection against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Access to sexual and reproductive health services and information, including a comprehensive range of contraceptive methods, is fundamental to the rights and well-being of women and adolescent girls (1)(2)(3)(4). There is a wide range of hormonal and non-hormonal modern contraceptive methods providing substantial individual and public health benefits. A core part of the work of the World Health Organization (WHO) is the development and maintenance of up-to-date, evidence-based guidance on contraceptive safety for individuals with particular medical conditions or medically relevant characteristics (5). The Medical eligibility criteria for contraceptive use (the MEC), fifth edition, offers national policy-makers and family planning programmes a comprehensive set of recommendations on the medical safety of contraceptive methods, allowing for the informed development of national policies, protocols and programmes (5). Global guidance about medical safety and eligibility facilitates the removal of unnecessary medical barriers to contraception. For over 20 years, the MEC has been used by countries to maximize safety and improve the quality of contraceptive care offered. Guidance about safety is kept up to date through continuous monitoring and reviews of published literature. In 2015, WHO released the fifth edition of the MEC (5). This edition contains more than 2000 recommendations for 25 different contraceptive methods, within the context of more than 80 medical conditions or medically relevant personal characteristics. Depending on the individual, more than one condition may need to be considered when making an informed contraceptive choice (5). The recommendations in the MEC are based on several considerations, including whether the use of a contraceptive method worsens the medical condition or creates additional health risks, and whether the condition makes the contraceptive method less effective (5). The MEC is part of a set of tools aiming to improve contraceptive coverage and care throughout the world. The MEC informs decisions about who might use a particular contraceptive method, through information and guidance about the safety and appropriateness of contraceptive care. The Selected practice recommendations for contraceptive use (the SPR) provides guidance on how to safely and effectively use various contraceptive methods (6). WHO produces a range of tools to support the use and implementation of contraceptive guidance, such as the MEC wheel and the Global handbook for providers (7,8). Since 1996, the MEC has applied a four-category scale to indicate medical eligibility for particular contraceptive methods in the presence of particular conditions or individual characteristics (e.g. at high risk of HIV). For each condition or characteristic, contraceptive methods are placed into one of four numbered categories: 1. A condition for which there is no restriction for the use of contraceptive method. 2. A condition where the advantages of using the method generally outweigh the theoretical or proven risks. 3. A condition where the theoretical or proven risks usually outweigh the advantages of using the method. 4. A condition which represents an unacceptable health risk if the contraceptive method is used. The interpretation and application of the categories in practice are shown in Table 1. In the past, there has been mixed evidence about whether hormonal contraceptive methods -particularly depot medroxyprogesterone acetate (DMPA) -are associated with an increased risk of HIV acquisition. The available evidence consisted of theoretical biological data and observational studies with important limitations. In 2016, the independent Method not to be used BACKGROUND 1 # Guideline Development Group The development of this guidance statement was undertaken by the independent Guideline Development Group (GDG) and an additional panel of external reviewers. The GDG consisted of 28 participants from 19 countries, including experts in family planning and HIV, representatives from affected populations, clinicians, epidemiologists, researchers, programme managers, policymakers and guideline methodologists (see Annex 1). Following WHO guidance, months prior to the July 2019 meeting of the GDG, the name and brief biography of each proposed GDG member was published at the WHO website (. int/reproductivehealth/publications/contraceptives-methods-hiv). The public was able to view and provide input on any perceived or real conflicts of interest of the proposed members. WHO responded to all comments and accordingly adjusted the final composition of the GDG. Prior to the GDG meeting, the WHO Secretariat and the GDG reviewed the members' declarations of interests (Annex 2) and found no conflicts of interest sufficient to preclude anyone from participating in the deliberations or the development of the recommendations. The members of the GDG were also asked to declare any new conflicts of interest at the start of the meeting. None were declared. 2 For further information, see: # Guideline development process This guidance statement was prepared according to the standards and requirements specified in the WHO handbook for guideline development (11). This process is used to ensure that WHO guidelines are of the highest quality and follow a transparent, systematic process. Key steps of the guideline process include determining the critical questions and outcomes, retrieving the evidence, synthesizing and grading the evidence, presenting it using a structured approach, and formulating recommendations. WHO's Family Planning Guideline Steering Group determined the critical questions and outcomes to be considered by the GDG. Distinct types of evidence were identified as essential to review. These included the health evidence (randomized trials and observational epidemiological data), the evidence on biological plausibility and the data on the values and preferences of contraceptive users. Applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, 2 multiple factors are considered when formulating recommendations (12). These include the quality of the epidemiological evidence (found in the GRADE evidence profiles, which are prepared based on up-to-date Guideline Development Group (GDG) for the MEC reviewed the accumulating evidence regarding women at high risk of acquiring HIV (9). The GDG concluded that there remained uncertainty about whether the increased risk of HIV acquisition seen in some observational studies was a real effect of the contraceptive method used or whether it was a statistical artefact resulting from key limitations of observational studies (residual confounding in particular) (9). There also continued to be uncertainty about the clinical relevance of the biological data. In addition, there was concern that previous attempts to inform women of the uncertainty about both the epidemiological and biological data (through the use of a MEC clarification, indicated by an asterisk had not been effective. Given these concerns, the GDG concluded that MEC guidance should be changed. Thus, in 2017, the recommendation for progestogenonly injectable use among women at high risk of HIV infection was changed from MEC Category 1 (no restrictions to use, with a clarification) to MEC Category 2 (the benefits of use outweigh the risks), with an accompanying clarification (9). This new classification indicated that progestogen-only injectables could be used by women at high risk of HIV, because the advantages of these methods generally outweighed the possible disadvantages, and it highlighted that, when choosing these methods, there might need to be extra consideration of possible HIV acquisition, and counselling. As part of the 2017 revision, WHO reaffirmed its commitment to monitoring and assessing any new evidence relevant to contraceptive safety. New information, including results from a large, multinational randomized clinical trial (RCT) (10), led WHO to convene another GDG meeting in July 2019 to review all the available evidence and assess whether the MEC guidance needed revision. # METHODS OF GUIDELINE REVIEW AND DEVELOPMENT systematic reviews); the values and preferences of contraceptive users; the balance of benefit and harms; the priority of the problem; equity and human rights; acceptability; and feasibility. The human rights principles and standards described in WHO's guidance, Ensuring human rights in the provision of contraceptive information and services, were incorporated into deliberations (1). Owing to the focus on contraceptive safety, opportunity costs were not formally assessed during the formulation of the recommendations, since costs may vary widely throughout different regions (13). The GRADE evidence-to-decision framework (a tool encompassing quality of evidence, balance of benefits versus harms, values and preferences, priority of the problem, equity and human rights, feasibility) was used to ensure that recommendations were based on the consideration of all standards (11). # Evidence Retrieval Existing WHO recommendations on the use of specific contraceptive methods by women at high risk of HIV were reviewed in accordance with procedures outlined by the WHO Guidelines Review Committee and the GRADE approach to evidence review (11,12). Three systematic reviews were conducted in preparation for the GDG meeting: two reviews pertained to the epidemiological evidence and the third review synthesized qualitative or quantitative studies on users' values, preferences, views and concerns regarding contraceptive methods. The two systematic reviews of epidemiological evidence conducted for the GDG meeting were: - An updated systematic review on hormonal contraception and risk of HIV acquisition was conducted to include new studies published since 2016, when the last systematic review was undertaken (14). The review question was: Among women at risk of HIV, does use of a hormonal contraceptive method compared with non-use of a hormonal contraceptive method (or use of another specific hormonal contraceptive method) increase risk of HIV acquisition? - A systematic review on copper-bearing intrauterine device (Cu-IUD) use and risk of HIV acquisition was also conducted. The review questions were: Among women at risk of HIV, does use of a Cu-IUD compared with use of another non-hormonal contraceptive method or no contraceptive method increase risk of HIV acquisition? Among women at risk of HIV, does use of a Cu-IUD compared with use of a specific hormonal contraceptive method increase risk of HIV acquisition? The selection criteria for the systematic reviews are listed in Table 2. The same study designs, population, comparators and outcomes were considered for all the contraceptive methods reviewed. Women of reproductive age at risk of HIV infection (women who were not living with HIV at baseline) Use of a specific contraceptive method: hormonal contraception (injectables, oral contraceptives, implants, patches, rings or levonorgestrel-releasing intrauterine devices) copper-bearing intrauterine devices (Cu-IUDs) One of two comparison groups: 1. non-use of a hormonal contraceptive method (either no contraceptive use or use of a non-hormonal method such as condoms or other barrier method, withdrawal, Cu-IUD or tubal ligation/vasectomy) 2. use of another specific method of hormonal contraception Incident, laboratory-confirmed HIV infection in women The two systematic reviews were conducted according to the preferred reporting items for systematic reviews and metaanalyses (PRISMA) (15). The PubMed and Embase databases were searched for studies published in any language in the peer-reviewed literature up to 26 June 2019. For individual studies, the risk of bias was assessed using a quality framework described in the previous review (14). Studies were classified into three levels: 1. "Unlikely to inform the primary question": studies that had (a) no adjustment for any measure of condom use or (b) unclear measurement of exposure to contraception. 2. "Informative but with important limitations": studies that had none of the flaws described above, but that still had the potential for unmeasured or residual confounding. 3. "Informative with few limitations": studies that had none of the above flaws -likely to be a randomized clinical trial (RCT) that was assessed as having a low risk of bias on standard criteria for evaluating RCTs. The focus of the systematic reviews was on information from studies that were considered "informative but with important limitations" or "informative with few limitations." to fall into levels 2 and 3. The values and preferences of contraceptive users were incorporated in multiple ways. First, an updated systematic review of qualitative or quantitative studies on users' values, preferences, views and concerns regarding the contraceptive methods considered under the Medical eligibility criteria for contraceptive use (MEC) guidelines was conducted (16). This review covered studies from any country published in the peer-reviewed literature between January 2005 and December 2017. Just prior to the GDG meeting in July 2019, this review was informally updated for studies in either the peer-reviewed or grey literature that specifically looked at the values and preferences of contraceptive users relating to the issue of hormonal contraception and HIV acquisition. Second, because the updated systematic review did not identify any information specific to key populations at risk of HIV, consultative engagements were conducted in May through July of 2019, including a global online survey of sex workers and participatory focus group discussions with female sex workers in Zimbabwe (through the Sisters with a Voice programme). Third, stakeholders representing specific affected populations, including women living with HIV, and young women, contributed their perspectives through a presentation and discussion of critical perspectives at the GDG meeting. An update about the biological data on the theoretical effect that contraception may have on HIV acquisition was prepared, reviewed and discussed at the GDG meeting, including consideration of the theoretical plausibility of individual methods of hormonal contraception having an influence on HIV acquisition. # Evidence Synthesis Epidemiological data were synthesized and evaluated according to the GRADE approach to evidence review (12). Based on this, randomized trials begin with a grade for strength of evidence of "high", and observational studies start with a grade of "low". The risk of bias was assessed for the summarized data using standard GRADE methods (17). Factors that could lower the evidence grade were limitations in the evidence (bias), inconsistency between studies, imprecision of estimates, indirectness of evidence, and publication bias (17)(18)(19)(20)(21)(22). Randomized trials were assessed for bias by systematically evaluating for inadequate randomization/ allocation concealment; inadequate blinding of treatments; attrition and failure to use intention-to-treat analyses; selective outcome reporting; and crossover/contamination (17). Observational studies were assessed for bias by examining whether there was failure to develop and apply appropriate eligibility criteria, flawed measurement of exposures or outcomes, failure to adequately address confounding, or incomplete follow-up (17). Factors that could increase the evidence grade of observational studies included the presence of a dose-response relationship, a large magnitude of observed associations, and adjustment for plausible confounders affecting observed associations (22). # Formulation of recommendations Findings from the systematic reviews and associated GRADE evidence profiles (Annex 3) were presented at the GDG meeting. A presentation on the biological plausibility of hormonal contraception modifying the risk of HIV acquisition, and several presentations on contraceptive users' values and preferences, were also given. These inputs were used to develop an evidence-to-decision framework (Annex 4), which served as the basis for the GDG's deliberations during the meeting (12). All recommendations were arrived at by consensus. After the GDG's recommendations were made, a small writing group prepared a draft guidance statement summarizing the decision and associated rationale. The draft was reviewed by the entire GDG and the external review group (see Annex 1). Comments received from the GDG and the external review group were considered and addressed by the writing group. The final version of this guidance statement was approved by the WHO Guidelines Review Committee on 22 August 2019. # SUMMARY OF THE EVIDENCE 3 The Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study 3 was the primary source of new evidence since the WHO last reviewed recommendations on contraception for women at high risk of HIV (9). The ECHO Study was a large randomized clinical trial (RCT) conducted in Eswatini, Kenya, South Africa and Zambia specifically designed to compare HIV incidence among users of three contraceptive methods: intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implants and copper-bearing intrauterine 3 For further information, see: devices (Cu-IUDs) (10). The trial randomized 7829 HIVseronegative women, aged between 16 and 35 years, who desired effective contraception and consented to be randomized to one of the three contraceptive methods. There was no group of non-users of contraception in the ECHO trial because all of the women enrolled desired effective contraception. Women returned every three months for HIV testing, contraceptive counselling, safety monitoring, behavioural assessment and a comprehensive package of HIV prevention services; for up to months. The main (primary) comparisons used a modified intention-to-treat analysis. In addition, pre-planned (secondary) analyses were conducted, restricted to continuous use of the assigned contraceptive method and adjusted for a number of important confounders, including vaginal sex without a condom, a new sexual partner in the previous three months, and more than one sexual partner. Statistical significance in the ECHO trial was taken to be a P-value less than 0.04 for the primary comparisons. No statistically significant associations were found for any of the primary comparisons between the three contraceptive methods (Annex 3). The quality of the evidence from this RCT was rated as high, due to its large size, strong randomization and allocation procedures, high follow-up rates, high continuation of the allocated contraceptive method, objective measurement of HIV incidence and comprehensive analysis of the results. Other evidence on hormonal contraception and HIV acquisition published since the 2016 review ( 14) was included in the evaluation of the body of evidence, along with a systematic review on Cu-IUDs and risk of HIV acquisition (Annex 3). For hormonal contraception, one new observational study and updated estimates from a previously included study were identified (23,24). Adding this evidence to the previous 14 observational studies (14) did not change the conclusions of the previous review. Thus, the body of observational evidence suggested some concern about an increased risk of HIV acquisition with DMPA-IM use, but was generally reassuring for other methods of hormonal contraception. For intrauterine devices (IUDs), two observational studies did not suggest an increased risk of HIV acquisition with Cu-IUD use (23,25). The quality of evidence from these observational studies was rated as low and low-to-moderate. # Progestogen-only injectables One RCT (the ECHO trial) observed no statistically significant differences in HIV acquisition when comparing DMPA-IM versus Cu-IUD, and DMPA-IM versus LNG implant (10). The quality of the evidence from this RCT was rated as high. Evidence from 14 observational studies of DMPA-IM, norethisterone enanthate (NET-EN) or unspecified progestogenonly injectables considered to be "informative but with important limitations" was assessed (14,23,24). Additional data from one new observational study and updated estimates from a previously included study did not change the conclusions of the previous review of observational evidence (14). The quality of the evidence from the observational studies was rated as low and low-to-moderate due to limitations that included unmeasured confounding. # Progestogen-only implants Three observational studies considered to be "informative but with important limitations" assessed implants. One had been included in the previous review (26), one provided an updated point estimate to that used for the previous review (24) and one provided an entirely new estimate of risk (23). Two of the studies assessed LNG implants (24,26) and the third assessed women using either LNG or etonogestrel implants (23). None of the three studies suggested an increased risk of HIV acquisition with implant use, consistent with the conclusion of the previous review (14). The quality of the evidence from these studies was rated as low. # Progestogen-only pills No studies considered "informative but with important limitations" or "informative with few limitations" were identified for progestogen-only pills. # Intrauterine devices One RCT (the ECHO trial) observed no statistically significant differences in HIV acquisition between DMPA-IM and Cu-IUD, or Cu-IUD and LNG implants (10). The quality of the evidence from this RCT was rated as high. Two observational studies considered "informative but with important limitations" did not observe an association with HIV acquisition when comparing Cu-IUD use with tubal ligation or no contraceptive method use, DMPA-IM, NET-EN or implants (23,25). The quality of this observational evidence was rated as low. No evidence was identified for LNG-IUDs. # Combined hormonal contraceptives Eleven observational studies deemed "informative but with important limitations" assessed the use of combined oral contraceptives (COC). (It was assumed that studies that did not specify the oral contraceptive type examined mostly, if not exclusively, examined COC use.) All of these studies were included in the previous review, while an updated estimate came from one newly available study (14,24). Overall, these studies suggested no association between COC use and HIV acquisition. The quality of the evidence was rated as low-to-moderate. No evidence was identified for the combined contraceptive patch, ring or injectable. # Additional evidence considered by the GDG # VALUES AND PREFERENCES OF CONTRACEPTIVE USERS The systematic review identified 375 studies from all regions of the world (27). Across studies, women's values and preferences centred on themes of choice and available options, ease of use, side-effect profiles and contraceptive efficacy. Contextual factors, such as the contraceptive methods available, counselling from providers, and the opinions of social networks, influenced decision-making. From the grey literature, two additional studies were identified that were relevant to hormonal contraception and HIV specifically (28,29). Both found that messages from the 4 "Free" means the freedom and ability to make a voluntary decision about contraceptive use without barriers or coercion; informed means complete, correct and clear information has been given about all the options, plus details about the chosen method 2017 WHO guidance were difficult for providers to explain fully and may not be completely understood by clients. The online survey of sex workers from multiple global regions found that individual preferences around contraception varied widely and could change over time; ongoing partnership and dialogue with sex workers is essential to understanding evolving priorities. In participatory focus groups, Zimbabwean sex workers said their contraceptive choices were shaped by a wide range of factors, including cost, accessibility, the way sex workers are treated at clinics, the influence of male partners, and contraceptive side-effects. Sex without a condom was common, and there was a need to strengthen access to HIV/STI prevention and contraceptive services. The community stakeholder presentation emphasized that, for some women, any level of increased HIV risk would be too high. It also highlighted that the ECHO trial was not set up to assess the difference in the risk of HIV acquisition between contraceptive users and non-users. Community stakeholders also emphasized that there was a lack of true contraceptive choice for many women and girls, saying the guidance should emphasize full, free and informed contraceptive choice, 4 the procurement of a range of contraceptive methods, and investment in integrated contraception and HIV services. The Guideline Development Group (GDG) reviewed, and discussed extensively, the new epidemiological and biological evidence, as well as related information about values and preferences, equity and human rights, and feasibility. After deliberating on all of the available evidence, the GDG recommended that the MEC category for DMPA and Cu-IUD should be changed to MEC Category 1. The GDG noted that there was no evidence regarding DMPA-SC and LNG-IUD, and only limited new information regarding NET-EN. Until more information becomes available, the GDG judged it was appropriate to follow the same approach as previously used, i.e. grouping all progestogen-only injectables together (DMPA-IM, DMPA-SC and NET-EN) as MEC Category 1, and to assign the same MEC category to the LNG-IUD as to the Cu-IUD (MEC Category 1). One key portion of the GDG's deliberations related to evaluating evidence from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study (see Annex 3). The GDG gave particular attention to this information because of its ability to address unmeasured confounding -a major cause of uncertainty when interpreting results from observational studies. The GDG recognized that the ECHO trial did not address the etiological or causal question of whether DMPA increases the risk of HIV acquisition when compared with not using any contraception. Nevertheless, since the MEC provides guidance for women wishing to use contraception, results from the ECHO trial about the comparative risk of HIV acquisition among users of the three contraceptives tested were highly pertinent to the GDG's deliberations. Furthermore, the GDG noted that the high incidence of HIV infection experienced by each contraceptive group during the ECHO trial was similar to the background incidence assumed when designing the trial. This was deemed to be indirect evidence addressing the question, suggesting no increased risk of HIV acquisition among users of these contraceptives compared with women not using any contraception. The ECHO trial was considered to be a well conducted study that provided high-quality evidence that superseded the low and low-to-moderate-quality observational evidence previously available to the GDG. This direct epidemiological evidence, from a trial specifically designed to address the issue, was judged to be more informative than theoretical biological evidence. The reasons for considering the ECHO trial to be of high quality included its large size; robust randomization methods; good adherence to the allocated contraceptive method; a low attrition rate; regular, standardized and objective outcome measurements; and a blinded, comprehensive analysis of the data (including sensitivity analyses for postulated confounders such as sexual activity and condom use). Although women and providers of services in the ECHO trial could not be blinded to the intervention allocation, there was no evidence that this led to the different groups of participants acting, or being managed, differently with respect to important issues such as HIV prevention counselling. This ensured that residual confounding, particularly in relation to condom use or sexual activity, was highly unlikely to have affected the ECHO trial. The GDG noted that although the ECHO trial was designed to detect a 50% increase in the risk of HIV acquisition between contraceptive groups assessed, the observed high HIV incidence and small losses to follow up meant that it could detect a 30% increase. When considering the ECHO trial results, the GDG focused on the point estimates for each primary comparison. The group noted that none of the point estimates for the primary comparisons were statistically significant. The 96% confidence intervals surrounding these point estimates included unity, and so encompassed the possibility of a small increased or decreased difference in risk between contraceptives. The GDG acknowledged, however, that for an individual woman at a high risk of HIV, any change in this risk may be important. After a full discussion, the GDG judged that unmeasured confounding was the most likely explanation for the apparent increased risk of HIV acquisition among DMPA-IM users seen in some observational studies. The GDG's decisions to revise the MEC classifications for DMPA and IUDs were further grounded by the values and preferences of women towards optimizing informed contraceptive choice and the availability of a wide range of contraceptive options, based on a systematic review of qualitative and quantitative evidence, consultative engagements with sex workers and the perspectives of GDG members representing specific affected populations. In previous editions of the MEC, IUDs were classified as MEC Category 2 for women at a high risk of HIV. This recommendation was given because of the absence of high-quality, direct evidence about the risk of acquiring HIV among IUD users. In addition, there was an assumption that most women at a high risk of HIV were also at an increased risk of other STIs. The ECHO trial provided direct, high-quality evidence about the risk of HIV acquisition risk among women using the Cu-IUD, enabling the GDG to review its recommendation regarding these women. Any new evidence related to IUD use in women at a high risk of other STIs will be reviewed for the next MEC update. The GDG was concerned about the high rates of both HIV and STIs among women in the ECHO trial, reflecting the background risk factors among women seeking contraception in the study areas. The high incidence of HIV was particularly striking given the extensive efforts made during the ECHO trial to provide HIV prevention counselling and interventions. Thus, while the GDG concluded that the risk of HIV acquisition was not affected by the contraceptive method used, it emphasized the need for renewed efforts to reduce the incidence of HIV and STIs. # IMPLICATIONS FOR POLICY-MAKERS, PROGRAMME MANAGERS AND HEALTH-CARE PROVIDERS 5 While the main audiences for the Medical eligibility criteria for contraceptive use (MEC) are policy-makers and programme managers, a fundamental tenet of the MEC is that they are woman-centred. The following were the key messages that came from the deliberations of the Guideline Development Group. # A woman's risk of HIV should not restrict her contraceptive choice While a risk of HIV should not restrict a woman's choice to use hormonal contraception or an intrauterine device, it is important to note that these methods do not protect her against acquiring HIV or other sexually transmitted infection (STI). The new MEC recommendations should not be interpreted as indicating that HIV and STI testing and prevention are no longer important. Indeed, the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study highlighted the critical need to strengthen and expand HIV and STI prevention services (10). Testing for HIV and STIs should be part of high-quality family planning services for women at risk, particularly for those living in areas of high HIV and STI incidence. # Efforts to expand access to contraceptive options must continue Women have the right to a range of short-acting, long-acting and permanent contraceptive methods, as well as to emergency contraception (1). A comprehensive range of contraceptive methods enables women to respond to changing needs and preferences during their reproductive lives. Informed decisionmaking and woman-centred, high-quality counselling are key components in the human rights-based provision of contraceptive information and services (2). The ECHO trial reinforced that offering a range of methods is possible and acceptable to women (10). Family planning and HIV services should be included in national universal health coverage initiatives. Efforts to expand safe and effective contraceptive options, and to ensure their availability and the access to them, must continue. Technical resources are available to support countries to introduce more contraceptive options into their programmes and services (Box 1). # A renewed emphasis on HIV and STI prevention services is urgently needed The ECHO trial showed high rates of both HIV and STIs in the study sites (10), highlighting the need for appropriate prevention, diagnosis and treatment of all STIs. Current HIV prevention measures remain unavailable or unsatisfactory for many women and adolescent girls living in settings of high HIV incidence. In such areas, the integration of family planning and HIV prevention services for all women is essential if the health of women and adolescent girls is to be improved. In settings of low HIV prevalence, there is a need for family planning providers to evaluate personal risk factors that may increase a woman's risk of acquiring HIV and then to provide appropriate services. The ECHO trial also showed that syndromic management did not decrease the prevalence of STIs at baseline and at the end of follow-up. STI programmes need to be strengthened, including a move towards diagnostic management. In settings with high HIV prevalence, HIV testing and prevention should be included in family planning services. HIV testing should be offered to all women and to partners of all women with HIV. HIV prevention options should be offered to all women, including pre-exposure prophylaxis (PrEP), as recommended in WHO guidelines (30). The offer of PrEP to women could also be considered where HIV incidence is high (but below 3/100 person-years overall) following, for example, a simple risk assessment. A risk assessment could include: desire to take PrEP (reflecting a self-identified risk); history of an STI; more than one sex partner in the last six months; or women with a sex partner with HIV who is not virally supressed on antiretroviral therapy. In settings with low HIV prevalence, the routine offer of HIV testing and prevention services in family planning settings is unlikely to be cost-effective. HIV testing and prevention services could nonetheless be offered to women who request these services. # BOX 2. WORK TO IDENTIFY WOMEN AT HIGH RISK OF HIV A person's HIV risk depends on the incidence of HIV in the area where they live, and their individual risk factors. Family planning programmes must work closely with their national and subnational HIV programmes to use local epidemiological data to identify geographical areas and risk factors that put women at a high risk of HIV infection. # Contraceptive methods and HIV acquisition The existing body of evidence is sufficient to guide practice on intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implants and copper-bearing intrauterine devices; additional observational data will not add substantially to the evidence base for these methods. However, in the absence of trial data similar to those in the ECHO Study (10), observational data about subcutaneous DMPA (DMPA-SC), LNG IUDs, etonogestrel implants, or future contraceptive or multi-purpose prevention technologies could still be useful, although unmeasured confounding would likely remain a concern. Studies should consider the potential impact of contraceptive use on other sexually transmitted infections as well as HIV. Additional research on the specific effects of contraception-related bleeding changes in relation to the risk of HIV or STI acquisition is also needed. # HIV prevention The Guideline Development Group was deeply concerned by the high HIV incidence found among women seeking family planning services in the ECHO Study sites, despite the fact that trial participants received an extensive HIV prevention package (including repeated HIV testing and counselling, partner HIV testing and condom distribution, as well as pre-exposure prophylaxis (PrEP) late in the study as this became the standard of care). More research is needed on ways to increase the acceptability and uptake of effective HIV prevention strategies for women at a high risk of HIV, tailored to settings of both high and low HIV prevalence and to women with a range of personal risk factors. In the ECHO trial, the uptake (and hence impact) of PrEP was minimal as it became available only late in the trial (10). Where it was available on site, as opposed to requiring referral to another site, acceptability and uptake were high. Ways to include HIV self-testing and PrEP in family planning services should be # KNOWLEDGE GAPS AND AREAS FOR RESEARCH explored. This should include behavioural and implementation science research on the effective integration of HIV and contraception services. # Community involvement The ECHO trial employed a range of strategies for directly engaging with civil society at the study site, and at regional and global levels (10). An in-depth assessment of the strengths and limitations of each strategy is likely to provide models for community engagement in contraceptive and HIV prevention research that could be adopted in the future. # Increased funding for high-quality, policy-relevant research The ECHO Study demonstrated that a well conducted, adequately powered randomized clinical trial is possible in contraceptive research, and can make an important contribution to global decision-making. Global policy should be based on comprehensive high-quality evidence, but additional investment in contraceptive research is critically overdue, including research addressing whether financial barriers affect the contraceptive choices of women. # DISSEMINATION OF THIS GUIDANCE STATEMENT 7 The World Health Organization (WHO) will work to communicate this guidance statement clearly and widely. WHO will evaluate whether the guidance achieves its intentions. The guidance will be published on the WHO website and in a limited quantity of printed documents. The guidance will be widely disseminated through the WHO regional and country offices, Additionally, webinars for stakeholders in multiple languages will be organized during 2020 to ensure Member States and stakeholders are fully informed of the new recommendations. These opportunities will enable WHO to disseminate the updated guidance effectively and efficiently. Derivative communication products highlighting key counselling issues (e.g. short briefs for front-line health-care providers and community-based organizations) will be prepared in collaboration with WHO's implementing partners, and in consultation with the GDG during 2020. A policy brief in the six official languages used by WHO will be developed to inform policy-makers about the contraception updates. As part of the dissemination of the recommendations in this guidance statement, WHO will update its digital contraceptive decision-support tools -the MEC mobile app (31), the humanitarian contraceptive delivery app (32) and the postpartum compendium (33). These mobile applications are free to download and available for both iOS and Android platforms. Additionally, the Global handbook for family planning providers and the online Family Planning Training Resource Package will be updated accordingly (8,34). WHO will continue to monitor the body of evidence informing these recommendations and will convene additional consultations when needed. # ANNEX 1. GUIDELINE DEVELOPMENT GROUP AND EVIDENCE SECRETARIAT # Guideline Development Group # ANNEX 2. DECLARATIONS OF CONFLICTS OF INTEREST Following guidance issued on 24 September 2014 by the WHO Office of Compliance, Risk Management and Ethics (CRE), and prior to the 29-31 July 2019 meeting, the name and brief biography of each proposed Guideline Development Group (GDG) member was published on the WHO website during 27 May to 10 June 2019 (/ reproductivehealth/publications/contraceptives-methods-hiv). The public was able to view and provide their comments to the WHO Secretariat using a general email address (hrx_info@who.int) regarding any perceived or real conflicts of interest of these proposed GDG members. In addition, prior to the public announcement period, the WHO Secretariat reviewed the curriculum vitae of each potential participant and conducted Internet searches (Google Scholar, Open Payments, PubMed) for information on potential financial and academic conflicts of interest related to the subject of the meeting. Following the public reporting period, and in consultation with CRE, official invitations for GDG membership were extended. Additionally, the WHO Secretariat reviewed potential financial and academic conflicts of interest related to the subject of the meeting of the proposed External Review Group: no conflicts were declared among this 11-member group. Of the 28 experts who participated in this work, six declared an interest related to contraception. The WHO Secretariat, CRE and GDG reviewed all declarations and found no conflicts of interest sufficient to preclude anyone from participating in the deliberations or the development of the recommendations relevant to hormonal contraception and HIV. Accordingly, the six participants who declared interests related to contraception, as well as the other 22 participants, fully participated in the meeting's deliberations, discussions and final decisions. Although not all interests declared were specifically related to contraception and susceptibility to HIV, they are disclosed and summarized below. b Few limitations noted in the trial, but not serious enough to downgrade the level of evidence. While the study was unblinded for participants and health-care providers, data were analysed centrally by statisticians who were blinded to the group. c Restricted to studies classified as "informative with but with important limitations". d Some limitations or imprecision noted across the body of evidence, but not serious enough to downgrade the level of evidence. e Evidence graded low to moderate due to consistent and precise results from well conducted observational studies, and coherence between studies of use versus non-use and head-to-head studies. While no direct evidence was available for combined contraceptive patch, combined contraceptive vaginal ring or combined injectable contraceptive, indirect evidence from COCs was used given that there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism, or different progestogen would modify HIV risk. # Balance is in favour of benefits of CHCs Factor Explanation/evidence Judgement # Values and preferences Women have the right to informed decision-making. Women prefer to have choice in methods, full information regarding benefits versus harms, and to make a final decision in conjunction with their provider (informed decision-making). Contraception is unique among medicines because a woman's needs and preferences with regard to the characteristics of contraceptive methods will vary both between individual women and across a single individual's lifespan. Common themes in contraceptive preferences include that they are discreet, have minimal side-effects and are long-acting, reversible and easy to use. Women who use progestogen-only injectables generally like them for these reasons, and feel comfortable using them after counselling. Women's preferences for methods are limited by what they have knowledge of, what is available to them and other factors that foster or limit access. Offering women the choice of a range of methods is important from both a health and a rights perspective. Support for optimizing informed contraceptive choice and the availability of a wide range of contraceptive options # Priority of the problem HIV is a serious illness and a major global epidemic. Unintended pregnancy is a very common problem globally, and the risks associated with it are highest where maternal mortality and severe morbidity are also common. Both are priorities for public health. Effective contraception and HIV prevention are both public health priorities # Equity and human rights Human rights principles and standards from existing World Health Organization (WHO) guidelines on human rights and contraception were followed by the Guideline Development Group (GDG) in its deliberations. These include non-discrimination, availability, accessibility, acceptability, quality, informed decision-making, privacy and confidentiality, participation, and accountability. During its deliberations, the GDG considered both potential positive and negative effects of its considerations. For example, it considered and emphasized the continuing need for integrated family planning and HIV services in settings with high HIV incidence. It also emphasized the need for expanding and optimizing contraceptive options. Recommendations within WHO's human rights guidance for contraception are paramount principles for decision-making on this topic The importance of clear communication from WHO on this topic was underscored. This was reinforced by recent studies that suggested that messages based on the 2017 WHO guidance were difficult to explain and may not be fully understood by clients or providers. Clear guidance and a woman-centred approach are essential for successful implementation # Hormonal contraceptive method use and HIV acquisition in women There was a previously published review on hormonal contraceptive use and HIV acquisition. The search strategies from that review were used to search for new evidence since. The following four new publications were identified that met the inclusion criteria. # Copper-bearing intrauterine device (Cu-IUD) use and HIV acquisition in women A systematic review was conducted on Cu-IUD use and HIV acquisition in women. The following six articles met the inclusion criteria. # Contraceptive values and preferences A systematic review was conducted on contraceptive values and preferences. The protocol and methods are published, and the manuscript presenting the main results of the review is under review for publication. As this review did not identify information specific to key populations at risk of HIV, consultative engagements were conducted in the spring of 2019, including a global online survey of sex workers, and participatory focus group discussions with female sex workers in Zimbabwe through the Sisters with a Voice programme. Presentations showing the findings from these engagements are listed below and available on request. A presentation shared by stakeholders representing affected populations to highlight their perspectives on the topic was part of the Guideline Development Group's discussions and is available on request. # Evidence Secretariat # WHO Secretariat The WHO Secretariat attended the meeting and several WHO staff provided background presentations (Rachel Baggaley, Mary Lyn Gaffield, James Kiarie, Nancy Kidula). The WHO Secretariat was present to serve as a background resource, if request by the GDG. Neither WHO, the Joint United Nations Programme on HIV/AIDS (UNAIDS) nor the United Nations Population Fund (UNFPA) staff participated in the decisionmaking or formulation of the recommendations, which was the sole responsibility of the GDG. Several WHO staff contributed to the systematic reviews (Mary Lyn Gaffield, James Kiarie, Petrus Steyn) and the writing of the statement. b Restricted to studies classified as "informative with but with important limitations". c Sample size is for the entire study population. # WHO headquarters d Some limitations or imprecision was noted across the body of evidence, but not serious enough to downgrade the level of evidence. e No direct evidence for ETG implants was identified for the comparisons of interest. For ETG implants, recommendations were extrapolated from the evidence on LNG implants. f Few limitations noted in the trial, but not serious enough to downgrade the level of evidence. # ANNEX 5: SYSTEMATIC REVIEWS Three systematic reviews were conducted as part of the development of this guidance statement. The details of the methods and search strategies are included in the reviews. Reviews published in peer-reviewed journals are available through open access. This appendix will be periodically updated as reviews are published. Access to unpublished reviews can be requested by sending an email to hrx-info@who.int.

SEOM clinical guidelines for anaemia treatment in cancer patients (2020) Anaemia is defined by the presence of haemoglobin (Hb) levels < 13 g/dL in men and 12 g/dL in women. Up to 39% of cancer patients present it at the time of diagnosis and up to 40% have iron deficiency. Anaemia causes fatigue, functional deterioration and a reduction in the quality of life; it has also been associated with a poorer response to anti-tumour treatment and lower survival. Basic diagnostic tests for anaemia are simple and should be a routine part of clinical practice. These guidelines review the available evidence on the use of different therapies for treating anaemia: erythropoiesis-stimulating agents, iron supplements, and transfusion of blood products.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. # Introduction Anaemia is defined by the presence of haemoglobin (Hgb) levels < 13 g/dl in men and 12 g/dl in women. Iron deficiency (ID) is characterized by low transferrin saturation (TSI < 20%) and can be absolute (depleted iron stores, serum ferritin < 30 ng/ml) or functional (normal or increased serum ferritin); both are common complications in patients with solid tumours. Up to 39% of cancer patients present anaemia at the time of diagnosis and up to 40% present ID; of these, about a third have Hgb levels < 12 g/dl. In addition, up to 53% of patients 1 3 who do not present anaemia at diagnosis will develop it during chemotherapy (CT) and/or radiotherapy (RT) treatment, so that up to 67% of cancer patients will present anaemia at some time during the evolution of their disease. Anaemia causes fatigue, functional deterioration and reduced quality of life. It has also been associated with a worse response to anti-tumour therapy and shorter survival. The aetiology of cancer-related anaemia is multifactorial, and two or more factors can be present in the same patient. For example, anaemia may be caused by a combination of: -A direct effect of the cancer (tumour bleeding, invasion of the bone marrow). -Chemical factors produced by the tumour (auto-antibodies, inflammatory cytokines that affect erythropoietin production and block iron metabolism). -An effect of cancer therapy (cell death induced by CT, RT, tyrosine kinase inhibitors (TKI) and monoclonal antibodies (mAb). Drug-induced anaemia is graded according to the CTCAE [3]. Cancer-related anaemia, therefore, is a multifactorial problem with immunologic, nutritional and metabolic components that affect its severity. For this reason, reversible causes must be identified and the different therapeutic options available for treatment must be used correctly (level of evidence I, recommendation grade A). ## Algorithm for the diagnosis of anaemia in cancer patients A correct diagnosis of anaemia requires a medical history that includes: personal history, status of the oncological disease (the type of primary tumour and stage of the disease, the different treatments received, chemotherapies with a high risk of haematological toxicity and their dates of administration are the most important data), clinical history and complete physical examination. The most common symptoms presented by patients with anaemia are fatigue, dyspnoea on exertion, oedema in the lower limbs, cognitive impairment, confusion and depression. Clinical signs include pallor, tachycardia, and worsening of performance status (PS-ECOG). Blood tests required include a basic blood count, a ferrokinetic study (serum ferritin levels and transferrin saturation), biochemistry with creatinine (to assess kidney function), and C-reactive protein (marker of chronic inflammation). Since anaemia in cancer patients can be multifactorial, other complementary tests should be requested to determine the cause: occult blood in stool, urinary sediment, blood smear, coagulation tests, thyroid hormones and immunological studies; bone marrow biopsy if tumour infiltration is suspected, an imaging test, such as computerized tomography and gastrointestinal endoscopy, to identify possible bleeding can also be useful. The algorithm shown incan be used to diagnose anaemia in cancer patients. It is important to differentiate between iron deficiency anaemia and chronic cancer-induced anaemia.shows the parameters used to differentiate between these entities. ## Treatment of anaemia in cancer patients ## Erythropoyetin-stimulating agents (esa) The cloning of the human erythropoietin (EPO) gene in 1984 opened a new option of treatment for cancer-related anaemia. Numerous clinical trials have shown the efficacy and safety equivalence of different ESAs, which reduce transfusion needs in patients with chemotherapy-induced anaemia, achieve more sustained correction of anaemia, are associated with fewer risks than transfusions, and improve both blood flow and quality of life. However, the use of these agents has decreased considerably since 2005 following the publication of data that associated them with decreased survival. Below, we analyse the indications and risks of the different ESAs available, as shown in . ## Indications for esas Leading agencies (EMA, FDA) and medical societies (ASCO/ASH, ESMO, NCCN) recommend the use of ESAs in: -Patients with solid tumours and symptomatic anaemia under treatment with chemotherapy (level of evidence I, grade of recommendation A) or chemoradiotherapy (level of evidence II, grade of recommendation B). -Patients with Hgb levels < 10 g/dl, or asymptomatic anaemia with Hgb levels < 8 g/dl after correction of iron levels and other underlying causes (level of evidence I, grade of recommendation A). -In patients with Hgb < 7-8 g/dl and/or symptomatic anaemia, red blood cell transfusion should be considered before ESAs (level of evidence II, grade of recommendation B). ## Risks and complications Venous thromboembolism (VTE): In 2005, the results of some studies that linked the use of ESAs with an increase in mortality in cancer patients caused some alarm. Subsequent analyses found that this effect was limited to patients treated with Hgb levels > 12 g/dl; therefore, prophylactic treatment in non-anaemic patients is not advised (level of evidence I, grade of recommendation A) due to the increased risk of thromboembolic complications. In these cases, other options should be considered, or the risks should be evaluated individually in elderly patients, patients on bed rest, with heart failure, thrombocytosis, a history of VTE, adenocarcinoma (particularly some subtypes, or pancreatic cancer) and with some cancer treatments. The use of antithrombotic prophylaxis or aspirin is not recommended in these cases. Other less common complications are: Pure red cell aplasia (described in patients with chronic renal failure and caused by the appearance of anti-erythropoietin antibodies), arterial hypertension, thrombocytopaenia and allergic reactions. ## Controversy: survival and disease control The lower survival observed in cancer patients with anaemia appears to be associated with a poorer response to certain therapies when tissue hypoxia is present. Based on this finding, some authors have suggested that achieving Hgb > 12 g/ dl with ESAs will improve survival in patients receiving chemoradiotherapy. Subsequent studies did not confirm this hypothesis, and suggested that this might be due to the appearance of thromboembolic phenomena in patients with Hgb 13-16 g/dl due to the presence of erythropoietin receptors on the surface of tumour cells that would promote angiogenesis, tumour growth and therapeutic failure, and also to the activation of neovascularization by mechanisms independent of the erythropoietin receptor. After analysing these studies, and on the assumption that ESAs are used in patients with symptomatic anaemia and Hgb < 10 g/dl, various agencies and scientific societies have maintained their recommendation for use of ESAs, adding that they should be avoided in patients receiving therapy for curative intent and in patients with advanced tumours but long-term survival expectations, even if they develop anaemia secondary to treatment. (Level of evidence IV, grade of recommendation C). shows the different ESAs available with their indications, risks and recommendations for use. ## Oral and intravenous iron supplementation The ECAS study found that more than 40% of patients included had iron deficiency (ID) and, of these, approximately one-third had Hgb levels < 12 g/dl; the same study indicated that the prevalence of ID in patients with solid tumours was higher than in haematological cancers and that, in these solid tumours, the prevalence of ID correlated with a more advanced tumour stage at the time of diagnosis, worse tumour response to treatment with chemotherapy and/or radiotherapy, and worse clinical status. ## Indications for iron supplementation Iron supplementation should be considered in patients undergoing chemotherapy who have anaemia with Hgb ≤ 11 g/dl or Hgb decrease ≥ 2 g/dl from a baseline level ≤ 12 g/dl. It is important to note that ID can also be associated with impaired physical function, weakness and fatigue even in the absence of anaemia, so iron supplementation must also be considered in this circumstance. The following situations are established based on three laboratory parameters to be determined before and during cancer therapy (serum iron-SI, transferrin saturation index -TSI, and ferritin) (level of evidence II and grade of recommendation A): Possible functional iron deficiency (ferritin 500-800 ng/ ml and TSI > 50%). In this case, treatment with an erythropoietin stimulating agent (ESA) or with iron supplements is not recommended; in certain selected patients, the use of intravenous (IV) iron may be considered to avoid the need for transfusion. All iron supplementation should be suspended when ferritin > 800 ng/dl and TSI > 50%. Functional iron deficiency (ferritin between 30-500 ng/ ml, TSI < 50% and SI <30 µ/dl). This shows insufficient availability of iron despite adequate iron stores. Administration of IV iron together with ESAs is recommended (unless the latter are not indicated), as this improves the haematological response and reduces the number of transfusions. There is insufficient clinical evidence to indicate the routine use of IV iron in monotherapy without the concomitant use of ESAs. Absolute iron deficiency (ferritin < 30 ng/ml, TSI < 20% and SI < 30 µ/dl). Indicates that iron stores are depleted. Oral or intravenous iron supplements can be given. Oral iron should only be administered in the absence of inflammation; if no response is obtained after four weeks, switch to IV iron. ## Risks of iron supplementation Although long-term side effects have not been fully established, IV iron therapy does not increase the risk of infections, thromboembolic events, or cardiovascular disease; however, it should be avoided in patients with active infection or concomitant cytotoxic chemotherapy; specifically, IV iron should be given before or after chemotherapy or at the end of a treatment cycle (level of evidence III and grade of recommendation C). Like any other drug, iron can induce allergic reactions. There is no clinical evidence linking IV iron therapy to cancer development or progression; in research models evaluating iron as a possible promoter of tumour growth, this effect has not been demonstrated . ## Iron supplement presentations Iron can be administered orally or intravenously. Although the oral form is suitable for most patients with iron deficiency anaemia, many with anaemia secondary to chemotherapy do not respond, may be intolerant, or may require higher doses than can be achieved with oral supplementation. In these cases, intravenous therapy is a better option. Several studies in which iron supplementation was given in conjunction with ESAs suggest that intravenous iron is superior to oral iron in improving haemoglobin response rates. No studies on iron supplementation in conjunction with ESAs provide evidence on how or when to repeat iron administration after the maximum initial dose has been administered. The most common adverse events associated with intravenous iron are: hypotension, hypertension, nausea, vomiting, diarrhoea, pain, fever, dyspnoea, itching, headache, and dizziness. The dosages of different intravenous iron supplements currently available are described in. ## Treatment of cancer-induced anaemia by transfusion of erythrocytary derivatives Data on red blood cell (RBC) transfusions in cancer patients come mainly from studies in surgical patients. Studies performed in large population groups and meta-analyses suggest an independent association between RBC transfusion and an increased risk of mortality, morbidity and cancer recurrence. However, there are few randomized studies in patients undergoing chemotherapy. Standard RBCs are obtained by fractionating whole blood. Currently, nearly all blood is fractionated by centrifugation into its main components: red blood cells, plasma and platelets. RBCs are stored suspended in a conservation medium containing an anticoagulant (citrate) together with glucose, adenine and phosphate, intended to maintain ATP levels by means of glycolytic metabolism. RBCs are stored at 4° ± 2° C to reduce their metabolic requirements and thus prolong conservation and delay bacterial growth in the rare event of the bag being accidentally contaminated by bacteria. RBC transfusion in cancer patients is indicated above all in patients with severe anaemia and symptoms that require rapid recovery of haemoglobin and haematocrit levels. Elevation of these parameters and the corresponding symptomatic improvement will be transitory; therefore, the aetiology of anaemia should always be investigated. In patients with no cardiovascular risk factors, transfusion is indicated if Hgb < 7-8 g/dl (Htc: 21-24%) and very rarely if Hgb > 9-10 g/dl (Htc: 27-30%). Unless justified, Hgb levels should not be allowed to remain below 7-8 g/d for any length of time. In patients with cardiovascular risk factors, particularly coronary heart disease, the minimum Hgb threshold should be higher, around 9 g/d; patients with symptomatic anaemia should be transfused, regardless of these Hgb thresholds. The correct RBC dose is calculated considering that 1 unit RBC increases Hgb from 1 to 1.5 g/l and haematocrit from 2 to 3%; therefore, dosage must be titrated individually, considering the characteristics of the patient and the minimum volume needed to correct the symptoms. Immunosuppressed patients, due to the risk of post-transfusion graft-versus-host disease (GVHD), should receive irradiated blood components. Washed RBCs are indicated in patients with a history of severe post-transfusion allergic or anaphylactic reactions. The main drawbacks of blood transfusion include the increased risk of thrombotic events and transfusion-related adverse effects. These include immediate reactions (during transfusion or over the following 24 h), such as acute haemolytic reaction, allergic reactions, transfusion-related acute lung injury (TRALY), volume overload, non-immune haemolytic anaemia, hypotensive reactions, and fever; and delayed reactions, such as delayed haemolytic transfusion reaction, transfusion-related graft-versus-host disease, transmission of infectious diseases, transfusion hemosiderosis, and particularly common in cancer patients, allergic reactions and volume overload. # Conclusion According to the above information, the following recommendations are established for anaemia treatment in cancer patients: ## Recommendations for esa administration ## Indications Patients with solid tumours and symptomatic anaemia under treatment with chemotherapy (level of evidence I, grade of recommendation A) or chemoradiotherapy (level of evidence II, grade of recommendation B) who present Hgb levels < 10 g/ dl or asymptomatic anaemia with Hgb levels < 8 g/dl, after correction of iron levels or other underlying causes (level of evidence I, grade of recommendation A). ESAs should not be used in patients who are not receiving chemotherapy (level of evidence I, grade of recommendation A). ## Duration and dosage Administer until stable Hgb values that avoid or reduce the need for red blood cell transfusion have been achieved, without exceeding 12 g/dl (level of evidence IV, grade of recommendation B). Increasing the dose or switching drugs after 6-8 weeks of treatment in non-responders is not recommended, except in the case of epoetin theta; instead, treatment should be suspended (level of evidence II, grade of recommendation B). ## Toxicity and contraindications The risk of thromboembolic events must be carefully evaluated and the patient duly informed. ESAs should not be used in patients with poorly controlled hypertension. (Level of evidence I, grade of recommendation A). ## Recommendations for iron supplementation ## Indications Iron supplementation should be considered in patients undergoing chemotherapy who have anaemia with Hgb ≤ 11 g/dl or Hgb decrease ≥ 2 g/dl from a baseline level ≤ 12 g/dl. IV iron + ESA is recommended to treat functional iron deficiency (ferritin 30-500 ng/ml, TSI < 50%, serum Fe < 30 µ/dl) (level of evidence II, grade of recommendation A). Oral or intravenous iron is recommended to treat absolute iron deficiency (ferritin < 30 ng/ml, TSI < 20%, serum Fe < 30 µ/dl). If no response is obtained with oral treatment after four weeks, switch to IV iron. (Level of evidence II, grade of recommendation A). Neither ESA nor iron supplementation is recommended to treat possible functional iron deficiency (ferritin 500-800 ng/ ml and TSI > 50%) All iron supplementation should be suspended when ferritin > 800 ng/dl and TSI > 50%. (Level of evidence II, grade of recommendation A). ## Toxicity and contraindications Iron does not increase the risk of infections, thromboembolic events, or cardiovascular morbidity; IV iron should be administered before or after chemotherapy or at the end of a treatment cycle (level of evidence III, grade of recommendation C). There is no clinical evidence linking IV iron therapy to cancer development or progression. ## Recommendations for blood transfusion Consider red blood cell transfusion in patients with Hb < 7-8 g/dl (and < 9 g/dl if cardiovascular risk factors are present) and/or severe symptoms of anaemia that need rapid correction of Hgb or symptoms (level of evidence II, grade of recommendation B). # Declarations Conflict of interest YE, RdP, JPA, SR, AS, AB, EB, JC, IGE have nothing to disclose. CB reports education Grants from Leo Pharma and Vifor. # Ethical approval The current study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Informed consent For this type of study formal consent is not required. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. 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Recommendations for accurate CT diagnosis of suspected acute aortic syndrome (AAS)—on behalf of the British Society of Cardiovascular Imaging (BSCI)/British Society of Cardiovascular CT (BSCCT) # Introduction Timely and accurate assessment of suspected acute aortic syndrome (AAS) is vital in this potentially life-threatening condition with significant pre-hospital and in-hospital mortality rates of up to 20% and 30%, respectively. [bib_ref] Thoracic aortic aneurysm and dissection: increasing prevalence and improved outcomes reported in..., Olsson [/bib_ref] There are many definitions of AAS; however, for the purpose of this document, AAS is defined as aortic dissection, intramural haematoma and the complications arising from penetrating atherosclerotic aortic ulcer. [bib_ref] A pictorial review of acute aortic syndrome: discriminating and overlapping features as..., Ueda [/bib_ref] [bib_ref] Nontraumatic acute aortic emergencies: Part 1, Acute aortic syndrome, Maddu [/bib_ref] [bib_ref] Acute aortic syndrome, Vilacosta [/bib_ref] These are not mutually exclusive and may represent variations on the same disease spectrum. [bib_ref] Acute aortic syndrome, Vilacosta [/bib_ref] [bib_ref] Imaging modalities for the early diagnosis of acute aortic syndrome, Evangelista [/bib_ref] [bib_ref] Don't get in a flap!: a case report of progression through the..., Choong [/bib_ref] [bib_ref] Acute aortic syndrome, Sheikh [/bib_ref] Different classifications of aortic dissection exist, [bib_ref] Acute aortic syndrome: CT findings, Chiu [/bib_ref] [bib_ref] Acute aortic syndrome: CT findings, Das [/bib_ref] but to avoid confusion, we recommend using the most recently proposed classification of defining dissection as follows: Type A, involving the ascending aorta; Type B, limited to aorta portion distal to left subclavian artery; and Type B with aortic arch involvement, involving the arch (between the innominate and left subclavian arteries) but not involving the ascending aorta. [bib_ref] Aortic arch dissection: a controversy of classification, Lempel [/bib_ref] The classification reflects the current management approach, which supports that Type B dissection can be managed conservatively. With recent advances in CT scanning technology and increasing expertise in cardiovascular CT, the purpose of these recommendations are to outline the best practice for the investigation of suspected AAS so that unequivocal diagnosis can be made based on imaging. Specifically, accurate motion-free imaging is vital to eliminate the possibility of false-positive diagnoses, needless patient transfer and potentially disastrous unnecessary surgery, all of which have been reported. [bib_ref] Motion artifact resulting in a false positive CT angiogram for a presumed..., Karras [/bib_ref] [bib_ref] Prevalence and factors associated with false positive suspicion of acute aortic syndrome:..., Raymond [/bib_ref] [bib_ref] Pitfalls in the diagnosis of thoracic aortic dissection at CT angiography, Batra [/bib_ref] [bib_ref] Transfer of patients with suspected acute aortic syndrome, Aggarwal [/bib_ref] [bib_ref] Transfer metrics in patients with suspected acute aortic syndrome, Aggarwal [/bib_ref] Assessment of pre-test likelihood Recommendation 1 Assessment of pre-test clinical probability of AAS should be performed using American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidance. [bib_ref] American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines;..., Hiratzka [/bib_ref] Initial evaluation of AAS should be based upon careful history and clinical examination (i.e. assessing for peripheral pulse deficits and potential end organ damage secondary to dissection) resulting in the ability to determine a pre-test likelihood of AAS. A summary of pre-test likelihood is shown in [fig_ref] Figure 1: Risk stratification for acute aortic syndrome and appropriate management strategy [/fig_ref] which categorizes patients into low, intermediate or high likelihood of AAS. 17 ## Recommendation 2 Patients deemed to have intermediate or high risk should proceed to have imaging to establish a definitive diagnosis. In patients with low clinical risk, an alternative diagnosis should be considered but definitive imaging may also be required. Patients with high-risk conditions such as those with increased wall stress (e.g. hypertension, phaeochromocytoma, cocaine use) and aortic medial abnormalities (e.g. Marfan, Loeys-Dietz, Ehlers-Danlos, Turner syndromes, inflammatory vasculitides) have increased risks of developing thoracic aortic aneurysm and dissection. [bib_ref] Familial thoracic aortic aneurysms and dissectionsincidence, modes of inheritance, and phenotypic patterns, Albornoz [/bib_ref] [bib_ref] Emergency repair of type A aortic dissection in type IV Ehlers-Danlos syndrome, Ascione [/bib_ref] [bib_ref] Clinical and genetic features of vascular Ehlers-Danlos syndrome, Germain [/bib_ref] [bib_ref] Imaging of cardiovascular risk in patients with Turner's syndrome, Marin [/bib_ref] [bib_ref] Treatment of aortic disease in patients with Marfan syndrome, Milewicz [/bib_ref] [bib_ref] Aortic dissection in children and adolescents with Turner syndrome: risk factors and..., Turtle [/bib_ref] High-risk clinical features and examinations should also be borne in mind, allowing for appropriate patient selection for imaging. Pre-test likelihood assessment should be performed to exclude other causes and select appropriate patients for timely imaging. ## Imaging modality and technique recommendation 3 When imaging is deemed appropriate, CT scan is the imaging modality of choice in acute scenario. Transthoracic echocardiography Transthoracic echocardiography usually allows adequate assessment of the aorta and can often diagnose involvement of the aortic root and proximal ascending aorta. However, other segments (e.g. the aortic arch, proximal descending aorta and abdominal aorta) are sometimes difficult to see owing to inadequate acoustic window. The value of transthoracic echocardiography is further limited in non-standard patients (e.g. abnormal chest wall configuration, obesity, pre-existing pulmonary emphysema, or patients on mechanical ventilation). Transoesophageal echocardiography The proximity of the oesophagus to the aorta allows high-quality images of the aorta to be obtained. The high accuracy of transoesophageal echocardiography for the diagnosis of aortic dissection has been reported previously. [bib_ref] Comparative diagnostic value of transesophageal echocardiography and retrograde aortography in the evaluation..., Chirillo [/bib_ref] [bib_ref] Accuracy of biplane and multiplane transesophageal echocardiography in diagnosis of typical acute..., Keren [/bib_ref] The largest series examining ascending aortic dissection shows a sensitivity and specificity of 96.8% and 100%, respectively. [bib_ref] Diagnosis of ascending aortic dissection by transesophageal echocardiography: utility of M-mode in..., Evangelista [/bib_ref] The main drawbacks of transoesophageal echocardiography are sedation requirement and access to appropriate expertise. CT The accuracy of CT in the diagnosis of aortic dissection is high with sensitivity and specificity ranging around 98-100%. As per evidence based on the International Registry of Acute Aortic Dissection registry 27 and the Spanish Registry of Acute Aortic Syndromes, [bib_ref] Better diagnosis is not reflected in reduced mortality, Evangelista [/bib_ref] CT is already the preferred imaging modality and was used in 74% and 77% of patients in each registry, respectively. One of the major drawbacks of CT is the pulsation artefact which is addressed in this article. MRI MRI has very high sensitivity (97-100%) and specificity (94-100%) for the diagnosis of aortic dissection. [bib_ref] Aortic dissection: a comparative study of diagnosis with spiral CT, multiplanar transesophageal..., Sommer [/bib_ref] [bib_ref] Diagnosis of thoracic aortic dissection. Magnetic resonance imaging versus transesophageal echocardiography, Nienaber [/bib_ref] MRI is free from ionizing radiation, but limitations are low availability and time taken for examination (even in experienced sites, imaging time can be 20-30 min) means lack of suitability in acute setting. Given the available evidence, CT is recommended as the imaging modality of choice in the acute scenario because of accuracy, ease of access and relatively quick examination time. [bib_ref] Imaging modalities for the early diagnosis of acute aortic syndrome, Evangelista [/bib_ref] [bib_ref] Management of acute aortic syndrome, Clough [/bib_ref] Once AAS is confirmed, in addition, echocardiography may be used to assess complications such as aortic valve dysfunction, pericardial tamponade, or wall motion abnormalities, but this should not delay definite surgical management. In equivocal cases of acute intramural haematoma, a characteristic ''echo-free space or echolucent area'' within the thickened aortic wall that may be sought in supportive of diagnosis. [bib_ref] Management of acute aortic syndrome, Clough [/bib_ref] [bib_ref] Update in acute aortic syndrome: intramural hematoma and incomplete dissection as new..., Song [/bib_ref] [bib_ref] Transesophageal echocardiographic and clinical features of aortic intramural hematoma, Harris [/bib_ref] [bib_ref] Clinical significance of echo-free space detected by transesophageal echocardiography in patients with..., Song [/bib_ref] MRI/MR angiogram is not recommended in acute scenario but is useful in the context of follow-up of known aortic dissections, particularly in young patients [bib_ref] Imaging of aortic aneurysms and dissection: CT and MRI, Hartnell [/bib_ref] in line with the as low as reasonably practical principle of radiation dose optimization. ## Recommendation 4 All CT scans should be performed with the aim of producing motion-free images of the aortic root, which is prone to pulsation artefact [fig_ref] Figure 2: Ungated CT angiogram of the aorta demonstrating pulsation artefact [/fig_ref]. In systems with 64-detector-row arrays (or 80-detector-row arrays-these systems may be configured as 128 or 160 slices per rotation systems depending upon technical details of reconstruction), this should involve routine use of electrocardiogram (ECG) synchronization. [bib_ref] Multi-detector row computed tomography: imaging in acute aortic syndrome, Manghat [/bib_ref] [bib_ref] Thoracic aorta: motion artifact reduction with retrospective and prospective electrocardiography-assisted multi-detector row..., Roos [/bib_ref] Prospective triggering should be used where possible in order to reduce radiation dose. Retrospective gating usually incurs a penalty of significantly higher radiation dose. A dose-length product (DLP) for retrospective thoracic CT angiogram can be as high as 2547 mGy cm 21 , 38 although there are specific instances where this may have to be performed (see Specific protocol examples section). Broad detector array systems, e.g. 128 detector rows (e.g. Philips iCT; Philips, Andover, MA), 256 detector rows (e.g. GE Revolution; General Electrics, Milwaukee, WI) or 320 detector rows (e.g. Toshiba Aquilion One; Toshiba, Irvine, CA) or dual-source systems, should be optimized to allow motion-free imaging which may not require ECG synchronization if temporal resolution is rapid enough, but this depends upon scanner capabilities. ## Recommendation 5 A non-contrast ECG synchronization CT scan should be performed to look for a rim of hyper-attenuation around the aortic wall [fig_ref] Figure 3: Non-contrast CT demonstrating typical appearance of a hyperattenuating crescentic ring that can... [/fig_ref]. This should be performed prior to the contrast-enhanced study. The use of a non-contrast scan may reduce the likelihood of false-negative diagnosis on contrast studies in cases of isolated subtle intramural haematoma. Incidences vary but range from 6% to 30%. [bib_ref] American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines;..., Hiratzka [/bib_ref] [bib_ref] Acute aortic intramural hematoma: an analysis from the International Registry of Acute..., Harris [/bib_ref] [bib_ref] Diagnostic errors in the evaluation of nontraumatic aortic emergencies, Souza [/bib_ref] [bib_ref] Diagnostic utility of unenhanced computed tomography for acute aortic syndrome, Kurabayashi [/bib_ref] In addition, a non-contrast scan may enable the visualization of acute haemorrhagic content within the aortic wall that can be associated with the other forms of AAS 2 and also localized rupture into the pericardium. Where possible, a low-dose setting should be utilized. The non-contrast scan does not need to encompass the whole aorta and can be limited to covering from aortic arch to diaphragmatic sulcus. ## Coverage ## Recommendation 6 Coverage should be limited to thorax from aortic arch to diaphragmatic sulcus in the first instance, unless the patient is deemed high risk or has known disease. Initial coverage should be as for a CT Thorax (covering aortic arch to diaphragmatic sulcus). As the diagnostic rate for positive findings may be as low as 2.7%, [bib_ref] Suspected aortic dissection and other aortic disorders: multi-detector row CT in 373..., Hayter [/bib_ref] [bib_ref] Preliminary development of a clinical decision rule for acute aortic syndromes, Lovy [/bib_ref] coverage should be limited in the first instance in patients with intermediate pre-test probability in order to avoid unnecessary radiation dose. If the scan proves positive, then a repeat scan can be performed with extended coverage to the common femoral arteries to allow for endovascular access planning and to fully delineate the full extent of the dissection. In those patients deemed "high risk" for dissection following risk assessment, particularly with abdominal and/or lower limb symptoms/signs, it is reasonable to perform complete coverage of the entire aorta and to include the iliofemoral arteries from the outset. In addition, in situations where there is known aortic dissection, extended coverage is mandatory. ## Premedication In the acute setting, we do not advocate the use of beta-blocker medication to slow the heart rate (HR). ## Patient size Patient size or body mass index (BMI)-adjusted tube current/ voltage should be employed for maximum dose optimization. As a general rule, lower BMI will allow for the use of flow tube voltage (kVp) and provided that tube current is also optimized, dose can be reduced. Lowering kVp will affect image contrast and will allow for the use of less iodine intravenous contrast (see Recommendation 8 section). ## Scan initiation and contrast regime recommendation 7 A dedicated injection protocol should be used, taking into account the speed of scan acquisition and coverage with the aim to achieve adequate contrast concentration of at least 250 HU in the aorta. There are three distinct methods of scan initiation that may be used. (a) Fixed delay: this must take into account the contrast injection rate, contrast concentration, table feed speed, scanner detector width and perceived patient cardiac output. This is effectively a prediction and is not recommended. (b) Test bolus: this technique will allow homogeneous contrast enhancement and takes into account the patient's haemodynamic status. However, a disadvantage is that it requires a small increase in the overall contrast medium dose for the test bolus (usually #20 ml). [bib_ref] Intravenous contrast medium administration at 128 multidetector row CT pulmonary angiography: bolus..., Rodrigues [/bib_ref] Lower tube voltage protocols for test bolus imaging can be used to reduce radiation further. 45 (c) Bolus tracking: with a region of interest placed in the ascending thoracic aorta, the scan is commenced once a predetermined threshold Hounsfield unit has been reached. It should be noted that in AAS, there is a risk that if the region of interest is incorrectly placed (e.g. as can occur in the false lumen of a dissected aorta), inappropriate triggering may occur. The operator should be aware that manual initiation may be required in this instance. The contrast injection should be given via the right arm to eliminate the streak artefacts that might be caused by injection from the left side, obscuring assessment of head and neck vessels that may potentially be involved. The amount of contrast and rate of injection depends upon the speed of scan acquisition, tube voltage, patient size and z-axis coverage, as well as the iodine concentration used and whether a saline bolus chaser is used. The aim is to achieve adequate contrast concentration of at least 250 HU in the aorta. [bib_ref] Cardiothoracic CT angiography: current contrast medium delivery strategies, Weininger [/bib_ref] The use of a saline flush is recommended as this produces a higher contrast peak opacification for any given iodine flux and makes most efficient use of administered contrast. [bib_ref] Saline flush effect for enhancement of aorta and coronary arteries at multidetector..., Kim [/bib_ref] On the most recent generation of CT scanners, it is now feasible to use low tube voltage for routine imaging of the aorta, even in large-sized patients (often in conjunction with iterative reconstruction techniques). Owing to the greater photon absorption of iodinated contrast at energies nearer 70 kVp, this results in greater relative vascular enhancement. This in turn allows for smaller volumes of contrast to be used at lower flow rates (iodine delivery rates of 1.3-1.5 g s 21 ). Similarly, the use of high-pitch dual-source systems need less iodine delivery rate but owing to acquisition speed, adjustment of the acquisition delay may be required. Biphasic or triphasic injections should be considered to reduce contrast dose, produce a uniform enhancement pattern without affecting the maximal enhancement and also minimize artefacts from dense contrast material within the superior vena cava. Patient-specific protocols can also be employed and may achieve more uniform contrast enhancement. 49 ## Recommendation 8 The key to adequate contrast opacification is to achieve an iodine delivery rate of at least 1.6 g s 21 (ideally up to 2 g s 21 ) when using a tube voltage of 120 kVp. The two factors to consider when calculating iodine flux are the iodine concentration of the contrast media and the injection rate, i.e. 300 mg of iodine per millilitre injected at 6.7 ml s 21 vs contrast media of 400 mg of iodine per millilitre injected at 5 ml s 21 . It is worth noting that patient factors also affect iodine delivery rate (i.e. cardiac output and weight). Therefore, it is recommended that contrast volume should be determined based on the patient's weight, usually delivering at least 300-mg iodine per kilogram for examinations of the whole aorta with 64-detector row systems. However, advanced broad detector array or dual-source systems may permit lower volumes in view of their increased speed of acquisition. 48 If using a 64-detector-row CT for the entirety of the aorta, a decrease in aortic enhancement in the descending aorta may be observed when using a biphasic protocol. However, the decrease in aortic enhancement usually does not fall below diagnostic acceptability and often remains above the 250 HU. [bib_ref] Effect of different saline chaser volumes and flow rates on intravascular contrast..., Behrendt [/bib_ref] Whilst the aim is to get uniform enhancement throughout the entire aorta, but in the descending and abdominal aorta, this may on occasion be difficult to achieve. However, in most cases, the abdominal aorta can be delineated sufficiently to visualize the dissection and the perfusion of the mesenteric and renal arteries without a need for a repeat examination. Moreover, intramural haematoma and penetrating atherosclerotic ulcer are relatively rare in the abdominal aorta. Multiphase injection protocols may enable more uniform vascular enhancement throughout the entire aorta, and if available should be considered. [bib_ref] Uniform vascular contrast enhancement and reduced contrast medium volume achieved by using..., Bae [/bib_ref] Optimizing CT parameters Although diagnosis of AAS can be made using non-gated CT techniques, image quality at the aortic root is often suboptimal owing to motion artefact. This limits the diagnostic confidence and may on occasion mimic aortic dissection, leading to unnecessary further investigation and treatment, including sternotomy/thoracotomy. The prevalence of aortic motion artefacts with non-gated CT has been reported to be high as 57-93% in some series. [bib_ref] Motion artifacts of the aorta simulating aortic dissection on spiral CT, Qanadli [/bib_ref] [bib_ref] A case report of a normal aorta misdiagnosed as type A dissection..., Hamilton [/bib_ref] [bib_ref] Effects of heart rate on motion artifacts of the aorta on non-ECGassisted..., Ko [/bib_ref] With ECG synchronization, the occurrence of this artefact is less common, allowing motionfree visualization of the aortic root and proximal coronary arteries in almost all cases. [bib_ref] Thoracic aorta at multidetector row CT: motion artifact with various reconstruction windows, Morgan-Hughes [/bib_ref] [bib_ref] Electrocardiographically gated 16-section CT of the thorax: cardiac motion suppression, Hofmann [/bib_ref] To allow for prospective acquisition of the aorta, systems with detector coverage of at least 32 mm in the z-axis are recommended to make breath-holding possible during the whole scan acquisition. ECG synchronization must be available to allow co-registration with heart rhythm. Scanners with $64 detector rows should be used in conjunction with narrow reconstructed slice thickness (,1 mm) in order to provide adequate multiplanar reformats, preferably with isotropic resolution utilizing small voxel size through the use of a small field of view tailored to the aorta. ## Specific protocol examples For each scanner type, it is important that dedicated protocols are used and optimized. The protocols outlined below should be used as a guide, and variations may exist depending on differing parameters as outlined above. These protocols are advocated based upon expert British Society of Cardiovascular Imaging user recommendations and in collaboration with UK application specialists. ## Basic concept For a 64-detector-row system (including "128-slice" scanners and similar), prospective ("step-and-shoot") acquisition should be employed where possible with phase selection based on HR. This is because the phase with minimal motion of the aortic root varies with HR. At HR ,65 beats per minute (bpm), this is usually the end-diastolic phase. With HR .65 bpm, this is usually end-systolic phase. [bib_ref] Thoracic aorta at multidetector row CT: motion artifact with various reconstruction windows, Morgan-Hughes [/bib_ref] Where phase selection is not adjustable (e.g. on a scanner with prospective helical acquisition with diastolic phase acquisition only for slow HRs), then a retrospective protocol may need to be employed for patients with faster HRs. Retrospectively gated acquisitions can be used but should be only employed where no prospectively triggering alternative exists. Iterative reconstruction algorithms should be used where deemed appropriate to allow reduced radiation dose. [bib_ref] Effects of model-based iterative reconstruction on image quality for low-dose computed tomographic..., Caywood [/bib_ref] [bib_ref] High-pitch, low-voltage and lowiodine-concentration CT angiography of aorta: assessment of image quality..., Shen [/bib_ref] [bib_ref] Impact of Adaptive Statistical Iterative Reconstruction (ASIR) on radiation dose and image..., Cornfeld [/bib_ref] For larger detector array or high-pitch dual-source systems, ECG synchronization may not be necessary for motionfree imaging of the aorta. A summary of all the protocols can be seen in [fig_ref] Table 1: Summary of scanning parameters for different types of CT scannersNon-gated helical acquisition... [/fig_ref]. Further discussions are as follows. Single-source systems: standard detector coverage-64and 80-detector row scanners (including "128and 160-slice" systems) Although, step artefact may be problematic in coronary imaging, this does not affect diagnostic confidence in the visualization of the aorta. The advantage of adopting prospective triggering is a significant reduction in radiation dose compared with nongated and retrospectively gated acquisitions. There may be a role for retrospective gating when the HR is fast (i.e. .100 bpm) or in systems where the threshold for prospective triggering under a pre-defined HR cannot be overridden [fig_ref] Table 1: Summary of scanning parameters for different types of CT scannersNon-gated helical acquisition... [/fig_ref]. When retrospective acquisition is used, dose modulation outside the 30-80% cardiac cycle should be applied. [bib_ref] Prospective and retrospective ECG gating for thoracic CT angiography: a comparative study, Wu [/bib_ref] Prospective triggering is recommended with phase selection taking into account the patient's HR. [bib_ref] Thoracic aorta at multidetector row CT: motion artifact with various reconstruction windows, Morgan-Hughes [/bib_ref] [bib_ref] Comparison of sequential and helical scanning for radiation dose and image quality:..., Bischoff [/bib_ref] [bib_ref] Prospective ECGtriggered CT angiography of the thoracic aorta in patients with atrial..., Blanke [/bib_ref] Regular HR ,65 bpm: prospective with end-diastolic triggering. HR .65 bpm or irregular HR: prospective with end-systolic triggering. For scanners that cannot utilize prospective triggering in a "stepand-shoot" manner at HR .65 bpm, the following protocol should is recommended. Regular HR ,65 bpm: prospective with end-diastolic triggering. HR .65 bpm or irregular heart rate: retrospective gating with dose modulation. For scanners that have a retrospective mode with adaptive dose modulation, this may be used as an alternative for fast HRs. This mode can be used to automatically tighten the dose modulation during retrospective acquisition. However, it is worth noting that the use of this mode should be performed with caution in irregular/variable HRs, where scanner may widen the modulation window and dose may increase significantly. In addition, dose modulation outside the acquisition window should be set at the lowest possible value if adjustable (this is vendor-specific but ranges from 4% to 20%), therefore lowering overall dose further in retrospective acquisition. For scanner types that only use prospective helical scanning during diastolic phase at HR ,65 bpm, retrospective gating should be used above this threshold. In this setting, the following protocol is recommended. Regular HR ,65 bpm: prospective helical scanning with enddiastolic triggering. HR .65 bpm or irregular HR: retrospective gating with dose modulation. Where a variable helical pitch function is available, this allows seamless switching to non-gated scanning with increased pitch outside the coverage for the heart. For example, for thorax only, one would scan variable helical pitch caudocranially. ECG synchronization only used within the heart, followed by ungated acquisition for the rest of the thorax to the apices. If extended coverage of whole aorta is required, scan can be performed craniocaudally, using ECG synchronization in the thoracic portion, and then changing pitch and switching to ungated acquisition for the remaining abdominal and pelvic coverage. Single-source systems: broad detector coverage-128-, 256-or 320-detector-row scanners (including "256and 640-slice" systems) For large detectors systems with increased z-axis coverage, the scanning time can be reduced. 128-detector-row scanners usually have a detector width of 8 cm. Imaging the entire thoracic aorta therefore requires more than one transverse section (and often 3-4 sections). It is recommended that a prospectively triggered approach is used, as with the 64-slice scanners. Recommendations are as follows: Where the ability to switch from gated to non-gated scan acquisition is available, this should also be utilized to minimize dose. 320-detector systems have a detector width of 16 cm; this coverage may be adequate to image the thoracic aorta in 1-2 rotations, and with this rapid acquisition, ECG synchronization may not be required. Non-gated helical acquisition with the middle 8-cm coverage (160 3 0.5 mm) can be used to image the thoracic aorta in 1-2 heartbeats with motion-free imaging of the aorta. However, if dedicated coronary assessment is also required (e.g. in the context of known AAS or a high pre-test probability), then prospectively triggered ECG synchronization (HR ,65 bpm 70-80% single pulse per volume, HR .65 bpm 30-80% single pulse per volume) covering the entire thoracic aorta should be performed. This will require 2 volumes of 16 cm (320 3 0.5 mm) for adequate coverage. Several investigators have reported similar protocols previously. [bib_ref] Initial experience with a chest pain protocol using 320-slice volume MDCT, Hein [/bib_ref] [bib_ref] Prospective ECG-gated 320-row CT angiography of the whole aorta and coronary arteries, Li [/bib_ref] Dual-source systems Dual-source systems have improved temporal resolution and thus allow higher tolerance for accelerated HRs. If temporal resolution ,100 ms can be achieved, HR-dependent prospectively ECG-synchronization protocols can be applied. For example, if the HR is ,65 bpm, the optimum phase is at end diastole. For HRs .65 bpm, the optimum phase is at end systole. [bib_ref] Robustness of end-systolic reconstructions in coronary dual-source CT angiography for high heart..., Adler [/bib_ref] [bib_ref] Optimal systolic and diastolic reconstruction windows for coronary CT angiography using dualsource..., Seifarth [/bib_ref] In a system that allows for high-pitch acquisition in conjunction with wide detector arrays, traditional ECG synchronization may not be required. [bib_ref] Lowdose, 128-slice, dual-source CT coronary angiography: accuracy and radiation dose of the..., Alkadhi [/bib_ref] [bib_ref] High-pitch dual-source CT angiography of the whole aorta without ECG synchronisation: initial..., Beeres [/bib_ref] [bib_ref] Thoracic aorta: prospective electrocardiographically triggered CT angiography with dual-source CT-feasibility, image quality,..., Blanke [/bib_ref] [bib_ref] High-pitch dual-source CT angiography of the aortic valve-aortic root complex without ECGsynchronization, Karlo [/bib_ref] [bib_ref] Dual source multidetector CT-angiography before transcatheter aortic valve implantation (TAVI) using a..., Wuest [/bib_ref] For example, using a pitch of .3 and gantry rotation time 0.28 s permits coverage of 9.6-11.6 cm s 21 with reduced radiation dose. [bib_ref] High-pitch dual-source CT angiography of the whole aorta without ECG synchronisation: initial..., Beeres [/bib_ref] [bib_ref] High-pitch dual-source CT angiography of the aortic valve-aortic root complex without ECGsynchronization, Karlo [/bib_ref] [bib_ref] Dual-source spiral CT with pitch up to 3.2 and 75 ms temporal..., Flohr [/bib_ref] CONCLUSION This document outlines the different methods of scan acquisition with an emphasis on the importance of performing motionfree imaging of the aorta in suspected AAS in order to provide accurate diagnosis. This is by no mean an exhaustive coverage of the multiple scanners available but should encompass most scanners being used routinely in UK practices. It serves to outline the basic principle of motion-free aortic imaging using the currently available evidence and expert opinions of the BSCI/BSCCT. With continuing rapid advancement of CT technologies and the need to standardize image acquisition coupled with an obligation for dose optimization, these recommendations should allow centres to adopt protocols specific to their scanners for timely and accurate assessment using the basic principles outlined in this document. Acquisition is only one aspect of the scan and to properly implement this imaging strategy, centres must also adopt appropriate reporting facilities (e.g. picture archiving and communication system must be able to manage ECG-gating data sets, including handling of multiphasic reconstruction of retrospective acquisition), radiographer's training, as well as reporting expertise. In terms of implementation, it has been shown that application of ECG gating by adequately trained staff has no impact on the workflow of the CT examination in acute setting. [bib_ref] Comparison of retrospectively ECG-gated and nongated MDCT of the chest in an..., Schertler [/bib_ref] We envisage that definitive diagnosis of ascending aortic pathology, eliminating false-positive scans, should become routine practice and that no patient should undergo sternotomy/ thoracotomy or other intervention without an optimal AAS CT scan. [fig] Figure 1: Risk stratification for acute aortic syndrome and appropriate management strategy. [/fig] [fig] Figure 2: Ungated CT angiogram of the aorta demonstrating pulsation artefact (arrows). [/fig] [fig] Figure 3: Non-contrast CT demonstrating typical appearance of a hyperattenuating crescentic ring that can be seen in acute intramural haematoma (arrowheads). [/fig] [table] Table 1: Summary of scanning parameters for different types of CT scannersNon-gated helical acquisition with the middle 8-cm coverage (160 3 0.5 mm) can be used to image the thoracic aorta in 1-2 heartbeats with motion-free imaging of the aortaExceptionIf dedicated coronary assessment is required (e.g. in the context of known AAS or a high pre-test probability), then use followingHR , 65 Prospectively triggered ECG synchronization with 70-80% single pulse per volume HR . 65 Prospectively triggered ECG synchronization with 30-80% single pulse per volume Dual source HR-dependent HR-dependent prospectively ECG-synchronization protocols can be applied similar to the systems above HR , 65 Prospective gating with end-diastolic acquisition HR . 65 Prospective gating with end-systolic acquisition In a system that allows for high-pitch acquisition in conjunction with wide detector arrays, traditional ECG synchronization may not be required e.g. a pitch of .3 and gantry rotation time 0.28 s permit coverage of 9.6-11.6 cm s 21 AAS, acute aortic syndrome; ECG, electrocardiogram; HR, heart rate. Regular HR ,75 bpm: prospective with end-diastolic triggering. HR .75 bpm or irregular HR: prospective with end-systolic triggering. [/table]

COVID19 and acute lymphoblastic leukemias of children and adolescents: Updated recommendations (Version 2) of the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE) d'hémato-immunologie pédiatrique, hôpital universitaire Robert-Debré (APHP), boulevard Sérurier, 75019 Paris, France 5. Groupe hospitalier Pellegrin, unité d'hémato-oncologie pédiatrique, place Amélie-Raba-Léon, 33000 Bordeaux, France 6. Service d'hémato-oncologie pédiatrique, CHU Rennes, 16, boulevard de Bulgarie, COVID19 and acute lymphoblastic leukemias of children and adolescents: Updated recommendations (Version 2) of the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents Preamble and general recommendations ## Preamble The situation of the current COVID-19 pandemic is continuously evolving. We thus have taken the more recent knowledge into account to update the previous recommendations from the Leukemia committee of the Société Française de lutte contre les Cancers et leucémies de l'Enfant et de l'adolescent (SFCE). Despite an increasing number of publications concerning severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pediatric oncology and hematology, data in children with cancer are still limited [fig_ref] TABLE I: Selected COVID-19 studies in children with leukemia [/fig_ref]. Published recommendations most often relies on an expert-opinion basis [bib_ref] Early advice on managing children with cancer during the COVID-19 pandemic and..., Bouffet [/bib_ref] [bib_ref] The COVID-19 pandemic: a rapid global response for children with cancer from..., Sullivan [/bib_ref]. While some early studies in adults with cancers suggested that the risk of severe COVID-19 is higher in this population [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref] [bib_ref] High mortality rate in cancer patients with symptoms of COVID-19 with or..., Assaad [/bib_ref] , more recent data indicate that patients with cancer may not be at greater risk than others when matched for comorbidities [bib_ref] COVID-19 severity and outcomes in patients with cancer: a matched cohort study, Brar [/bib_ref]. However, mortality appears to be higher in adults with haematological malignancies [bib_ref] Outcomes of patients with hematologic malignancies and COVID-19: a report from the..., Wood [/bib_ref] [bib_ref] Clinical characteristics and risk factors for mortality in hematologic patients affected by..., Cattaneo [/bib_ref]. In pediatric oncology, most reports have been limited to cases or small sample populations [bib_ref] COVID-19 in children with cancer in New York City, Boulad [/bib_ref] [bib_ref] COVID-19 infection in children and adolescents with cancer in Madrid, De Rojas [/bib_ref] [bib_ref] SARS-CoV-2 disease and children under treatment for cancer, Terenziani [/bib_ref] [bib_ref] Favourable outcome of coronavirus disease 2019 in a 1-year-old girl with acute..., Sieni [/bib_ref] [bib_ref] Severe COVID-19 disease in two pediatric oncology patients, Stokes [/bib_ref] [bib_ref] SARS-CoV-2 infection during induction chemotherapy in a child with high-risk T-Cell Acute..., Dantonello [/bib_ref] [bib_ref] COVID-19 disease in New York City pediatric hematology and oncology patients, Gampel [/bib_ref] while larger clinical studies have recently been published and/or are still ongoing [bib_ref] Impact of COVID-19 on cancer care: a survey from the French Society..., Rouger-Gaudichon [/bib_ref] [bib_ref] Clinical characteristics and outcome of severe acute respiratory syndrome coronavirus 2 infection..., Bisogno [/bib_ref] [bib_ref] Severity of COVID-19 in children with cancer: report from the United Kingdom..., Millen [/bib_ref]. These reports suggest that COVID-19 is generally asymptomatic, mild or moderate in children receiving anti-cancer therapy. Thus children with cancer appear to have a similar risk of developing severe COVID-19 compare to those in their healthy counterparts. However, some severe cases have been described, mostly in highly immunocompromised children and/or with severe oncologic conditions [bib_ref] Severe COVID-19 disease in two pediatric oncology patients, Stokes [/bib_ref] [bib_ref] Impact of COVID-19 on cancer care: a survey from the French Society..., Rouger-Gaudichon [/bib_ref] [bib_ref] Severe COVID-19 infection in a child receiving immunotherapy for cancer, Smith [/bib_ref]. Since April 2020, a real-time prospective survey has been set up among the 30 SFCE centers. On 17 th of December 2020, 127 cases of COVID-19 have been reported, most of them being enrolled in the PEDONCOVID study (NCT04433871). Eight patients required hospitalization in intensive care unit (ICU) and one patient with relapsed acute lymphoblastic leukemia (ALL) died from ARDS with multi-organ failure. Thus, SARS-CoV-2 infection can be severe in some children with cancer and/or HSCT, as suggested by the first reports from the SFCE [bib_ref] Impact of the first wave of COVID-19 on pediatric oncology and hematology:..., Rouger-Gaudichon [/bib_ref] or available through the St-Jude Research Hospital Registry (to which the SFCE is participating). Fortunately, SARS-CoV-2 infection appears nevertheless to be mild in most children with cancer/ALL [bib_ref] Severity of COVID-19 in children with cancer: report from the United Kingdom..., Millen [/bib_ref] [bib_ref] Impact of the first wave of COVID-19 on pediatric oncology and hematology:..., Rouger-Gaudichon [/bib_ref] [bib_ref] Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients..., Hrusak [/bib_ref] [bib_ref] Lessons after the early management of the COVID-19 outbreak in a pediatric..., Balduzzi [/bib_ref]. Thus, the main threat to the vast majority of children with ALL still remains the ALL itself. Long-term data including well-matched casecontrol studies will tell if treatment delays/modifications due to Covid 19 have impacted the outcome if children with ALL. Beyond the risk of SARS-CoV-2 infection in patients currently treated for a leukemia vigilance must be maintained regarding the danger of delaying the diagnosis of acute leukemia. Such situations have already been reported with tragic consequences [bib_ref] Delayed cancer diagnoses and high mortality in children during the COVID-19 pandemic, Ding [/bib_ref] [bib_ref] Collateral effects of COVID-19 pandemic in pediatric hematooncology: fatalities caused by diagnostic..., Parasole [/bib_ref]. ## General recommendations There are still insufficient data to support recommendations applicable to all local cases and situations during the care of children and adolescents and young adults (AYA) with ALL. The most experienced practitioners of the hematology-oncology unit must therefore help to decide, on a case-by-case basis, for which patients should the leukemia treatment be initiated or continued, or identify those in whom a delay is possible, depending on clinical symptoms and tumor biology. For patients in the advanced stage of their disease, the real benefit of the treatment in the context of the risk of COVID-19 must be considered and discussed. Some general recommendations should be reiterated: it is recommended to test for SARS-CoV-2 (preferably by PCR or at least by immunological tests, on nasopharyngeal swab) before starting intensive induction chemotherapy or other intensive phase of treatment, for ALL patients, with or without symptoms, especially in the most affected regions. Due to the unpleasant nature of nasopharyngeal swab tests, they may be difficult to repeat in children. Although salivary tests may be an interesting alternative in the general population, their sensitivity is lower than the one of nasopharyngeal tests. ## Summary Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very specific nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations. Here is the second version of these recommendations updated according to the evolution of knowledge on COVID19. Review until negativity, especially before the beginning of an intensive course; if the SARS-CoV-2 test is not available, carefully look for suggestive symptoms (dry cough, high fever, anosmia, rhinorrhoea, digestive signs) and/or any notion of contact with a symptomatic individual and consider a chest CT scan; carefully isolate any COVID-negative child or adolescent to allow him to securely advance in the treatment (facial mask, social distancing, barrier measures, no contact with individuals suspect of COVID or COVID + for 3 weeks. . .), in particular for those intended to be allografted; visits should be limited to parents and potentially to siblings in hospitalized children, and in the course of hematopoietic stem cell transplantation, with respect of sanitary measures. Patients with ALL in first line, included in the CAALL-F01 or ESPhALL 2017 protocols or treated according to the FRALLE/EORTC protocols or INTERFANT 06 Are you changing your approach to initial induction? ## General considerations Corticosteroids are a key part of induction therapy and, more generally, of ALL treatments. Initial outcomes of the use of corticosteroids in SARS-CoV-2 infection were controversial. Recent data suggested that dexamethasone is effective in severe COVID-19 in immunocompetent patients [bib_ref] Dexamethasone in hospitalized patients with Covid-19 -preliminary report, Recovery Collaborative Group [/bib_ref]. The benefit of using corticosteroids in immunocompromised patients with severe COVID-19 is less clear and has not been proven yet. Still, ALL is life-threatening and very probably more than COVID-19 in most situations. Thus, we consider that the riskbenefit ratio calls for regular protocol induction. However, chemotherapy doses and scheduled administration should be weighted with the clinical status and oxygen saturation of the patient, as well as the results of chest computed tomography scan, which should be performed in all patients during this induction phase. In case of significant desaturation (e.g. < 94% of oxygen), signs of respiratory distress and/or more than a 50% lung parenchyma impairment, we recommend pausing chemotherapy. Chemotherapy doses may also be delayed/reduced. Overall, we recommend a multidisciplinary discussion and/or with the protocol coordinators. After completion of chemotherapy, the use of G-CSF in a SARS-CoV-2-positive patient can be discussed to reduce the duration of neutropenia, in the absence of inflammatory signs attributable to COVID-19. The implementation of all or part of treatment on an outpatient basis must be carefully weighed. Indeed, the comings and goings to the ambulatory clinic and blood samplings at home increase the number of contacts at risk. Conversely, return at home could limit contact with caregivers, also possibly being SARS-CoV-2 carriers. A strict policy for family members is obviously to be established. Note that the risk of needing an intensive care bed during induction therapy of ALL is low (probably <5%). However, in certain regions and/or time frames, the decrease in the number of pediatric ICU beds (transformed into adult resuscitation beds) implies that the pediatric need is being forcefully re-expressed. Specific populations a. Philadelphia chromosome ALL: some adult hematologists (see ASH adult ALL COVID19 recommendations) offer treatment with a tyrosine kinase inhibitor with minimal steroid exposure rather than aggressive induction with multidrug therapy for the initial treatment, in the hope of avoiding prolonged hospitalization during the pandemic [bib_ref] Special considerations in the management of adult patients with acute leukaemias and..., Zeidan [/bib_ref]. However, the recommendation to keep on, including our patients in the EsPhall 2017 protocol with a regular use of imatinib, still seems appropriate to us. b. Infants under one year of age: the risk of serious forms of COVID-19 in infants has been reported. The test for SARS-CoV-2, possibly repeated, is absolutely necessary here. Again, the recommendation is to follow the current guidelines i.e. to follow the Interfant 06 protocol. c. Adolescents and young adults: clinicians may consider adolescents and young adults with a particular attention also taking into account the risk factors observed in adults, such as asthma, obesity and diabetes. To insist on compliance with treatment in general but also on adherence to barrier gestures and general sanitary measures, is of paramount importance. d. Children with Down syndrome: vigilance is essential in these children susceptible to infections in general, even if this susceptibility rarely concerns viral infections. Some reports suggest that patients with Down syndrome have a greater risk of developing severe COVID-19 [bib_ref] Individuals with Down syndrome hospitalized with COVID-19 have more severe disease, Malle [/bib_ref]. Of note, this group benefits from an induction with "only'' 3 drugs in the CAALL-F01 protocol, including dexamethasone. Are you changing the approach to intensive postremission therapy (consolidation, delayed intensification)? In the absence of data, our recommendation is to follow the protocol, including for corticosteroid therapy. As said in the general recommendations paragraph, each intensive course is to be preceded by a test. For patients with high-risk ALL, an individualized decision regarding transplantation and its timing is necessary, weighing the risks of transplantation in an epidemic context of COVID-19 against the risk linked to ALL. Are you changing your recommendations for maintenance treatment? Three problems are mainly to be discussed: intensity of maintenance treatment with 6MP/MTX and targets for leukocytosis/neutrophils/lymphocytes: we suggest to follow the usual recommendations of the protocol; pulses: monthly pulses (CAALL-F01, B-SR group) or every 10 weeks (CAALL-F01, B-MR group) with vincristine and steroids are to be maintained. In case of symptoms, COVID19 testing the day before, should be performed: if COVID +, then postpone the pulse for about 2 weeks and perform another test before performing the pulse; high dose methotrexate cycles in maintenance for T-ALL with high initial leucocyte count ( 100 G/L) and/or CNS3 status: any concern could be discussed with the protocol coordinators. In addition, minimizing hospital visits seems appropriate. Home blood tests are to be preferred and partial use of telemedicine may be considered. However, a physical examination should be performed regularly to avoid any delay in the diagnosis of treatment complications or relapse. Of course, such an attitude is beneficial only if preventive measures are also applied at home. ## Patients with second line or more all Patients with relapsed ALL may be at greater risk of severe COVID-19 [bib_ref] Impact of the first wave of COVID-19 on pediatric oncology and hematology:..., Rouger-Gaudichon [/bib_ref]. Test must be performed before starting a chemotherapy block, and postponing chemotherapy in case of positive test should be discussed in accordance with each specific situation and benefits/risks ratio regarding the leukemia. First relapse: we propose to include all eligible patients and/or to follow the INTREALL protocol as much as possible. Patients who reach complete remission n82 should be considered promptly for allogeneic transplantation, as indicated in the protocol, despite the pandemic. Second relapse and refractory relapses: Phase I-II trials: most if not all academic or industrial promoters ask now for SARS-CoV2 testing before inclusion. Any positivity is an at least temporary exclusion criterion. CAR-T cells: The indication for treatment with CAR-T cells must be weighed with the center which would perform the procedure: feasibility of performing apheresis (systematic patient testing, problem of using an operating room for apheresis central line placement for example)? Manufacturing feasibility? Feasibility of administration according to the possible rooms in intensive care unit? [bib_ref] Chimeric Antigen Receptor T Cell Therapy during the COVID-19 pandemic, Bachanova [/bib_ref] [bib_ref] The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management..., Ljungman [/bib_ref] What to do if an ALL patient is diagnosed with SARS-CoV-2 infection? What are the interactions between ALL chemotherapy and potential COVID-19 therapy? ## General recommendations 1. The diagnosis of SARS-CoV-2 infection during the treatment of ALL should imply to discuss the stopping and/or postponing of all chemotherapies, according to the severity of the ALL, the stage of treatment and the severity of clinical and/or radiological signs. Even if severe forms have been described, most of the experience is currently reassuring [bib_ref] Clinical characteristics and outcome of severe acute respiratory syndrome coronavirus 2 infection..., Bisogno [/bib_ref] [bib_ref] Severity of COVID-19 in children with cancer: report from the United Kingdom..., Millen [/bib_ref] [bib_ref] Impact of the first wave of COVID-19 on pediatric oncology and hematology:..., Rouger-Gaudichon [/bib_ref]. Review 2. Any "specific'' treatment must be discussed with the infectious diseases team. Potential interactions: They are described in table II aiming to list some of the treatments with antiviral potential and some of those proposed to act against the inflammatory process. Of note, the inflammatory stage of covid19 infection is generally the one of aggravation, and often involves hospitalization in ICU. Chemotherapy, except for steroids, is obviously interrupted at this stage. Which treatments may be considered in case of severe COVID-19? As underlined above, any specific anti-COVID-19 treatment should be considered and discussed with the infectious diseases team. Great efforts have been made to evaluate the efficacy of repurposed drugs against SARS-CoV-2 infection (tables II and III). Accordingly with the recently published interim analysis of the Solidarity study, there is no clear evidence of efficacy on COVID-19-related mortality of any antiviral agent [bib_ref] Repurposed antiviral drugs for Covid-19 -Interim WHO Solidarity Trial Results, Who Solidarity Trial Consortium [/bib_ref]. Though hydroxychloroquine and lopinavir/ritonavir therapeutic should be abandoned, remdesivir use could eventually be considered. In children, remdesivir may be proposed to positive patients who present potential risk factors of severe COVID-19 and should be given as early as possible in the course of the infection, for 10 days. Above 40 kg of weight, children may receive 200 mg the first day and 100 mg per day the next nine days. Below 40 kg of weight, children may receive 5 mg/kg on the first day and then 2.5 mg/kg once a day until 10 days of treatment [bib_ref] Compassionate use of remdesivir in children with COVID-19, Méndez-Echevarría [/bib_ref]. ## Table ii ## Current treatments used or tested in clinical trials Treatments with antiviral potential: Corticosteroids: proven efficacy of dexamethasone in immunocompetent adults with a severe form of COVID-19 [bib_ref] Dexamethasone in hospitalized patients with Covid-19 -preliminary report, Recovery Collaborative Group [/bib_ref] Unproven efficacy in immunocompromised patients Interestingly, evidence of prolonged viral shedding has been shown in immunosuppressed patients and could lead to discuss a more prolonged administration [bib_ref] Persistent replication of SARS-CoV-2 in a severely immunocompromised treated with several courses..., Camprubí-Ferrer [/bib_ref] [bib_ref] Case study: prolonged infectious SARS-CoV-2 shedding from an asymptomatic immunocompromised individual with..., Avanzato [/bib_ref] [bib_ref] Acute immune signatures and their legacies in severe acute respiratory syndrome coronavirus-2..., Baù [/bib_ref]. Among therapies acting on immune system and inflammation, there is no clear evidence that tocilizumab or anakinra are effective. However, dexamethasone use has been proven to be effective [bib_ref] Dexamethasone in hospitalized patients with Covid-19 -preliminary report, Recovery Collaborative Group [/bib_ref]. Convalescent plasma use may be safe and beneficial [bib_ref] Dexamethasone in hospitalized patients with Covid-19 -preliminary report, Recovery Collaborative Group [/bib_ref] [bib_ref] Treatment of COVID-19 with convalescent plasma: lessons from past coronavirus outbreaks, Wooding [/bib_ref] [bib_ref] Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2, Diorio [/bib_ref] [bib_ref] SARS-CoV-2 convalescent plasma therapy in pediatric patient after hematopoietic stem cell transplantation, Balashov [/bib_ref]. Convalescent plasma may especially be useful in immunosuppressed patients [bib_ref] Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19, Hueso [/bib_ref] , but it may not be easily available and, at best, should be considered in a clinical trial setting. Food and Drug Administration (FDA) has delivered in November 2020 an emergency use authorization for the specific monoclonal antibodies casirivimab and imdevimab against SARS-CoV-2, which may prevent aggravation of COVID-19 in patients who present a high risk of a severe disease [bib_ref] REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19, Weinreich [/bib_ref]. An emergency use authorization has also been delivered for a Janus kinase inhibitor, baricitinib, which may be beneficial for patients requiring non-invasive ventilation in association with remdesivir [bib_ref] Baricitinib plus Remdesivir for hospitalized adults with Covid-19, Kalil [/bib_ref]. Interestingly pediatric data are available for baricitinib in the setting of autoinflammatory diseases [bib_ref] Efficacy and safety of baricitinib combined with topical corticosteroids for treatment of..., Reich [/bib_ref]. The french agency (ANSM) has implemented two temporary cohort use authorizations (ATUc) for the casirivimab / imdevimab combination (Roche) and the bamlanivimab / etesevimab combination (Lilly). It is too soon to claim that the monoclonal antibodies and baricitinib are really effective. Their use should ideally be considered in a clinical trial context, which is nevertheless unlikely to occur in the pediatric setting. What are the recommendations regarding anticoagulation? SARS-CoV-2 infection is associated with hypercoagulability and an increased risk of thrombosis, which participates to disease morbidity and mortality [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref]. In children infected with SARS-CoV-2, hemostasis parameters also suggest a state of hypercoagulability, though the thrombotic risk is not well established in this population [bib_ref] Are children with SARS-CoV-2 infection at high risk for thrombosis? Viscoelastic testing..., Al-Ghafry [/bib_ref]. D-dimers and fibrinogen should be dosed and disseminated intravascular coagulation should be sought in the case of proven infection, and such dosages should be repeated during the course of COVID-19 [bib_ref] COVID-19 anticoagulation recommendations in children, Loi [/bib_ref]. The combination of the prothrombophilic status of the leukemia, the use of asparaginase and the presence of central venous line potentially increase the COVID-19-related thrombotic risk. Therefore, preventive anticoagulation with low molecular weight heparin should be considered. In case of suggestive symptoms, cerebral thrombophlebitis or any other thrombotic complication should be searched for, even in patients treated with preventive anticoagulation. Are there biomarkers to predict COVID-19 complications? There are currently no specific marker to predict COVID-19 complications. However, COVID-19 may be complicated by inflammation dysregulation and macrophage activation syndrome that may require a higher level of care. Thus, one could recommend to monitor ferritin levels, fibrinogen as well as hepatic enzymes and triglyceride levels, especially for patients who may be at a greater risk. Unfavorable outcomes may also be correlated to high SARS-CoV-2 viremia for which monitoring may be beneficial [bib_ref] Challenges in treatment of patients with acute leukemia and COVID-19: a series..., Ghandili [/bib_ref]. Tests may also be repeated until virus clearance, since virus shedding seems to be prolonged in the most immunocompromised patients [bib_ref] Case study: prolonged infectious SARS-CoV-2 shedding from an asymptomatic immunocompromised individual with..., Avanzato [/bib_ref]. Although its prognostic value is less clear in children, lymphopenia is associated with severe SARS-CoV-2 infection in both immunocompetent and immunocompromised adults [bib_ref] Clinical characteristics of Covid-19 in New York City, Goyal [/bib_ref] [bib_ref] Chemotherapy and COVID-19 outcomes in patients with cancer, Jee [/bib_ref] [bib_ref] Factors associated with severe SARS-CoV-2 infection, Ouldali [/bib_ref]. Lymphopenia is common in children treated with chemotherapy, making difficult to clearly associate it with severe COVID-19. However, closely monitoring lymphocyte counts may be interesting in that context. ## Review Who should be vaccinated primarily in the current era? The recent availability of several vaccines brings a great hope among global population, even if evidence of long-term efficacy and safety are lacking [bib_ref] Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an..., Voysey [/bib_ref] [bib_ref] Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine, Polack [/bib_ref] [bib_ref] Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine, Baden [/bib_ref]. The availability of such vaccines will still be limited in the next months and the priority use will be determined by HTAs (Health Technology Assessments) such as the Haute Autorité de Santé in France. Health care providers aged 50 years or more, or with comorbidities, have been the first professionals in France to receive the vaccine. Those working in our hematology-oncology units should be seen as an example for all health care providers and finally parents and families. Indeed when available, we may recommend to perform the vaccination of parents and siblings of patients who are the most at risk of developing COVID-19 complication (e.g. patients with recent HSCT history, relapsed leukemia under intensive treatment and any patient with significant comorbidity). A recent study suggests that patients with solid tumors may have an effective immune response to SARS-CoV-2, making vaccination in these patients a feasible option [bib_ref] Acute immune signatures and their legacies in severe acute respiratory syndrome coronavirus-2..., Baù [/bib_ref]. However, the immune response of patients with hematological cancers seems to be impaired, particularly those with B-cell malignancies, which on the one hand may explain their vulnerability and on the other hand argues in favour of vaccination of their relatives [bib_ref] Acute immune signatures and their legacies in severe acute respiratory syndrome coronavirus-2..., Baù [/bib_ref]. Another issue is the age, since the marketing authorization has been only given according to trial populations age range (lower age limit of 16 and 18 years for the Pfizer and Moderna vaccines respectively). The final issue is that those 2 first vaccines contain polyethylene glycol (PEG), which could be a problem, since children with ALL receive pegylated asparaginase. Vaccination after pegasparagas containg phases or using vaccines without PEG could be reasonable options. # Conclusion Despite extremely rapid advances obtained in less than one year, our knowledge of SARS-Cov2 and its complications is still incomplete. We presented here an updated version of previous recommendations of the Leukemia committee of the SFCE. We can anticipate that this current version will need an update in the next few months. Disclosure of interest: the authors declare that they have no competing interest. ## Références [table] TABLE I: Selected COVID-19 studies in children with leukemia [/table]

Raltegravir how supplied # How Supplied ## ISENTRESS tablets 400 mg ISENTRESS tablets 400 mg are pink, oval-shaped, film-coated tablets with "227" on one side. They are supplied as follows: NDC 0006-0227-61 unit-of-use bottles of 60. No. 3894 ## ISENTRESS tablets 100 mg ISENTRESS tablets 100 mg are pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the Merck logo and "477" on opposite sides of the score. They are supplied as follows: NDC 0006-0477-61 unit-of-use bottles of 60. No. 3972 ## ISENTRESS tablets 25 mg ISENTRESS tablets 25 mg are pale yellow, round, orange-banana flavored, chewable tablets with the Merck logo on one side and "473" on the other side. They are supplied as follows: NDC 0006-0473-61 unit-of-use bottles of 60. No. 3965 ## Storage and Handling 400 mg Film-coated Tablets and Chewable Tablets Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F). See USP Controlled Room Temperature. Chewable Tablets Store in the original package with the bottle tightly closed. Keep the desiccant in the bottle to protect from moisture.

Data dredging Data dredging (data fishing, data snooping) is the inappropriate (sometimes deliberately so) search for 'statistically significant' relationships in large quantities of data. This activity was formerly known in the statistical community as data mining, but that term is now in widespread use with an essentially positive meaning, so the pejorative term data dredging is now used instead. Conventional statistical procedure is to formulate a research hypothesis, (such as 'people in higher social classes live longer') then collect relevant data, then carry out a statistical significance test to see whether the results could be due to the effects of chance. A key point is that every hypothesis must be tested with evidence that was not used in constructing the hypothesis. This is because every data set must contain some chance patterns which are not be present in the population under study, or simply disappear with a sufficiently large sample size. If the hypothesis is not tested on a different data set from the same population, it is likely that the patterns found are chance patterns. As a simplistic example, first throwing five coins, with a result of 2 heads and 3 tails, might lead one to ask why the coin favors tails by fifty percent, whereas first forming the hypothesis might lead one to conclude that only a 5-0 or 0-5 result would be very surprising, since the odds are 93.75% against this happening by chance. In the latter case, it becomes obvious that the data is not anomalous. It is important to realise that the alleged statistical significance here is completely spurious - significance tests do not protect against data dredging. When testing a data set on which the hypothesis is known to be true, the data set is by definition not a representative data set, and any resulting significance levels are meaningless. # Examples In meteorology, dataset A is often weather data up to the present, which ensures that, even subconsciously, subset B of the data could not influence the formulation of the hypothesis. Of course, such a discipline necessitates waiting for new data to come in, to show the formulated theory's predictive power versus the null hypothesis. This ensures no one can accuse the researcher of hand-tailoring the predictive model to the data on hand, since the upcoming weather is not yet available. Consider an analysis of sales in the period following an advertising campaign. Suppose that aggregate sales were unchanged, but that analysis of a sample of households found that sales did go up more for Spanish-speaking households, or for households with incomes between $35,000 and $50,000, or for households that had refinanced in the past two years, or whatever, comparing the treatment and control groups, and that such increase(s) was/were 'statistically significant'. There would certainly be a temptation to report such findings as 'proof' that the campaign was successful, or would be successful if targeted to such group(s) in other markets. # Remedies One way to construct hypotheses while avoiding the problems of data dredging is randomization. The researcher collects a data set, then randomly partitions it into two subsets, A and B. Only one subset - say, subset A - is examined for creating hypotheses. Once a hypothesis has been formulated, it must be tested on subset B, which was not used to construct the hypothesis. Only where such a hypothesis is also supported by B is it reasonable to believe that the hypothesis might be valid. Another remedy for data dredging is to record the number of all significance tests conducted during the experiment and simply multiply the final significance level by this number (the Bonferroni correction). This solution does not prevent from collective data mining, because the probability that a certain null hypothesis is being tested is influenced by the number of previous successful rejections of this hypothesis, which in itself reduces the probability of rejecting the null.

Divalproex sodium contraindications # Contraindications Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction . Depakote is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder. Depakote is contraindicated in patients with known hypersensitivity to the drug . Depakote is contraindicated in patients with known urea cycle disorders . Depakote is contraindicated for use in prophylaxis of migraine headaches in pregnant women .

Spinal cord injury # Overview Spinal cord injury causes myelopathy or damage to white matter or myelinated fiber tracts that carry sensation and motor signals to and from the brain. It also damages gray matter in the central part of the spinal, causing segmental losses of interneurons and motorneurons. Spinal cord injury can occur from many causes, including: - Trauma such as automobile accidents, falls, gunshots, diving accidents, war injuries, etc. - Tumor such as meningiomas, ependymomas, astrocytomas, and metastatic cancer. - Ischemia resulting from occlusion of spinal blood vessels, including dissecting aortic aneurisms, emboli, arteriosclerosis. - Developmental disorders, such as spina bifida, meningomyolcoele, and other. - Neurodegenerative diseases, such as Friedreich's ataxia, spinocerebellar ataxia, etc. - Demyelinative diseases, such as Multiple Sclerosis. - Transverse myelitis, resulting from spinal cord stroke, inflammation, or other causes. - Vascular malformations, such as arteriovenous malformation (AVM), dural arteriovenous fistula (AVF), spinal hemangioma, cavernous angioma and aneurysm. # Classification The American Spinal Cord Injury Association or ASIA defined an international classification based on neurological levels, touch and pinprick sensations tested in each dermatome, and strength of ten key muscles on each side of the body, i.e. shoulder shrug (C4), elbow flexion (C5), wrist extension (C6), elbow extension (C7), hip flexion (L2), knee extension (L3), ankle dorsiflexion (L4), long toe extension (L5), and ankle plantar flexion (S1). Each muscle is graded on a scale of 0-5 where 0 is paralyzed, 1 is slight movement, 2 is definite movement, 3 is movement against gravity, 4 is movement against manual resistance, and 5 is normal. The scores of the muscles add up to 100. The pinprick and touch sensations are grade separately for each dermatome on a scale of 0-2 where 0 is absent sensation, 1 is abnormal sensation, and 2 is normal. These add up to 112 points each for pinprick and touch. Traumatic spinal cord injury is classified into five types by the American Spinal Injury Association (ASIA) and the International Spinal Cord Injury Classification System. - A indicates a "complete" spinal cord injury where no motor or sensory function is preserved in the sacral segments S4-S5. A complete injury is one in which there is some neurological level below which there is no motor or sensory function. Since the S4-S5 segment is the lower segmental, absence of motor and sensory function indicates "complete" spinal cord injury. - B indicates an "incomplete" spinal cord injury where sensory but not motor function is preserved below the neurological level and includes the sacral segments S4-S5. This is typically a transient phase and if the person recovers any motor function below the neurological level, that person essentially becomes a motor incomplete, i.e. ASIA C or D. - C indicates an "incomplete" spinal cord injury where motor function is preserved below the neurological level and more than half of key muscles below the neurological level have a muscle grade of less than 3. - D indicates an "incomplete" spinal cord injury where motor function is preserved below the neurological level and at least half of the key muscles below the neurological level have a muscle grade of 3 or more. - E indicates "normal" where motor and sensory scores are normal. Note that it is possible to have spinal cord injury and neurological deficit with completely normal motor and sensory scores. In addition, there are several clinical syndromes associated with incomplete spinal cord injuries. - The Central Cord syndrome is associated with greater loss of upper limb function compared to lower limbs. - The Brown-Séquard syndrome results from injury to one side with the spinal cord, causing weakness and loss of proprioception on the side of the injury and loss of pain and thermal sensation of the other side. - The Anterior Spinal syndrome results from injury to the anterior part of the spinal cord, causing weakness and loss of pain and thermal sensations below the injury site but preservation of proprioception that is usually carried in the posterior part of the spinal cord. - Tabes Dorsalis results from injury to the posterior part of the spinal cord, usually from infection diseases such as syphilis, causing loss of touch and proprioceptive sensation. - Conus Medullaris syndrome results from injury to the tip of the spinal cord, located at L1 vertebra. - Cauda Equina syndrome is, strictly speaking, not really spinal cord injury but injury to the spinal roots below the L1 vertebra. One can have spine injury without spinal cord injury. Many people suffer transient loss of function ("stingers") in sports accidents or pain in "whiplash" of the neck without neurological loss and relatively few of these suffer spinal cord injury sufficient to warrant hospitalization. In the United States, the incidence of spinal cord injury has been estimated to be about 35 cases per million per year, or approximately 10,500 per year (35 - 300). In China, the incidence of spinal cord injury was recently estimated to be as high as 65 cases per million per year in urban areas. If so, assuming a population of 1.3 billion, this would suggest an incidence of 84,500 per year (65 - 1300). The prevalence of spinal cord injury is not well known in many large countries. In some countries, such as Sweden and Iceland, registries are available. About 450,000 people in the United States live with spinal cord injury (one in 670), and there are about 11,000 new spinal cord injuries every year (one in 30,000). The majority of them (78%) involve males between the ages of 16-30 and result from motor vehicle accidents (42%), violence (24%), or falls (27%). # The Effects of Spinal Cord Injury The exact effects of a spinal cord injury vary according to the type and level injury, and can be organized into two types: - In a complete injury, there is no function below the "neurological" level, defined as the lowest level that has intact neurological function. If a person has some level below which there is no motor and sensory function, the injury is said to be "complete". Recent evidence suggest that less than 5% of people with "complete" spinal cord injury recover locomotion. - A person with an incomplete injury retains some sensation or movement below the level of the injury. The lowest spinal cord level is S4-5, representing the anal sphincter and peri-anal sensation. So, if a person is able to contract the anal sphincter voluntarily or is able to feel peri-anal pinprick or touch, the injury is said to be "incomplete". Recent evidence suggest that over 95% of people with "incomplete" spinal cord injury recover some locomotory ability. In addition to a loss of sensation and motor function below the point of injury, individuals with spinal cord injuries will often experience other complications of spinal cord injury: - Bowel and bladder function is regulated by the sacral region of the spine, so it is very common to experience dysfunction of the bowel and bladder, including infections of the bladder, and anal incontinence. - Sexual function is also associated with the sacral region, and is often affected. - Injuries of the C-1, C-2 will often result in a loss of breathing, necessitating mechanical ventilators or phrenic nerve pacing. - Inability or reduced ability to regulate heart rate, blood pressure), sweating and hence body temperature. - Spasticity (increased reflexes and stiffness of the limbs). - Neuropathic pain. - Autonomic dysreflexia or abnormal increases in blood pressure, sweating, and other autonomic responses to pain or sensory disturbances. - Atrophy of muscle. - Osteoporosis (loss of calcium) and bone degeneration. - Gallbladder and renal stones. ## The Location of the Injury Knowing the exact level of the injury on the spinal cord is important when predicting what parts of the body might be affected by paralysis and loss of function. Below is a list of typical effects of spinal cord injury by location (refer to the spinal cord map to the right). Please keep in mind that while the prognosis of complete injuries are predictable, incomplete injuries are very variable and may differ from the descriptions below. ### Cervical injuries Cervical (neck) injuries usually result in full or partial tetraplegia. Depending on the exact location of the injury, one with a spinal cord injury at the cervical level may retain some amount of function as detailed below, but are otherwise completely paralyzed. - C3 vertebrae and above : Typically lose diaphragm function and require a ventilator to breathe. - C4 : May have some use of biceps and shoulders, but weaker - C5 : May retain the use of shoulders and biceps, but not of the wrists or hands. - C6 : Generally retain some wrist control, but no hand function. - C7 and T1 : Can usually straighten their arms but still may have dexterity problems with the hand and fingers. C7 is generally the level for functional independence. ### Thoracic injuries Injuries at the thoracic level and below result in paraplegia. The hands, arms, head, and breathing are usually not affected. - T1 to T8 : Most often have control of the hands, but lack control of the abdominal muscles so control of the trunk is difficult or impossible. Effects are less severe the lower the injury. - T9 to T12 : Allows good trunk and abdominal muscle control, and sitting balance is very good. ### Lumbar and Sacral injuries The effect of injuries to the lumbar or sacral region of the spinal canal are decreased control of the legs and hips, urinary system, and anus. ### Central Cord and Other Syndromes Central cord syndrome (picture 1) is a form of incomplete spinal cord injury characterized by impairment in the arms and hands and, to a lesser extent, in the legs. This is also referred to as inverse paraplegia, because the hands and arms are paralyzed while the legs and lower extremities work correctly. Most often the damage is to the cervical or upper thoracic regions of the spinal cord, and characterized by weakness in the arms with relative sparing of the legs with variable sensory loss. This condition is associated with ischemia, hemorrhage, or necrosis involving the central portions of the spinal cord (the large nerve fibers that carry information directly from the cerebral cortex). Corticospinal fibers destined for the legs are spared due to their more external location in the spinal cord. This clinical pattern may emerge during recovery from spinal shock due to prolonged swelling around or near the vertebrae, causing pressures on the cord. The symptoms may be transient or permanent. Anterior cord syndrome (picture 2) is also an incomplete spinal cord injury. Below the injury, motor function, pain sensation, and temperature sensation is lost; touch, proprioception (sense of position in space), and vibration sense remain intact. Posterior cord syndrome (not pictured) can also occur, but is very rare. Brown-Séquard syndrome (picture 3) usually occurs when the spinal cord is hemisectioned or injured on the lateral side. On the ipsilateral side of the injury (same side), there is a loss of motor function, proprioception, vibration, and light touch. Contralaterally (opposite side of injury), there is a loss of pain, temperature, and deep touch sensations. # Treatment Treatment for acute traumatic spinal cord injuries have consisted of giving high dose methylprednisolone if the injury occurred within 8 hours. The recommendation is primarily based on the National Acute Spinal Cord Injury Studies (NASCIS) II and III. Some of the claims of the studies have been challenged as being from faulty interpretation of the data. Breakthrough medical research shows stem cell transplants could have the potential to help or cure paralysis caused by spinal injury. Stem cells are primal cells found in all multi-cellular organisms. They can be made to differentiate into a range of specialized cells including nerve cells, which can be transplanted into the body. Special Tests to Determine Spine Pathology Sign Pathology Long Tract Signs Babinski: first toe dorsiflexion with fanning out of other toes when sharp instrument is rubbed on lateral border of foot from calcaneus to head of first metatarsal Upper motor neuron lesion; corticospinal tract. Hoffman: flick distal phalanx away from palm; look for pincer effect between thumb and index finger; look for asymmetry. Cord compression; CNS dysfunction; brisk muscle stretch reflex Tramner reflex: Elevate middle finger above other fingers and flick distal phalanx toward palm; look for pincer effect between thumb and index finger; look for asymmetry. Cord compression; CNS dysfunction; brisk muscle stretch reflex Inverted radial reflex: finger flexion upon testing brachioradialis reflex Cervical myelopathy Finger escape: abduction of fifth finger because of weak hand intrinsics Cervical myelopathy Lhermitte: neck flexion causing lightning-like sensation radiating down back Cervical stenosis; disk herniation; multiple sclerosis with posterior column dysfunction (original description) Cross adductor: stimulate patellar reflex and note contralateral thigh adductor contraction UMN lesion Chaddock: laterally abduct the little toe briskly and let it slap back against the other toes or flick the third or fourth toe down rapidly; note dorsiflexion of the great toe. UMN lesion Jaw jerk reflex: gently tap on patient's jaw with patient's mouth slightly open; a positive reflex is when the jaw closes In a patient with UMN signs, a positive jaw jerk test suggests that the etiology is not in the cervical spine but that the pathology is located above the level of the pons Nerve Root Compression Spurling: extend and bend the neck laterally and apply axial load to the top of the head; patient will report radicular pain. Cervical nerve root compression Straight-leg raise (SLR): with patient supine or sitting perform, SLR and patient will report pain in the distribution of the nerve root irritated; for sciatic involvement, the pain must extend distal to the knee Nerve root compression Contralateral SLR (Frajerstajn): raising asymptomatic side causes pain down symptomatic side Indicates either a central disk herniation or an axillary herniation on the symptomatic side Lasegue: perform SLR and then dorsiflex the ankle; should exacerbate SLR radiculopathy; less than 70 degrees of hip flexion is a positive Lasegue sign Nerve root compression Bowstring: with patient supine, raise leg, flex knee, then apply pressure to popliteal fossa to elicit radicular pain Nerve root compression Cram test: similar to Lasègue sign; extend hip then straighten leg to elicit pain Nerve root compression Milgram: patient raises both legs off examining table and holds for 30 seconds; note radiculopathy Nerve root compression Naffziger: compress neck veins for 10 seconds with patient supine; coughing produces radiculopathy Nerve root compression Hoover: examiner places hands under patient's heel while the supine patient tries to perform SLR with the contralateral leg If the patient is malingering or not trying, then there will be a lack of downward pressure on the hand under the heel (opposite foot not performing the SLR) Femoral stretch: with patient prone or lying on side, the hip is held in extension and the knee is flexed Femoral neuritis or L3 or L4 radiculopathy Other Signs Wartenberg: unopposed abduction of the little finger Ulnar nerve paresis Beevor: have patient perform a quarter abdominal sit-up with arms crossed behind head; note any up, down, or sideways movement of the umbilicus Lower abdominal muscles (controlled by spinal cord below T9) are weaker than upper abdominal muscles Cremasteric reflex (males): stroke the inner thigh (genitofemoral nerve) and note ascent of the ipsilateral testicle Bulbocavernosus reflex: compress glans penis or pull on a Foley catheter; note contraction of the anal sphincter When present, signals end of spinal cord shock after cord injury Anal wink: apply sharp stimulus and note contraction of the external anal sphincter When present, signals end of spinal cord shock after cord injury Patrick (FABER) test: the hip is placed in a flexed, abducted, and externally rotated position, and ipsilateral foot is placed on opposite knee; pressure is put on ipsilateral knee and opposite ASIS Sacroiliac pain Localizing dermatomes C6: thumb C7: middle finger C8: small finger T4: nipple T10: umbilicus L1: inguinal ligament Waddell Signs for Nonorganic Pathology Signs Outcome Observations: Pain out of proportion to stimulus (example, light touch) Pain in a nonanatomic distribution Poor outcome after operative or nonoperative treatment if 3 or more positive signs Exaggerated pain response Four tests (none should be positive): 1. Skin roll test: roll skin between index and thumb and note radicular symptoms 2. Head compression: apply 5 pounds of load and note 3. Twist test: patient standing with feet planted, examiner rotates torso left and right and notes pain 4. Flip test: Perform sitting and supine SLR and note any difference in pain Introduction: Fractures and dislocations of the spine are serious injuries that most commonly occur in young people. The most common causes of severe spinal trauma are motor vehicle accidents, falls, diving accidents, and gunshot wounds. Spinal injury should be suspected in any patient with a head injury or severe facial or scalp lacerations. In any patient with recent trauma, complaints of neck pain or spinal pain should be considered indicative of a spinal injury until proved otherwise. Risk factors for spinal injury: 1.inability to assess neck pain because of a secondary distracting injury, 2.abnormal neurological findings, 3. a history of transient neurological symptoms, 4physical signs of spinal trauma (e.g., ecchymosis and abrasions), 5.unreliable examination, significant head or face trauma, or 6.an inconsolable child . Manifestations of Spinal Shock:After a spinal cord injury, spinal shock occurs. It is manifested by 1) flaccid paralysis, 2)hypotonia, 3)areflexia, and 4)an absent bulbo-cavernosus reflex (BCR). At this time, the neurologic level cannot be determined. The BCR typically returns during the first 24 to 48 hours after the injury and can be tested by squeezing the glands penis, pubis, or pulling on a Foley and eliciting contraction of the anal sphincter. Goals of Spine Trauma Care 1. Protect against further injury during evaluation and management 2. Quickly identify spine injury or document absence of spine injury 3. Optimize conditions for maximal neurological recovery 4. Maintain or restore spinal alignment 5. Minimize loss of spinal mobility 6. Obtain a healed and stable spinal column 7. Facilitate rehabilitation Complete Spinal Cord Injury (SCI): Indicates no function below a given levels after spinal shock is over, where an incomplete injury has some distal neurologic function present especially sacral sparing. Acute Management for SCI: Initial management : 1)spine immobilization 2) full traumawork-up, and 3) methylprednisolone within the first 8 hours after injury. Steroid Protocol for SCI:The steroid protocol for giving methylprednisolone after SCI is given. Most benefit occurs in the first 8 hours, and additional effect occurs within the first 24 hours it is as follows: - 0 to 3 hours: 30 mg/kg loading dose, then 5.4 mg/kg for 23 hours - 3 to 8 hours: 30 mg/kg loading dose, then 5.4 mg/kg for 48 hours - 8 hours: no methylprednisolone Definitions of Terms Describing Spinal Cord Injury Impairment Loss of motor and sensory function Disability Loss in daily life functioning Tetraplegia Loss of motor and or sensory function in the cervical segments Paraplegia Loss of motor and or sensory function in the thoracic, lumbar, or sacral segments Dermatome Area of skin innervated by sensory axons within each segmental nerve Myotome Collection of muscle fibers by the motor axons within each segmental nerve Neurologic level The most caudal segment with normal sensory and motor function on both sides Sensory level The most caudal segment with normal sensory function on both sides Motor level The most caudal segment with normal motor function on both sides Skeletal level Radiographic level of greatest vertebral damage Sensory score Numeric summary value of sensory impairment Motor score Numeric summary value of motor impairment Incomplete injury Partial preservation of sensory and/or motor function below the neurologic level and sensory and/or motor preservation of the lowest sacral segment Complete injury Absence of sensory and motor function in the lowest sacral segment Dermatomes and myotomes caudal to the neurologic level that remain partially innervated Diagnostic imaging: 1.Plain radiography : anteroposterior and lateral views. 2.Computed Tomography. 3.Magnetic Resonance Imaging. Most common sites for spine injuries are: 1. cranio-cervical, 2. cervico-thoracic, and 3. thoraco-lumbar. Initial evaluation of trama patient: Following 3 images provide crucial information that facilitates resuscitation. 1. lateral cervical spine x-ray 2. Obtaining an AP chest x-ray, an 3. AP pelvis x-ray They are often the most difficult to see on standard x-rays. Among these injuries, the most serious and most frequently missed is the cranio-cervical dissociation. A systematic approach to reading cervical x-rays can help reduce the chances of missing an important injury. What to look for in lateral xray? 1.Alignment of the cervical vertebrae is assessed by examining longitudinal lines along vertebral bodies, lamina, and spinous processes. 2.Examining alignment of the lamina in the upper cervical vertebrae is particularly helpful in excluding injuries of the cranio-cervical junction in both children and adults. 3.The prevertebral soft tissues can be useful as an indicator of swelling from acute hemorrhage. 4.Increased thickness and altered contour of the pharyngeal tissue anterior to C2 (i.e., convexity instead of concavity caudal to the C1 anterior arch) suggest acute cranio-cervical injury. Computed Tomography: CT and MRI may be useful together in determining the presence and extent of spinal column injury . MRI is superior in demonstrating spinal cord pathology and intervertebral disc herniation. CT is superior to MRI in demonstrating bony injury. Magnetic Resonance Imaging: MRI is useful for imaging soft tissues and bone. MRI shows edema and hemorrhage associated with acute spinal cord injury. Increased cord signal and parenchymal cord hemorrhage indicate poor prognosis for neurologic recovery . MRI is useful for assessing the cranio-cervical junction. MRI provides noninvasive assessment of the vertebral artery blood flow in cervical trauma, which can be frequently disrupted in cervical spine injuries. Descriptions of Incomplete Cord Injury Patterns Syndrome Lesion Clinical Presentation Bell's cruciate paralysis Long tract injury at the level of decussation in brainstem Variable cranial nerve involvement, greater upper extremity weakness than lower, greater proximal weakness than distal Anterior cord Anterior gray matter, descending corticospinal motor tract, and spinothalamic tract injury with preservation of dorsal columns Variable motor and pain and temperature sensory loss with preservation of proprioception and deep pressure sensation Central cord Incomplete cervical white matter injury Sacral sparing and greater weakness in the upper limbs than the lower limbs Brown-Sequard Injury to one lateral half of cord and preservation of contralateral half Ipsilateral motor and proprioception loss and contralateral pain and temperature sensory loss Conus medullaris Injury to the sacral cord (conus) and lumbar nerve roots within the spinal canal Areflexic bladder, bowel, and lower limbs May have preserved bulbocavernosus and micturition reflexes Cauda equina Injury to the lumbosacral nerve roots within the spinal canal Areflexic bladder, bowel, and lower limbs Root injury Avulsion or compression injury to single or multiple nerve roots (brachial plexus avulsion) Dermatomal sensory loss, myotomal motor loss, and absent deep tendon reflexes Neurogenic and Hypovolemic Shock Neurogenic Shock* Hypovolemic Shock As the result of loss of sympathetic outflow As the result of hemorrhage Hypotension Hypotension Bradycardia Tachycardia Warm extremities Cold extremities Normal urine output Low urine output ASIA Impairment Scale A Complete No motor or sensory function in the lowest sacral segment (S4-S5) B Incomplete Sensory function below neurologic level and in S4-S5, no motor function below neurologic level C Incomplete Motor function is preserved below neurologic level and more than half of the key muscle groups below neurologic level have a muscle grade <3 D Incomplete Motor function is preserved below neurologic level and at least half of the key muscle groups below neurologic level have a muscle grade = 3 E Normal Sensory and motor function is normal (ASIA, American Spinal Injury Association.)

miR-296 miR-296 is a family of microRNA precursors found in mammals, including humans. The ~22 nucleotide mature miRNA sequence is excised from the precursor hairpin by the enzyme Dicer. This sequence then associates with RISC which effects RNA interference. miR-296 has been named an "angiomiR" due to being characterised as a microRNA which regulates angiogenesis, the process of growth and creation of new blood vessels. miR-296 is thought to have a specific role in cancer in promoting tumour angiogenesis. It achieves this by targeting HGS mRNA, reducing its expression in endothelial cells which then results in greater number of VEGF receptors. miR-296 has predicted target sites in the transcription factor NANOG and may also contribute to carcinogenesis by dysregulating p53.

Drospirnone # Overview Drospirenone (INN, USAN), also known as 1,2-dihydrospirorenone, is synthetic, steroidal progestin with additional antimineralocorticoid and weak antiandrogen properties which is used as a hormonal contraceptive. It is sold under the brand names Yasmin, Yasminelle, Yaz, Beyaz, Ocella, Zarah, and Angeliq, all of which are combination products of drospirenone with an estrogen such as ethinylestradiol. # Medical uses Drospirenone is part of some birth control pills and hormone replacement therapy. In combination with ethinyl estradiol it is used as contraception, to treat moderate acne, and for premenstrual dysphoric disorder. In combination with estradiol it is used to treat menopausal symptoms and premenstrual dysphoric disorder. # Adverse effects Women who take contraceptive pills containing drospirenone have a six- to sevenfold risk of developing thromboembolism compared to women who do not take any contraceptive pill, and twice the risk of women who take a contraceptive pill containing levonorgestrel. Drospirenone can potentially cause hyperkalemia in high-risk patients, and is comparable to a 25 mg dose of spironolactone. The medication is contraindicated in people with hepatic dysfunction, renal insufficiency, adrenal insufficiency, or in whom the use of oral contraceptives is contraindicated, such as smokers and patients with a history of DVT, stroke, or other blood clots. Because of the anti-mineralocorticoid effects care needs to be exercised when other drugs that may increase potassium levels are taken. Such medications include ACE inhibitors, angiotensin-II receptor agonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs. Although there have been concerns raised regarding the safety of drospirenone containing oral contraceptives, the data is conflicting and it is unclear whether the increased risk of venous thrombembolic events seen in recent studies represents a true increase in this risk or whether flaws in the design of these studies are resulting in a false safety signal. Further study in this regard appears to be warranted. However, the FDA recently updated the label for contraceptives containing drospirenone to include warnings for stopping use prior to and after surgery; moreover, the FDA acknowledges that contraceptives with drospirenone may be associated with a higher risk of venous thromboembolism. # Pharmacology ## Pharmacodynamics Drospirenone differs from other synthetic progestins in that its pharmacological profile in preclinical studies shows it to be closer to the natural progesterone. As such it has potent antimineralocorticoid properties, counteracts the estrogen-stimulated activity of the renin-angiotensin-aldosterone system, and has also been shown to possess mild antiandrogen activity. The antimineralocorticoid properties exhibited by drospirenone promote sodium excretion and prevent water retention. ## Pharmacokinetics Drospirenone is taken orally with about 76% bioavailability. It is bound not by sex hormone-binding globulin or corticosteroid binding globulin, but by other serum proteins. Metabolites have not been shown to be biologically active, show up in urine and feces, and are essentially completely excreted within 10 days. # Chemistry It is an analog to spironolactone, with a molecular weight of 366.5 and the molecular formula C24H30O3. # Formulations The compound is part of certain newer oral contraceptive formulations: - Yasmin contains 3 mg drospirenone and 30 mcg ethinylestradiol per tablet. It is indicated for the prevention of pregnancy in women who elect an oral contraceptive. - Yasminelle contains 3 mg drospirenone and 20 mcg ethinylestradiol per tablet and is used for contraception. - Yaz and Beyaz contain 3 mg drospirenone and 20 mcg ethinylestradiol per tablet and is given for 24/4 days with the same indications. - Ocella contains 3 mg drospirenone and 30 mcg ethinylestradiol per tablet and is taken daily. It has also been formulated in medication to manage menopausal symptoms using 0.5 mg drsp and 1 mg estradiol per day by oral application. This medication was introduced in the United States in 2007 as Angeliq. # Litigation In 2008, a series of television commercials prompted the FDA to cite Bayer for overstating the approved uses of Yaz while failing to adequately address the risks of the drug. Bayer was required to dispel the inaccurate information contained in those ads by creating new ads that clarified the drug's approved uses. On October 8, 2009, Bayer disclosed that 129 lawsuits had been brought against them over the side effects and marketing of Yaz and Yasmin. The allegations include (but are not limited to): - Glossing over risks associated with the products and overstating their approved uses in an effort to mislead users of Yaz and Yasmin into believing that the drugs were safe. - Failure to properly research the medication. - Failing to recall the drug after post-marketing reports demonstrated that the risk of potentially life-threatening side effects of Yasmin and Yaz outweighed potential benefits that could be achieved via other available oral contraceptives. In September 2009, the FDA cited Bayer for sending out potentially low-quality batches of drosperinone. Bayer justified the shipments by explaining that they monitor the "average" quality of all shipments, not the quality of each individual batch. In October 2011 the CBC TV program Marketplace ran a segment discussing issues involved with the usage of Yaz/Yasmin

Triamcinolone Nasal Inhalation (patient information) # Why is this medication prescribed Triamcinolone, a corticosteroid, is used to prevent allergy symptoms including sneezing, itching, and runny or stuffed nose. This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. # How should this medicine be used Triamcinolone comes as a solution to inhale through the nose. It usually is inhaled one to four times a day at evenly spaced intervals. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Use triamcinolone exactly as directed. Do not use more or less of it or use it more often than prescribed by your doctor. Triamcinolone controls allergy symptoms but does not cure them. Continue to use triamcinolone even if you feel well. Do not stop using triamcinolone without talking to your doctor. Before you use triamcinolone the first time, read the written instructions that come with it. Ask your doctor, pharmacist, or respiratory therapist to demonstrate the proper technique. Practice using the inhaler while in his or her presence Before using triamcinolone, gently blow your nose to clear your nasal passages. Avoid blowing your nose for 15 minutes after inhaling the prescribed dose. # What special precautions should I follow Before using triamcinolone - tell your doctor and pharmacist if you are allergic to triamcinolone or any other drugs. - tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially anticoagulants ('blood thinners') such as warfarin (Coumadin), arthritis medication, aspirin, cyclosporine (Neoral, Sandimmune), digoxin (Lanoxin), diuretics ('water pills'), estrogen (Premarin), ketoconazole (Nizoral), oral contraceptives, phenobarbital, phenytoin (Dilantin), rifampin (Rifadin), theophylline (Theo-Dur), and vitamins. - if you have a nose infection or a fungal infection (other than on your skin), do not use triamcinolone without talking to your doctor. - tell your doctor if you have or have ever had tuberculosis (TB); liver, kidney, intestinal, or heart disease; diabetes; an underactive thyroid gland; high blood pressure; mental illness; myasthenia gravis; osteoporosis; herpes eye infection; seizures; or ulcers. - tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while using triamcinolone, call your doctor. # What should I do if I forget a dose Use the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not use a double dose to make up for a missed one. # Side Effects ## Minor Side Effects Triamcinolone may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away: - headache - nasal irritation or dryness - sore throat - sneezing - nosebleed ## Severe Side Effects If you experience any of the following symptoms, call your doctor immediately: - increased difficulty breathing - swollen face, lower legs, or ankles - vision problems - cold or infection that lasts a long time - muscle weakness If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online or by phone . # What storage conditions are needed for this medicine Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication. Avoid puncturing the aerosol container, and do not discard it in an incinerator or fire. # What other information should I know Keep all appointments with your doctor. Your symptoms may improve after just a few days. If they do not improve within 3 weeks, call your doctor. Avoid exposure to chicken pox and measles. This drug makes you more susceptible to these illnesses. If you are exposed to them while using triamcinolone, call your doctor. Do not have a vaccination or other immunization unless your doctor tells you that you may. Report any injuries or signs of infection (fever, sore throat, pain during urination, and muscle aches) that occur during treatment. If your sputum (the matter that you cough up during an asthma attack) thickens or changes color from clear white to yellow, green, or gray, call your doctor; these changes may be signs of an infection. Inhalation devices require regular cleaning, and some require periodic replacement. Follow the directions that come with your inhaler. Do not let anyone else use your medication. Ask your pharmacist any questions you have about refilling your prescription. # Brand names - Nasacort® AQ Nasal Spray - Nasacort® Nasal Inhaler - Tri-Nasal® Spray

Reticular fiber # Overview Reticular fibers or reticulin is a histological term used to describe a type of structural fiber composed of type III collagen. Reticular fibers crosslink to form a fine meshwork (reticulum). This network acts as a supporting mesh in soft tissues such as liver, bone marrow, and the tissues and organs of the lymphatic system. # History The term reticulin was coined in 1892 by M. Siegfried. Today the term reticulin or reticular fiber is restricted to fibers composed of type III collagen. However, during the pre-molecular era, there was confusion in the use of the term 'reticulin', which was used to describe two structures: - the argyrophilic (silver staining) fibrous structures present in basement membranes - histologically similar fibers present in developing connective tissue. The history of the reticulin silver stain is reviewed by Puchtler et al. (1978). The abstract of this paper says: Maresch (1905) introduced Bielschowsky's silver impregnation technic for neurofibrils as a stain for reticulum fibers, but emphasized the nonspecificity of such procedures. This lack of specificity has been confirmed repeatedly. Yet, since the 1920's the definition of "reticulin" and studies of its distribution were based solely on silver impregnation technics. The chemical mechanism and specificity of this group of stains is obscure. Application of Gomori's and Wilder's methods to human tissues showed variations of staining patterns with the fixatives and technics employed. Besides reticulum fibers, various other tissue structures, e.g. I bands of striated muscle, fibers in nervous tissues, and model substances, e.g. polysaccharides, egg white, gliadin, were also stained. Deposition of silver compounds on reticulum fibers was limited to an easily removable substance; the remaining collagen component did not bind silver. These histochemical studies indicate that silver impregnation technics for reticulum fibers have no chemical significance and cannot be considered as histochemical technics for "reticulin" or type III collagen. # Structure Reticular fiber one or more types of very thin and delicately woven strands of type III collagen, these strands build a highly ordered cellular network and provide a supporting network. Many of these types of collagen have been combined with carbohydrate. Thus, they react with silver stains and with periodic acid-Schiff reagent but are not demonstrated with ordinary histological stains such as those using hematoxylin. The 1953 science article mentioned above concluded that the reticular and regular collagenous materials contained the same four sugars - galactose, glucose, mannose and fucose - but in a much greater concentration in the reticular than the collagenous material. In a 1993 paper the reticular fibers of the capillary sheath and splenic cord were studied and compared in the pig spleen by transmission electron microscopy. This paper attempted to reveal their components and the presence of sialic acid in the amorphous ground substance. Collagen fibrils, elastic fibers, microfibrils, nerve fibers and smooth muscle cells were observed in the reticular fibers of the splenic cord. On the other hand, only microfibrils were recognized in the reticular fibers of the capillary sheath. The binding of LFA lectin to the splenic cord was stronger than the capillary sheath. These findings suggested that the reticular fibers of the splenic cord included multiple functional elements and might perform an important role during contraction or dilation of the spleen. On the other hand, the reticular fiber of the capillary sheath resembled the basement membrane of the capillary in its components.

Ergogenic aid Ergogenic aids are any external influences which can positively affect physical or mental performance. These include mechanical aids, pharmacological aids, physiological aids, nutritional aids, and psychological aids. Ergogenic aids may directly influence the physiological capacity of a particular body system thereby improving performance, remove psychological constraints which impact performance, and increase the speed of recovery from training and competition. These can be as simple as water used before and after exercising to aid in hydration, to something as advanced as anabolic steroids.

CRABP2 Cellular retinoic acid-binding protein 2 is a cytoplasmic binding protein that in humans is encoded by the CRABP2 gene. CRABP2 is structurally similar to CRABP1, but CRABP2 has a lower affinity for retinoic acid (RA). CRABP2 is associated with cells that produce large amounts of retinoic acid and may play a role in mediating the effects of retinoic acid in the cell. # Function A number of specific carrier proteins for members of the vitamin A family have been discovered. Retinoic acid is an active metabolite of vitamin A (retinol). Cellular retinoic acid binding proteins (CRABP) are low molecular weight proteins whose precise function remains largely unknown. The inducibility of the CRABP2 gene suggests that this isoform is important in retinoic acid-mediated regulation of human skin growth, differentiation and development. CRABP2 is involved in the metabolism and transportation of retinoic acid from the cytosol to the RARs (retinoic acid receptors) located in the nucleus. CRABP2 is specifically co-expressed with RAR-β and cellular retinol binding protein 1 genes in certain tissues. It has been postulated that the CRABP2 gene is transcriptionally regulated by a newly synthesized regulatory protein. # Tissue distribution Tissue distribution of the CRABP2 gene has primarily been studied using mouse models. During embryonic development, CRABP2 is present in tissues throughout the body in a more diffuse pattern than CRABP1. CRABP1 is more isolated to specific regions, though it does appear in higher concentrations. CRABP1 and 2 often overlap in tissues. CRABP2 gene expression is abundant in the trunk and hindbrain (and to a lesser extent the forebrain), but are present in other areas of the body. Structures such as the limbs, hindbrain and cranial neural crest cells have been shown to be excessively sensitive to high levels of retinoic acid. Rhombomere segmentation in the hindbrain and the development of cranial ganglia V, VII, VIII, IX, and X also appear to be partially dependent on CRABP2 expression. CRABP2 is abundant in the dorsal part of the limb during development. CRABP2 genes are also expressed in structures that are less sensitive to retinoid levels throughout the body during embryonic development. These structures include the pharyngeal pouches, foregut, midgut, mandibular and frontal mesenchyme, developing muscle, interdigital mesenchyme, the urogenital system, optic vessels, and inner ear sensory epithelium. # Defects Vitamin A deficiency in mice has been shown to cause problems with spermatogenesis, irregular estrous cycles, changes in the uterine epithelium and reproductive failure ending with fetal death and reabsorption. Tissues with CRABP2 can be sensitive to high levels of retinoic acid which may cause defects in the development of those tissues. CRABP2 gene knockout studies should be performed to determine any specific defects caused by loss of this gene. # Interactions CRABP2 has been shown to interact with Cyclin D3.

Settled insanity Settled insanity is defined as a permanent or "settled" condition caused by long-term substance abuse and differs from the temporary state of intoxication. In some United States jurisdictions "settled insanity" can be used as a basis for an insanity defense, even though voluntary intoxication cannot, if the "settled insanity" negates one of the required elements of the crime such as malice aforethought. However, U.S. federal and state courts have differed in their interpretations of when the use of "settled insanity" is acceptable as an insanity defense and also over what is included in the concept of "settled insanity". # History Early English common law recognized "settled insanity" as a complete defense for a person who is a habitual drunk but is not intoxicated at the time of the offense. A complete defense exonerates the accused and is a verdict of not guilty. Thus a person meeting the criteria of "settled insanity" is not considered responsible for his actions. Under the M'Naghten Rules, the first attempt in criminal law to address the issue of a mentally ill defendant, mentally illness (or insanity) can be used as a defense if the defendant was unable to understand the criminal nature of his act or was unable to distinguish right from wrong at that time of the offense. The standard for an insanity defense developed by the American Law Institute requires a showing that the defendant's mental illness prevented him from abiding by the law. Traditionally, under English common law intoxication, no matter to what degree, was not considered grounds for excusing the defendant's criminal behavior. However, over the last half century, there has been a movement toward allowing intoxication as evidence admissible in court to help the jury understand the criminal act and perhaps use it as an excuse or a mitigating factor. Although voluntary intoxication is not considered an excuse for a criminal act, if it can be shown that the defendant was too intoxicated to deliberate or premeditate the wrongful act, (lacking malice aforethought), a defense of diminished capacity, while not excusing the defendant from responsibility for the act, can serve to reduce the charges. Similarly, the plea of temporary insanity (applicable only to charges of murder) can serve to reduce the charges from first degree murder to assault or lessen the sentence if it can be shown that the defendant, due to intoxication, acted without deliberation or reflection (lacking malice aforethought), thus negating specific intent. However, ten states have rejected that specific intent can be negated by voluntary intoxication. Some jurisdictions allow voluntary intoxication in the context of a preexisting mental disorder to qualify for an insanity defense. # Settled insanity Over time, as United States court ruling have been refining the insanity defense, the concept of "settled insanity" has been evolving. Originally, any form of insanity caused by the voluntary use of drugs was not an eligible defense for a criminal offense. The rationale was that any act that results from voluntary behavior, including the voluntary intake of drugs, is choosing to increase the risk of breaking the law. Most United States jurisdictions now recognize that the long-term voluntary use of an intoxicating substance can cause a stable or "settled insanity" that can serve as a defense to a criminal act, especially if the long-term use exacerbated a preexisting mental condition. For example the concept of "settled insanity" includes delirium tremens brought on by the abstinence of an alcoholic from alcohol, in contrast to the temporary insanity of intoxication. California law recognizes "settled insanity" but distinguishes between the effect of long-term use qualifying as insanity and a temporary mental state resulting from recent use of an intoxicant which would not qualify as insanity. Recent rulings have upheld that insanity does not have to be permanent to qualify as a defense of "settled insanity". In a case where a woman with a substance-induced psychosis murdered her mother, expert witnesses testified that the defendant had "personality defects" that predisposed her to psychosis, and that the psychosis was triggered by chronic substance abuse resulting nine months of hospitalization. The defendant was found guilty because the court ruled her insanity was temporary. The Supreme Court of California overturned the lower court's guilty finding, ruling not guilty by reason of insanity, and stating that in a case in which a temporary psychosis occurs in instances other than during episodes of intoxication constitutes settled insanity and qualifies as a complete defense. In People v. Skinner, the California Supreme Court further specified the criteria for "settled insanity". The person must have a mental illness that is relatively stable over time and not caused solely by the length of time the substance was abused, and must also meet the legal definition of insanity in that jurisdiction. Thus it appears that the court is stating that a threshold condition for the insanity defense exists when there is a permanent impairment caused by chronic substance abuse in a person with a preexisting mental illness unrelated to substance abuse, but aggravated or set off by voluntary intoxication. However, a 2007 decision by the Colorado Court of Appeals in People v. Grant upheld a lower court ruling that did not allow expert testimony on the defendant's state of mind due to voluntary intoxication, thus ruling out any possibility that the issue of "settled insanity" might be raised. # Case example In Jervon Lamont Herbin v. Commonwealth of Virginia, Herbin appealed his conviction for attempted rape. The facts of the case are that Herbin was temporarily residing with the victim and was on crutches due to a gunshot wound received when he tried to enter his mother's house while on crack cocaine a week before. After requesting the victim to help him put on his socks, he threatened her with a knife and instructed her to take off her clothes. When the victim attempted to resist, Herbin stabbed her several times with the knife. The victim ceased resisting, and after threatening to kill her, Herbin pretended to call for assistance and eventually did call paramedics, giving them a false story regarding the victim's knife wounds. At his trial Herbin testified that he felt disturbed that day and had no memory of what happened except seeing the victim sitting in a pool of blood. He also testified to numerous stressors, including the gunshot wound, breaking up with his girlfriend, and recent attempts at suicide. He introduced extensive evidence of a history of physical and sexual abuse, drug abuse, and suicide attempts as well as a lengthy hospitalization. Further, he had attended a sex offender treatment program. Virginia does allow for a drug induced "settled insanity" as a defense to crime. However, Virginia draws a distinction between intoxication and long term substance abuse. In order to qualify for this defense, Herbin was required to provide substantial evidence of the presence of a mental disorder and the connection between it and the substance abuse. Herbin provided evidence of recent drug abuse and the victim testified that she had provided him with prescription drug, Halcion, and lay witnesses introduced evidence of his behavior on the day the offense was committed. The appeals court held that a "settled insanity" defense requires substantial evidence of not only long-term and heavy substance abuse, but convincing evidence of a mental disorder that is related to the substance abuse. Although Herbin did provide evidence of substantial drug abuse, he was unable to provide expert witness testimony of a serious mental disorder. The court held that the substance abuse did not serve as evidence for a "settled insanity" defense alone without the link to a mental disorder. Although lay witnesses testified to his behavior, the court held that lay witnesses were not in a position to provide testimony on the issue of "settled insanity". Also, although Herbin did provide an extensive history of drug and sexual abuse, the court said no evidence showed either of these issues were causes or results of a mental disorder. Therefor the appeals court upheld his conviction. # Conclusion In those states allowing a "settled insanity" defense, the expert witness must first determine whether any symptoms of a mental disorder were present at the time of the offense, and if there were, determine if those symptoms were the result of a lasting impairment rather than caused by intoxication no matter how acute. If it can be shown that any existing the mental disorder is lasting or relatively enduring, then the expert must be able to show how the mental illness interfered with the defendant's ability to know the nature and consequences of his behavior and know that his behavior was wrong, or if it impaired his ability to control his behavior. Aggressiveness, memory lapses and other common symptoms resulting from acute intoxication are not sufficient in themselves to excuse criminal acts. Further, not all psychotic reactions caused by substance abuse result in behavior that can be related to the criminal act in a way that can support an insanity defense. The presence of psychosis does not mean that the criminal act was caused by the psychosis. A relationship must be shown to exist between the psychosis and the behavior of the defendant. # Footnotes - ↑ "The Insanity Defense" (PDF). Loyola of Los Angeles Law Review. Retrieved 2007-10-23..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Jump up to: 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Intoxication and Settled Insanity: A Finding of Not Guilty by Reason of Insanity". Journal of the American Academy of Psychiatry and the Law. 2007. Retrieved 2007-10-23. - ↑ Jump up to: 3.0 3.1 "Drug and alcohol intoxication: mens rea defenses". American Association of Psychiatry and the Law Newsletter. 1999. Retrieved 2007-10-24. Unknown parameter |month= ignored (help) - ↑ Jump up to: 4.0 4.1 4.2 "Lawyers' Reports Annotated". Retrieved 2007-10-23. - ↑ Jump up to: 5.0 5.1 "Drugs, Alcohol and the Insanity Defense" (PDF). hawaii.gov. Retrieved 2007-10-24. - ↑ "Colorado Court of Appeals -- January 25, 2007 No. 03CA1034. People v. Grant". cobar.org. 2007. Retrieved 2007-10-24. Unknown parameter |month= ignored (help) - ↑ Jump up to: 7.0 7.1 7.2 7.3 "Jervon Lamont Herbin v. Commonwealth of Virginia". www.courts.state.va.us. Retrieved 2007-10-24.

Pentose # Overview A pentose is a monosaccharide with five carbon atoms. They either have an aldehyde functional group in position 1 (aldopentoses), or a ketone functional group in position 2 (ketopentoses). The aldopentoses have three chiral centres ("asymmetric carbon atoms") and so 8 different stereoisomers are possible. The 4 D-aldopentoses are: A mnemonic suggested that can be used to remember the four D-aldopentoses is "ribs are extra lean." The ketopentoses have 2 chiral centres and therefore 4 possible stereoisomers — ribulose (L- and D-form) and xylulose (L- and D-form). The D-isomers of both are known to occur naturally as is the L-isomer of xylulose: The aldehyde and ketone functional groups in these carbohydrates react with neighbouring hydroxyl functional groups to form intramolecular hemiacetals or hemiketals, respectively. The resulting ring structure is related to furan, and is termed a furanose. The ring spontaneously opens and closes, allowing rotation to occur about the bond between the carbonyl group and the neighbouring carbon atom — yielding two distinct configurations (α and β). This process is termed mutarotation. Ribose is a constituent of RNA, and the related deoxyribose of DNA.

Evidence and recommendation on antenatal multiple micronutrient supplements 7 # Dissemination and implementation of the recommendation 20

Prostaglandin DP2 receptor Prostaglandin D2 receptor 2 (DP2 or CRTH2) is a human protein encoded by the PTGDR2 gene and GPR44. DP2 has also been designated as CD294 (cluster of differentiation 294). It is a member of the class of prostaglandin receptors which bind with and respond to various prostaglandins. DP2 along with Prostaglandin DP1 receptor are receptors for prostaglandin D2 (PGD2). Activation of DP2 by PGD2 or other cognate receptor ligands has been associated with certain physiological and pathological responses, particularly those associated with allergy and inflammation, in animal models and certain human diseases. # Gene The PTGDR2 gene is located on human chromosome 11 at position q12.2 (i.e. 11q12.2). It consists of two introns and three exons and codes for a G protein coupled receptor (GPCR) composed of 472 amino acids. DP2, is related to members of the chemotactic factor class of GPCRs, sharing an amino acid sequence identity of 29% with the C5a receptor, Formyl peptide receptor 1, and Formyl peptide receptor 2 receptors. DP2 has little or no such amino acid sequence relationship to the eight other Prostanoid receptors (see Eicosanoid receptor#Prostenoid receptors). # Expression DP2 was found to stimulate the directed movement or chemotaxis of human T-helper type 2 cells (see T helper cell#Th1/Th2 Model for helper T cells) by binding to a receptor initially termed GPR44 and thereafter CRTH2 (for Chemoattractant Receptor-homologous molecule expressed on T-Helper type 2 cells). In addition to these T helper cells, DP2 messenger RNA is also expressed by human basophils, eosinophils, a subpopulation of cytotoxic T cells (i.e. CD8+ T cells), thalamus, ovary, and spleen, and, in the central nervous system, by the frontal cortex, pons, hippocampus, and at lower levels, hypothalamus and caudate nucleus/putamen. These transcripts are also detected in fetal liver and thymus. # Ligands ## Activating ligands The following standard prostaglandins have the following relative affinities and potencies in binding to and activating DP2: PGD2>>PGF2alpha=PGE2>PGI2=thromboxane A2. The cyclopentenone prostaglandins, PGJ2, Δ12-PGJ2, and 15-d-Δ12,14-PGJ2 are spontaneously formed or protein-facilitated derivatives of PGD2 that are generated in vitro as well as in vivo; these derivatives have binding affinities and activating potencies on DP2 that are similar to PGD2. Studies suggest that at least some if not most or all of the cytotoxic effects of cylopenenone prostaglandin derivatives of PGD2 act independently of DP2. Certain metabolites and derivatives of PGD2 viz., 13,14-dihydro-15-keto-PGD2 and 15(S)-15-methyl-PGD2, are ~10-fold less active than PGD2 while the drug indomethacin is weak in activating DP2. ## Inhibiting ligands The following compounds are selective receptor antagonists of and thereby inhibit the activation of DP2: fevipiprant, setipiprant, ADC-3680, AZD-1981, MK-1029, MK-7246, OC-459, OC000459, QAV-680, and TM30089. Ramatroban, vidupiprant, and Bay U3405 are non-selective (i.e. known to influence other receptors) antagonists of DP2. # Mechanisms of cell activation G protein-coupled receptors (GPCRs) such as DP2 are integral membrane proteins that, when bound by their cognate ligands (or, in some cases, even when not ligand-bound and thereby acting continuously in a constitutive manner {see Receptor (biochemistry)#Constitutive activity}), mobilize one or more types of Heterotrimeric G proteins. DP2 is classified as a "contractile" prostanoid receptor in that it can cause the contraction of smooth muscle. As evidenced by its initial discovery as a receptor for PGD2 in T-helper type 2 cells, activated DP2 triggers Gi alpha subunit-linked heterotrimeric G proteins to dissociate into their component a) Gi alpha subunits (also termed Giα subunits) which simulate phospholipase C to cleave phosphatidylinositol triphosphate into inositol triphosphate (IP3) and diacylglycerol (DAG) and b) G beta-gamma complex of subunits (Gβγ) which inhibit adenyl cyclase. IP3 raises cytosolic Ca2 levels thereby regulating Ca2-sensitive signal pathways; DAG activates certain protein kinase C enzymes )PKCs) that phosphorylate and thereby regulate target proteins involved in cell signaling; and adenyl cyclase converts AMP into cyclic AMP (cAMP) thereby down-regulating cAMP-responsive proteins involved in cell signalling. Concurrently with the mobilization of these pathways, activated DP2 also mobilizes G protein-coupled receptor kinases (GPKs, GPK2, GPK5, and/or GPK6) and Arrestin-2 (also termed Arrestin beta 1 or β-arrestin). The GPKs, along with the DAG-activated PKCs, phosphorylate DP2 to promote its internalization while arrestin-2 inhibits DP2 from further activating heterotrimeric G proteins while also linking DP2 to elements, clathrin and clathrin adaptor AP2, of the receptor internalization machinery. These pathways render DP2 unable to mobilize heterotrimereic G proteins thereby rendering the cell less sensitive or insensitive to further stimulation by DP ligands. The process, termed Homologous desensitization, serves as a physiological limiter of cell responses to DP2 activators. # Function ## Allergy Ligands that activate DP2 stimulate the in vitro chemotaxis (i.e. directed migration) of leukocytes active in mediating allergic responses viz., eosinophils, basophils, and Th2 cells. DP2 activation also stimulates eosinophils and basophils to release the many pro-allergic elements of their granules to the extracellular milieu. Ligand-induced activation of DP2 has similar activities in vivo it stimulates the accumulation on and activation of eosinophils, basophils, and Th2 cells at sites of nascent inflammation in animal models. PGD2, acting through DP2, stimulates the in vitro chemotaxis of CD8+ cells, although the contribution of this to the in vivo function of DP2 has not been clarified. PDP2 receptor antagonists have been shown to allergic reactions induced in the airways mice and sheep as well as the airways and nose of guinea pigs. Mice genetically engineered to be deficient in DP2 (i.e. DP2−/-) mice are defective in mounting asthmatic responses in models of: a) allergen-induced asthma, b) dermal allergy, c) ACTH and cortisol release in response to inflammatory stimuli, and c) perception of pain caused by inflammation in peripheral tissues. DP2−/- mice are also highly resistant to the gram (-) bacterial sepsis caused by cecal ligation and puncture; the protective effect was associated with lower bacterial load and lower production of pro-inflammatory cytokines (i.e. TNF-α, IL-6, and CCL3) and increased production of an anti-inflammatory cytokine (IL-10). ## Embryogenesis Studies in Dp2 gene-deficient (i.e. Dp2−/-) mice indicate that DP2 is essential for controlling cell cycle genes in fetal testes which contribute to the arrest of mitotic process and to the differentiate of germ cells. This control involves, at least in part, the DP2-dependent activation of the male germ cell marker Nanos2 and the inhibition of meiosis through repression of Stra8. # Human genomics studies The 1544G-1651G haplotype in the 3'-Untranslated region of the DP2 gene increased the stability of the gene's mRNA; this haplotype has been associated with an increased incidence of asthma in Chinese population and African but not Japanese sampling studies. The rs545659 C/G Single-nucleotide polymorphism (SNP) variant of DP2 has been associated with an increase in the percentage of circulating eosinophils, an increase in the expression of DP2 by these cells, an enhanced rate of differentiation of precursor cells to Th2 cells in culture, enhanced Th2 cytokine (i.e. IL-4 and IL-13) production by these cells, and an increased incidence of asthma in a sampling of multi-ethnic Caucasian Canadians. # Clinical studies ## Allergic Diseases Setipiprant (ACT-129968), a selective, orally active antagonist of the (DP2) receptor, proved to be well-tolerated and reasonable effective in reducing allergen-induced airway responses in asthmatic patient clinical trials. However, the drug, while supporting the concept that DP2 contributes to asthmatic disease, did not show sufficient advantage over existing drugs and was discontinued from further development for this application (see setipiprant). Patients with he chronic spontaneous urticarial form of hives exhibit significantly lower surface membrane expression of the DP22 receptor on their blood eosinophils and basophils, a result fully consistent with this receptor being initially activated and subsequently desensitization (refer to above section on "Mechanisms of cell activation"). The DP2 receptor antagonist, AZD1981, is in a phase 2 clinical trial for the treatment of chronic idiopathic urticarial. A randomized, partially-blinded, placebo-controlled, two-way crossover, proof of concept study comparing the efficacy of the DP2 receptor antagonist, QAV680, in the treatment of allergic rhinitis and a study on the effectiveness of OC000459, a DP2 receptor antagonist, in reducing the exacerbation of asthma induced by experimentally-induced rhinovirus infection in subjects has just been completed or is underway, respectively. ## Other diseases and conditions ## Baldness Acting through DP2, PGD2 can inhibit hair growth, suggesting that this receptor is a potential target for bald treatment. A potential drug for blocking the DP2 receptor and thereby ameliorating baldness is the compound setipiprant. A phase 2A study is underway to evaluate the safety, tolerability, and efficacy of oral setipiprant relative to a placebo in 18 to 49 year old males with androgenetic alopecia.

Chick slaughtering Chick slaughtering is the culling of newly hatched male chickens for which breeders have no use. In an industrial egg-producing facility, about half of the newly hatched chicks will be male and would grow up to be roosters, which do not lay eggs and therefore there is no incentive for the breeder to keep alive. Most of the male chicks are usually killed shortly after birth. # History Prior to the development of modern meat breeds, most male chickens (cockerels) would usually be slaughtered for meat, whilst females(pullets) would be kept for egg production. However, once farmers bred separate meat and egg breeds, it became apparent that there was no reason to keep males of the egg breed alive. As a result the males of every 'batch' of egg-laying chickens would be killed as soon as possible to reduce losses incurred by the breeder through the feeding and sheltering of them. Special techniques were developed to accurately determine the sex of chicks at as young an age as possible. # The culling of unwanted chicks In industrial factory farms, Chicks that are not intended for rearing are culled shortly after their sex is determined, usually before they are 72 hours old. Chicks are generally killed through use of a mechanically operated apparatus approved for that purpose in accordance with national legislation. ## Methods Several methods have been used to cull chicks: - Maceration, using a large high-speed grinder into which the chicks are thrown. - Gases or gas mixtures, often carbon dioxide is used to induce unconsciousness and then death. - Cervical dislocation, manually induced dislocation of the spinal column from the skull. - Burying alive. - Electrocution, a new method that has been touted as being cheap, reliable, and humane by its developers ## Recommended culling practices The American Veterinary Medical Association recommends cervical dislocation and asphyxiation by carbon dioxide as the best options, but has recently amended their guidelines to include maceration. The 2005-2006 American Vetinary Medical Association Executive Board held its final meeting July 13 in Honolulu, prior to the 2006 session of the House of Delegates and the AVMA Annual Convention. It proposed a policy change, which was recommended by the Animal Welfare Committee on disposal of unwanted chicks, poults, and pipped eggs. The new policy states, in part, "Unwanted chicks, poults, and pipped eggs should be killed by an acceptable humane method, such as use of a commercially designed macerator that results in instantaneous death. Smothering unwanted chicks or poults in bags or containers is not acceptable. Pips, unwanted chicks, or poults should be killed prior to disposal. A pipped egg, or pip, is one where the chick or poult has not been successful in escaping the egg shell during the hatching process. # Controversy Animal rights activists maintain that the practice of chicken slaughtering is inhumane. Many vegans cite this practice as part of the reason they avoid eating eggs. It is largely unknown by the public that the practice of chicken slaughtering takes place. Chicken culling usually occurs with little or no oversight by the public or official authorities, a fact which breeders have been known to take advantage of, with instances such as the placement of thousands of live chickens into a woodchipper having occurred.

Psilocybe azurescens Psilocybe azurescens is a psychedelic mushroom whose main active compounds are psilocybin and psilocin. It is among the most potent of the tryptamine-bearing mushrooms, containing up to 1.8% psilocybin, 0.5% psilocin, and 0.4% baeocystin by dry weight, averaging to about 1.1% psilocybin and 0.15% psilocin. It belongs to the family Strophariaceae in the order Agaricales. # Appearance Pileus 30-100 mm in diameter, conic to convex, expanding to broadly convex and eventually flattening with age with a pronounced, persistent broad umbo; surface smooth, viscous when moist, covered by a separable gelatinous pellicle; chestnut to ochraceous brown to caramel in color often becoming pitted with dark blue or bluish black zones, hygrophanous, fading to light straw color in drying, strongly bruising blue when damaged; margin even, sometimes irregular and eroded at maturity, slightly incurved at first, soon decurved, flattening with maturity, translucent striate and often leaving a fibrillose annular zone in the upper regions of the stem. Lamellae ascending, sinuate to adnate, brown, often stained info-black where injured, close, with two tiers of lamellulae, mottled, edges withish. Spore-print dark purplish brown to purplish black in mass. Stipe 90-200 mm long by 3-6 mm thick, silky white, dingy brown from the base or in age, hollow at maturity. Composed of twisted, cartilaginous tissue. Base of stem thickening downwards, often curved, and characterized by coarse white aerial tufts of mycelium, often with azure tones. Mycelium surrounding stipe base densely rhizomorphic (i.e., root-like), silky white, tenaciously holding the wood-chips together, strongly bruising bluish upon disturbance. They have no odor to slightly farinaceous. Their taste is extremely bitter. # Habitat and distribution Cespitose to gregarious on deciduous wood-chips and/or in sandy soils rich in lignicolous debris. Aspect collyboid, generating an extensive, dense and tenacious mycelial mat, Psilocybe azurescens causes the whitening of wood. Fruitings begin in late September and continue until harsh frost, usually mid-November. Cultivated patches occurr worldwide, but natural patches are found along the US Pacific coast, north of Seaside, Oregon. # Legal status Possession and/or cultivation of this species is illegal in a number of countries. # Effects See Psilocybin: Effects.

Calponin 3, acidic Calponin 3. acidic is a protein that in humans is encoded by the CNN3 gene. The CNN3 gene is located at 1p22-p21 in the human chromosomal genome. CNN3 gene contains 7 exons and encodes calponin 3, a 36.4-kDa protein consisting of 329 amino acids with isoelectric point (pI) of 5.84. Calponin 3 is known as acidic calponin. Among three isoforms of calponin, less is known for the gene regulation and function of calponin 3. Nonetheless, much has been learned from extensive studies on the homologous genes CNN1 and CNN2 that encode calponin 1 and calponin 2. # Evolution CNN3 is one of the three homologous calponin isoform genes. Calponin 3 is significantly diverged from calponin 1 and calponin 2 in the C terminal variable region. The higher degree of divergence among vertebrate CNN3 genes than that in the CNN1 and CNN2 gene families suggests possibly earlier emergence of CNN3, indicating that calponin 3 may represent a prototype of calponin ancestral of the three present-day isoforms (Fig. 1). # Structure-function relationships The primary structure of calponin 3 is similar as that of calponin 1 and calponin 2, consisting of a conserved N-terminal calponin homology (CH) domain, a conserved middle region containing two actin-binding sites, and a C-terminal variable region. The unique length amino acid sequence of the C-terminal segment of the three calponin isoforms are responsible for their size and overall charge differences. Calponin 3 has been shown to participate in actin cytoskeleton-based activities such as that in embryonic development and myogenesis. Unlike calponin 1, calponin 3 has little effect on actomyosin Mg2+-ATPase activity and does not cause actin filaments bundling at the same condition as calponin 1 does. # Tissue distribution Calponin 3 is found in the brain with expression in neurons, astrocytes, and glial cells, where it may function in regulating the actin cytoskeleton with a proposed role in the plasticity of neural tissues. Calponin 3 is also present in embryonic trophoblasts and myoblasts with functions in cell fusion during embryonic development and myogenesis Calponin 3 is also expressed in B lymphocytes. # Function Calponin 3 was found in stress fibers of skin fibroblasts and myofibroblasts during wound healing. Cnn3 knockdown in primary fibroblasts impaired stress fiber formation, resulting in decreased cell motility and contractile ability.> Calponin 3 in the brain has a potential function in regulating actin filaments during neuronal remodeling. Calponin 3 was also found in dendritic spines of adult hippocampal neurons to regulate dendritic spine plasticity. While mice with systemic knockout of Cnn1 or Cnn2, or both Cnn1 and Cnn2 survive to adulthood and fertile, systemic knockout of calponin 3 in mice results in embryonic and neonatal lethality due to defect in the development of central nervous system. CNN3 was found in the trophoblasts of human placenta and plays a role of negative regulator of trophoblast fusion. Knockdown or dissociation of calponin 3 from cytoskeleton in response to PKC phosphorylation promoted fusion of trophoblasts. Consistently, calponin 3 was also present in myoblasts as an inhibitory regulator of cell fusion. Overexpression of calponin 3 in mouse C2C12 myoblasts inhibited cell fusion during in vitro differentiation, whereas Cnn3 gene knockdown promoted cell fusion and the expression of skeletal muscle myosin. The inhibitory effect of calponin 3 was reversed upon phosphorylation by Rho-associated kinase 1/2 (ROCK1/2). # Notes

Rifampin isoniazid indications and usage # Indications And Usage For pulmonary tuberculosis in which organisms are susceptible, and when the patient has been titrated on the individual components and it has therefore been established that this fixed dosage is therapeutically effective. This fixed-dosage combination drug is not recommended for initial therapy of tuberculosis or for preventive therapy. In the treatment of tuberculosis, small numbers of resistant cells, present within large populations of susceptible cells, can rapidly become the predominating type. Since rapid emergence of resistance can occur, culture and susceptibility tests should be performed in the event of persistent positive cultures. This drug is not indicated for the treatment of meningococcal infections or asymptomatic carriers of N. meningitidis to eliminate meningococci from the nasopharynx.

Water model In computational chemistry, classical water models are used for the simulation of water clusters, liquid water, and aqueous solutions with explicit solvent. These models use the approximations of molecular mechanics. Many different models have been proposed; they can be classified by the number of points used to define the model (atoms plus dummy sites), whether the structure is rigid or flexible, and whether the model includes polarization effects. An alternative to the explicit water models is to use an implicit solvation model, also known as a continuum model. # Simple water models The simplest water models treat the water molecule as rigid and rely only on non-bonded interactions. The electrostatic interaction is modeled using Coulomb's law and the dispersion and repulsion forces using the Lennard-Jones potential. The potential for models such as TIP3P and TIP4P is represented by where kC, the electrostatic constant, has a value of 332.1 Å·kcal/mol in the units commonly used in molecular modeling; qi are the partial charges relative to the charge of the electron; rij is the distance between two atoms or charged sites; and A and B are the Lennard-Jones parameters. The charged sites may be on the atoms or on dummy sites (such as lone pairs). In most water models, the Lennard-Jones term applies only to the interaction between the oxygen atoms. The figure below shows the general shape of the 3- to 6-site water models. The exact geometric parameters (the OH distance and the HOH angle) vary depending on the model. # 3-site The simplest models have three interaction sites, corresponding to the three atoms of the water molecule. Each atom gets assigned a point charge, and the oxygen atom also gets the Lennard-Jones parameters. The 3-site models are very popular for molecular dynamics simulations because of their simplicity and computational efficiency. Most models use a rigid geometry matching the known geometry of the water molecule. An exception is the SPC model, which assumes an ideal tetrahedral shape (HOH angle of 109.47°) instead of the observed angle of 104.5°. The table below lists the parameters for some 3-site models. The SPC/E model adds an average polarization correction to the potential energy function: where μ is the dipole of the effectively polarized water molecule (2.35 D for the SPC/E model), μ0 is the dipole moment of an isolated water molecule (1.85 D from experiment), and αi is an isotropic polarizability constant, with a value of 1.608 × 10−40 F m. Since the charges in the model are constant, this correction just results in adding 1.25 kcal/mol (5.22 kJ/mol) to the total energy. The SPC/E model results in a better density and diffusion constant than the SPC model. The TIP3P model implemented in the CHARMM force field is a slightly modified version of the original. The difference lies in the Lennard-Jones parameters: unlike TIP3P, the CHARMM version of the model places Lennard-Jones parameters on the hydrogen atoms. The charges are not modified. Other models: - Fergunson (flex. SPC) - CVFF (flex.) # 4-site The 4-site models place the negative charge on a dummy atom (labeled M in the figure) placed near the oxygen along the bisector of the HOH angle. This improves the electrostatic distribution around the water molecule. The first model to use this approach was the Bernal-Fowler model published in 1933, which may also be the earliest water model. However, the BF model doesn't reproduce well the bulk properties of water, such as density and heat of vaporization, and is therefore only of historical interest. This is a consequence of the parameterization method; newer models, developed after modern computers became available, were parameterized by running Metropolis Monte Carlo or molecular dynamics simulations and adjusting the parameters until the bulk properties are reproduced well enough. The TIP4P model, first published in 1983, is widely implemented in computational chemistry software packages and often used for the simulation of biomolecular systems. There have been subsequent reparameterizations of the TIP4P model for specific uses: the TIP4P-Ew model, for use with Ewald summation methods; the TIP4P/Ice, for simulation of solid water ice; and TIP4P/2005, a general parameterization for simulating the entire phase diagram of water. Others: - TIP4PF (flexible) # 5-site The 5-site models place the negative charge on dummy atoms (labeled L) representing the lone pairs of the oxygen atom, with a tetrahedral-like geometry. An early model of these types was the BNS model of Ben-Naim and Stillinger, proposed in 1971, soon succeeded by the ST2 model of Stillinger and Rahman in 1974. Mainly due to their higher computational cost, five-site models were not developed much until 2000, when the TIP5P model of Mahoney and Jorgensen was published. When compared with earlier models, the TIP5P model results in improvements in the geometry for the water dimer, a more "tetrahedral" water structure that better reproduces the experimental radial distribution functions from neutron diffraction, and the temperature of maximum density of water. The TIP5P-E model is a reparameterization of TIP5P for use with Ewald sums. Note, however, that the BNS and ST2 models do not use Coulomb's law directly for the electrostatic terms, but a modified version that is scaled down at short distances by multiplying it by the switching function S(r): S(r_{ij}) = \begin{cases} \end{cases} Therefore the RL and RU parameters only apply to BNS and ST2. # 6-site A 6-site model that combines all the sites of the 4- and 5-site models was developed by Nada and van der Eerden. It was found to reproduce the structure and melting of ice better than other models. # Other - MB model. A more abstract model resembling the Mercedes-Benz logo that reproduces some features of water in two-dimensional systems. It is not used as such for simulations of "real" (i.e., three-dimensional) systems, but it is useful for qualitative studies and for educational purposes. - Coarse-grained models. One- and two-site models of water have also been developed. # Computational cost The computational cost of a water simulation increases with the number of interaction sites in the water model. The CPU time is approximately proportional to the number of interatomic distances that need to be computed. For the 3-site model, 9 distances are required for each pair of water molecules (every atom of one molecule against every atom of the other molecule, or 3 × 3). For the 4-site model, 10 distances are required (every charged site with every charged site, plus the O-O interaction, or 3 × 3 + 1). For the 5-site model, 17 distances are required (4 × 4 + 1). Finally, for the 6-site model, 26 distances are required (5 × 5 + 1). When using rigid water models in molecular dynamics, there is an additional cost associated with keeping the structure constrained, using constraint algorithms (although with bond lengths constrained it is often possible to increase the time step).

Home remedy # Overview A home remedy is a treatment to cure a disease or ailment that employs certain spices, vegetables, or other common items from the kitchen. Home remedies may or may not have actual medicinal properties that serve to treat or cure the disease or ailment in question, as they are typically passed along by laypersons (which has been facilitated in recent years by the Internet).; many are merely used as a result of tradition or habit or because they are quite effective in inducing the placebo effect. A significant number, however, have been demonstrated to effectively treat ailments such as sprains, minor lacerations, headaches, fevers, and even the common cold. One of the more popular examples of a home remedy is the use of chicken soup to treat respiratory infections such as a cold or mild flu, and according to recent studies, this may actually be effective. Other examples of medically successful home remedies include: willow bark tea to cure headaches and fevers (willow bark contains a form of acetylsalicylic acid, also known as aspirin); duct tape to help with setting broken bones; and duct tape or superglue to treat plantar warts, and Kogel mogel to treat sore throat. In earlier times mothers were entrusted with all but serious remedies. Historic cookbooks are frequently full of remedies for dyspepsia, fevers and female complaints. Many of the European liqueurs or digestifs were originally medicinal remedies. In Chinese folk medicine, medicinal congees (long cooked rice soups with herbs), foods and soups are part of the healing repertoire. A common error is to confuse home remedies with homeopathic remedies. In fact, the two concepts are unrelated.

Medieval demography Medieval demography is the study of human demography in Europe during the Middle Ages. It is an estimate of the number of people who were alive during the Medieval period, population trends and movements. In many ways, demography was one of the most crucial factors of historical change throughout the Middle Ages. # Demography The population levels of Europe during the Middle Ages can be roughly categorized: - 400-1000: stable at a low level. - 1000-1250: population boom and expansion. - 1250-1350: stable at very high level. - 1350-1420: steep decline - 1420-1470: stable at a low level. - 1470-onward: slow expansion gaining momentum in the early 16th century. As the ancient world came to an end there was a steep decline in population, reaching its lowest point around 542 with the bubonic plague (the Plague of Justinian, the last great plague in Europe until the Black Death of the 14th century). Estimates of total population of Europe are speculative, but at the time of Charlemagne it is thought to be between 25 and 30 million, and of this 15 million are in Carolingian France. Unlike the frontier settler image of a lone self-sufficient farmer who moves when he sees smoke from the neighbor's chimney, medieval settlements were thickly populated, with large zones of unpopulated wilderness in between. To be alone in the Middle Ages, and not part of a community, carried great risks. Crowded communities existed as islands in a sea of uncultivated wilderness. In the 11th century, people began to move outward into the wilderness, in what is known as the "great clearances". During the High Middle Ages, forests and marshes were cleared and cultivated. At the same time, settlements moved beyond the traditional boundaries of the Frankish Empire to new frontiers in eastern Europe, beyond the Elbe River. Crusaders expanded to the Crusader States, the Iberian Peninsula was reconquered from the Moors, and the Normans colonized southern Italy. These movements and conquests are part of larger pattern of population expansion and resettlement that occurred in Europe at this time . Reasons for this expansion and colonization include an improving climate known as the Medieval warm period allowing longer and more productive growing seasons; the end of barbarian raids by Vikings, Arabs, and Magyars resulting in greater political stability; advancements in medieval technology allowing more land to be farmed; reforms of the Church in the 11th century further increasing social stability; and the rise of Feudalism, which also brought increased social stability and thus more mobility. Nobles encouraged colonization. The bonds of serfdomthat tied peasants to the land began to weaken with the rise of a money economy. Land was plentiful while labor to clear and work the land was scarce; lords who owned the land found new ways to attract and keep labor. Urban centers began to emerge, able to attract serfs with the promise of freedom. As new regions were settled, both internally and externally, population naturally increased. By 1300 Europe had become, some say, overpopulated. England, which had around 1 million people in 1086, was estimated to have a population that ranges from 5 to 7 million. France in 1328 (which was geographically smaller than France is today) was believed to have between 18 to 20 million people, which it would not surpass again until the early modern period. The region of Tuscany had 2 million people in 1300, which it would not reach again until 1850. Overall, the population of Europe is believed to have reached a peak of 70 to 100 million. By comparison, the 25 member-states of the European Union in 2007 had a population of 494 million. This compares to grain yields that in the 14th century were between 2:1 and 7:1 (2:1 means for every seed planted, 2 are harvested). Modern grain yields are 30:1 or more, but the population is only 5-7 times higher. By the 14th century the frontiers had ceased to expand and internal colonization was coming to an end, but population levels remained high. Then in the 14th century a number of calamities struck that devastated millions. Starting with the Great Famine in 1315, then the Hundred Years' War and the Black Death of 1348-1350, the population of Europe plummeted. The period between 1348 and 1420 witnessed the heaviest loss. In Germany, about 40% of the named inhabitants disappeared. The population of Provence was reduced by 50% and in some regions in Tuscany 70% were lost during this period. Historians have struggled to explain how so many could have died. There are problems with the long-standing theory that it was just caused by a medical illness (see further discussions at Black Death) and so social factors are looked at. A classic Malthusian argument has been put forward that says Europe was overcrowded with people, even in good times it was barely able to feed its population. A gradual malnutrition developed over decades lowering resistance to disease, and competition for resources meant more warfare. In short, the catastrophes were Malthusian checks on a population too large for its available resources. However, critics say that if this were true, the sudden fall in population would have endowed the survivors with abundant resources that would enable them to recover quickly. This was not the case; populations continued to fall and remained low almost to the 16th century. Thus, classic Malthusian theory does not offer a fully satisfactory explanation. The most recent, although still tentative, explanation goes like this: by 1250, the population peaked and competition for resources meant that there was a great imbalance between property owners and workers. Rents went up, and wages sank, the unequal distribution of wealth increased between rich and poor. The conditions of the poor became so bad, they achieved net zero population growth. The economic conditions of the poor also aggravated the calamities of the plague because they had no recourse, such as fleeing to a villa in the country like the nobles in the Decameron, the poor lived in crowded conditions and could not isolate the sick, and had weaker immunities from a lacking diet and difficult subsistence lifestyle. After the plague and other exogenous causes of population decline this caused wage increases because of a lower labor supply, and a redistribution of wealth; however this did not happen right away because property owners resisted change through wage freezes and price controls. The wage freezes and price controls were partly responsible for popular uprisings, such as the Peasants' Revolt of 1381, and not until the later 15th century did the lower classes start to gain benefits. By 1500 the total population of Europe was substantially below that of 200 years earlier, but all classes overall had a higher standard of living. # Science and art of medieval demography The science of medieval demography is a fairly new one, but one that has received considerable attention lately, in particular with interest in the social issues of the Middle Ages in the later part of the 20th century. Most modern scholarly works today contain a section or chapter on the demographics of a particular town, region or kingdom. Because the sources traditionally used for demographics, such as marriage, birth and death records are generally not available for this period, scholars rely on other sources, which can roughly be broken down in to two categories: field data (archaeological) and written records. Examples of field data include the physical size of a settlement, and how it grows over time. The appearance, or disappearance, of settlements, for example after the Black Death the archaeological record shows the abandonment of upwards of 25% of all villages in Spain. However there are problems that limit the use of archaeological data. It is often difficult to assign a precise age to discoveries. As well, some of the largest and most important sites are still occupied and can not be investigated, thus limiting the archaeological record to the more peripheral regions, for example early Middle Ages Anglo-Saxon burials at Sutton Hoo, in East Anglia in England, for which otherwise no records exist. Because of the limitations of field data, most of what is known about Medieval demographics comes from written records, which can be categorized into descriptive accounts, and administrative accounts. Descriptive accounts include those left by chroniclers when they wrote of the size of armies, victims of war or famine, participants in an oath. However, many of these accounts were embellishments, and thus act as supporting evidence and never taken factually on their own. The most important written accounts are those taken from administrative records. These accounts are more objective and accurate because the motivations for writing them were not to influence others. These records can be divided in to two categories: surveys and serial documents. Surveys cover an estate or region on a particular date, rather like a modern inventory. Manorial surveys were very common throughout the Middle Ages, in particular in France and England, but faded as serfdom gave way to a money economy. Fiscal surveys came with the rise of the money economy, the most famous and earliest being the Domesday Book in 1086. The Book of Hearths from Italy in 1244 is another example. The largest fiscal survey was of France in 1328. As kings continued to look for new ways to raise money, these fiscal surveys increased in number and scope over time. Surveys have limitations, because they cover only a snapshot in time they do not give long term trends, and they tend to exclude elements of society. Serial records come in different forms. The earliest are from the 8th century and are land conveyances such as sales, exchanges, donations, and leases. Other types of serial records include death records from religious institutions and baptism registrations. Other helpful records include heriots, court records, food prices and rent prices, from which inferences can be made.

Complement component 3 Complement component 3, often simply called C3, is a protein of the immune system. It plays a central role in the complement system and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called C3. # Function C3 plays a central role in the activation of complement system. Its activation is required for both classical and alternative complement activation pathways. People with C3 deficiency are susceptible to bacterial infection. One form of C3-convertase, also known as C4b2b, is formed by a heterodimer of activated forms of C4 and C2. It catalyzes the proteolytic cleavage of C3 into C3a and C3b, generated during activation through the classical pathway as well as the lectin pathway. C3a is an anaphylotoxin and the precursor of some cytokines such as ASP, and C3b serves as an opsonizing agent. Factor I can cleave C3b into C3c and C3d, the latter of which plays a role in enhancing B cell responses. In the alternative complement pathway, C3 is cleaved by C3bBb, another form of C3-convertase composed of activated forms of C3 (C3b) and factor B (Bb). Once C3 is activated to C3b, it exposes a reactive thioester that allows the peptide to covalently attach to any surface that can provide a nucleophile such as a primary amine or a hydroxyl group. Activated C3 can then interact with factor B. Factor B is then activated by factor D, to form Bb. The resultant complex, C3bBb, is called the alternative pathway (AP) C3 convertase. C3bBb is deactivated in steps. First, the proteolytic component of the convertase, Bb, is removed by complement regulatory proteins having decay-accelerating factor (DAF) activity. Next, C3b is broken down progressively to first iC3b, then C3c + C3dg, and then finally C3d. Factor I is the protease that performs these cuts but it requires the help of another protein (Factor H, CR1, MCP or C4BP) to supply cofactor activity. # Structure Several crystallographic structures of C3 have been determined and reveal that this protein contains 13 domains. # Biochemistry ## Biosynthesis In humans, C3 is predominantly synthesised by liver hepatocytes and to some degree by epidermis keratinocytes. # Clinical use Levels of C3 in the blood may be measured to support or refute a particular medical diagnosis. For example, low C3 levels are associated with Systemic Lupus Erythematosus (SLE) and some types of kidney disease such as post-infectious glomerulonephritis, membranoproliferative glomerulonephritis, and shunt nephritis. # Interactions Complement component 3 has been shown to interact with Factor H. # Pathology Deficiencies in C3 lead to genetic infections, usually fatal to the newborn.

Anatomical pathology Anatomical pathology (Commonwealth) or Anatomic pathology (U.S.) is a medical specialty that is concerned with the diagnosis of disease based on the gross, microscopic, and molecular examination of organs, tissues, and cells. In many countries, physicians who practice pathology are trained in both anatomical pathology and clinical pathology, the diagnosis of disease through the laboratory analysis of bodily fluids. Anatomical pathologists diagnose disease and gain other clinically significant information through the examination of tissues and cells. This generally involves gross and microscopic visual examination of tissues, with special stains and immunohistochemistry employed to visualize specific proteins and other substances in and around cells. More recently, anatomical pathologists have begun to employ molecular biology techniques to gain additional clinical information from these same specimens. # Skills and procedures The procedures used in anatomic pathology include: - Gross examination - the examination of diseased tissues with the naked eye. This is important especially for large tissue fragments, because the disease can often be visually identified. It is also at this step that the pathologist selects areas that will be processed for histopathology. The eye can sometimes be aided with a magnifying glass or a stereo microscope, especially when examining parasitic organisms. - Histopathology - the microscopic examination of stained tissue sections using histological techniques. The standard stains are haematoxylin and eosin, but many others exist. The use of haematoxylin and eosin-stained slides to provide specific diagnoses based on morphology is considered to be the core skill of anatomic pathology. The science of staining tissues sections is called histochemistry. - Immunohistochemistry - the use of antibodies to detect the presence, abundance, and localization of specific proteins. This technique is critical to distinguishing between disorders with similar morphology, as well as characterizing the molecular properties of certain cancers. - In situ hybridization - Specific DNA and RNA molecules can be identified on sections using this technique. When the probe is labeled with fluorescent dye, the technique is called FISH. - Cytopathology - the examination of loose cells spread and stained on glass slides using cytology techniques. - Electron microscopy - the examination of tissue with an electron microscope, which allows much greater magnification, enabling the visualization of organelles within the cells. Its use has been largely supplanted by immunohistochemistry, but it is still in common use for certain tasks, including the diagnosis of kidney disease and the identification of immotile cilia syndrome among many others. - Tissue cytogenetics - the visualization of chromosomes to identify genetics defects such as chromosomal translocation. - Flow immunophenotyping - the determination of the immunophenotype of cells using flow cytometry techniques. It is very useful to diagnose the different types of leukemia and lymphoma. # Subdisciplines ## Surgical pathology Surgical pathology is the most significant and time-consuming area of practice for most anatomical pathologists. Surgical pathology involves the gross and microscopic examination of surgical specimens, as well as biopsies submitted by non-surgeons such as general internists, medical subspecialists, dermatologists, and interventional radiologists. ## Cytopathology Cytopathology is a sub-discipline of anatomical pathology concerned with the microscopic examination of whole, individual cells obtained from smears or fine needle aspirates. Cytopathologists are trained to perform fine-needle aspirates of superficially located organs, masses, or cysts, and are often able to render an immediate diagnosis in the presence of the patient and consulting physician. In the case of screening tests such as the Papanicolaou smear, non-physician cytotechnologists are often employed to perform initial reviews, with only positive or uncertain cases examined by the pathologist. Cytopathology is a board-certifiable subspecialty in the U.S. ## Molecular Pathology Molecular pathology is an emerging discipline within anatomical pathology which is focused on the use of nucleic acid-based techniques such as in-situ hybridization, reverse-transcriptase polymerase chain reaction, and nucleic acid microarrays for specialized studies of disease in tissues and cells. Molecular pathology shares some aspects of practice with both anatomic and clinical pathology, and is sometimes considered a "crossover" discipline. ## Autopsy pathology General anatomical pathologists are trained in performing autopsies, which are used to determine the disease factors contributing to a person's death. Autopsies are important in the ongoing medical education of clinicians, and in efforts to improve and verify the quality of medical care. Dieners are non-physicians who assist pathologists in the gross dissection portion of the autopsy. Autopsies represent less than 10% of the workload of typical pathologists in the United States. However, the autopsy is central to public perceptions of the field, in part due to portrayals of pathologists on television programs such as Quincy, M.E. and Silent Witness. ## Forensic pathology Forensic pathologists receive specialized training in determining the cause of death and other legally relevant information from the bodies of persons who died in a non-medical or potentially criminal circumstances. Autopsies make up much, but not all of the work of the practicing forensic pathologist, and forensic pathologists are occasionally consulted to examine a survivor of a criminal attack. Forensic pathology is a board-certifiable sub-specialty in the U.S. # Training and certification of Anatomical Pathologists ## USA Anatomic Pathology (AP) is one of the two primary certifications offered by the American Board of Pathology. The other is Clinical Pathology (CP). To be certified in anatomic pathology, the trainee must complete four years of medical school followed by three years of residency training. Many US pathologists are certified in both AP and CP, which requires a total of four years of residency. After completing residency, many pathologists enroll in further years of fellowship training to gain expertise in a subspecialty of AP. ## Canada Anatomical Pathology (AP) is one of the specialist certificates granted by the Royal College of Physicians and Surgeons of Canada. Other certificates related to pathology include general pathology (GP), forensic pathology, hematopathology, and neuropathology. Candidates for any of these must have completed four years of medical school and five years of residency training. After becoming certified in either AP or GP, it is common for pathologists to seek further fellowship training in a subspecialty of AP. # Anatomical pathology practice settings - Academic anatomical pathology is practiced by pathologists who are also faculty members of a university medical center often have a diverse set of responsibilities, such are practicing diagnostic anatomical pathology, conducting basic or translational research, training pathology residents, and teaching medical students. Anatomical pathologists in the academic setting are often more specialized in a specific area of expertise, than their private-practice counterparts. - Group practice is the most traditional private practice model. In this arrangement, a group of senior pathologists will control a partnership which employs more junior pathologists, and which contracts independently with hospitals to provide diagnostic services, as well as attracting referral business from local clinicians who practice in the outpatient setting. The group often owns a lab for histology and ancillary testing of tissue, and may hold contracts to run hospital-owned labs. Many pathologists who practice in this setting are trained and certified in both anatomical pathology and clinical pathology, which allows them to blood banks, clinical chemistry laboratories, and medical microbiology laboratories as well. - Large corporate providers of anatomical pathology services have emerged in recent years, most notably AmeriPath in the United States. In this model, pathologists are employees, rather than independent partners. This model has been criticized for reducing physician independence, but defenders claim that the larger size of these practices allow for economies of scale and greater specialization, as well a sufficient volume to support more specialized testing methods. - Multispecialty groups, composed of physicians from clinical specialties as well as radiology and pathology, are another practice model. In some case, these may be large groups controlled by an HMO or other large health care organization. In others, they are essentially clinician group practices which employ pathologists to provide diagnostic services for the group. These groups may own their own laboratories, or, in some cases have made controversial arrangements with "pod labs" which allow clinician groups to lease space, with the clinican groups receiving direct insurance payments for pathology services. Proposed changes to Medicare regulations may essentially eliminate these arrangements in the United States.

Laparoscopic surgery for inguinal hernia repair Evidence-based recommendations on laparoscopic surgery for treating inguinal hernia. # Guidance This guidance replaces 'Laparoscopic surgery for hernia' (NICE Technology Appraisal Guidance 18) issued in January 2001. For details, see 'About this guidance'. Laparoscopic surgery is recommended as one of the treatment options for the repair of inguinal hernia. To enable patients to choose between open and laparoscopic surgery (either by the transabdominal preperitoneal or by the totally extraperitoneal procedure), they should be fully informed of all of the risks (for example, immediate serious complications, postoperative pain/numbness and long-term recurrence rates) and benefits associated with each of the three procedures. In particular, the following points should be considered in discussions between the patient and the surgeon: the individual's suitability for general anaesthesia the nature of the presenting hernia (that is, primary repair, recurrent hernia or bilateral hernia) the suitability of the particular hernia for a laparoscopic or an open approach the experience of the surgeon in the three techniques. Laparoscopic surgery for inguinal hernia repair by TAPP or TEP should only be performed by appropriately trained surgeons who regularly carry out the procedure.# Clinical need and practice An inguinal hernia is a protrusion of a sac of peritoneum (often containing intestine or other abdominal contents) through a weakness in the abdominal wall in the groin. It usually presents as a lump, with or without some discomfort that may limit daily activities and the ability to work. Around 98% of inguinal hernias are found in men because of the vulnerability of the male anatomy to the formation of hernias in this region. Inguinal hernias can occasionally be life-threatening if the bowel within the peritoneal sac strangulates and/or becomes obstructed. In England, there were approximately 70,000 surgical repairs of inguinal hernia in 2001/02, affecting 0.14% of the population and utilising over 100,000 NHS bed-days of hospital resources. Of these procedures, 62,969 were for the repair of primary hernias and 4939 for the repair of recurrent hernias. Surgical repair (herniorraphy) is undertaken in most individuals presenting with inguinal hernia in order to close the defect, alleviate symptoms of discomfort, prevent serious complications (that is, obstruction or strangulation of the bowel) and reduce the risk of recurrence. Most hernia repairs are undertaken as elective procedures. However, 4.8% of primary repairs and 8.6% of recurrent hernias present as an emergency with a complication. Some individuals present with bilateral hernias, which may be repaired during the same operation or at a later date, and up to 30% of people with a primary unilateral hernia subsequently develop a hernia on the opposite side. Traditional methods of open repair (for example, the Bassini method), which repair the hernia defect by suturing, have not changed significantly since their introduction in the late 19th century. Recently, the availability of prosthetic meshes has led to an increase in the number of 'tension-free' methods of reinforcing the inguinal region. Open mesh methods of repair are classified as open flat mesh (OFM; for example, the Lichtenstein method), open preperitoneal mesh (OPPM; for example, the Stoppa and Nyhus methods) and open plug and mesh repair (OPM; for example, the Rutkow method). Open methods of hernia repair are associated with postoperative pain and numbness because of the large inguinal incision. OFM repairs are thought to be the principal surgical method of hernia repair in the UK.# The technology Laparoscopic surgery is a minimal-access technique that allows the hernia repair to be undertaken without the need to open the abdominal wall. Small incisions are made for the laparoscope and operating instruments, and synthetic mesh is usually used to close the hernia and prevent recurrence. There are two main approaches for the laparoscopic repair of inguinal hernias. Transabdominal preperitoneal (TAPP) repair involves access to the hernia through the peritoneal cavity. Mesh is inserted through the peritoneum and placed over all potential hernia sites in the inguinal region. The peritoneum is then closed above the mesh. Totally extraperitoneal (TEP) repair is the newer laparoscopic technique, in which the hernia site is accessed via the preperitoneal plane without entering the peritoneal cavity. TEP repair is considered to be technically more difficult than the TAPP technique, but it may reduce the risk of damage to intra-abdominal organs. The surgical approach to inguinal hernia repair is the main focus of this appraisal; other issues, such as comparisons between TAPP and TEP and the use of laparoscopic surgery in special subgroups (for example, bilateral or recurrent hernia), are subsidiary considerations. The potential benefits of using a laparoscopic approach include reduced postoperative pain, earlier return to normal activities and a reduction in long-term pain and numbness. The repair of bilateral hernias (including occult hernias detected during contralateral inspection at the time of a unilateral repair) may be undertaken during the same operation. Laparoscopic surgery is associated with additional costs, for the endoscopy system (video unit, monitor, endoscope and CO2 insufflator) and instruments (staplers, diathermy scissors or ports), although these may be reusable. The cost of laparoscopic surgery is highly dependent on whether disposable or reusable equipment is used.# Evidence and interpretation The Appraisal Committee (Appendix A) considered evidence from a number of sources (Appendix B). # Clinical effectiveness Outcomes of interest, against which the effectiveness of laparoscopic and open surgery were assessed, were primary outcomes of recurrence and persistent pain, and secondary outcomes of the rate of complications and persistent numbness, the duration of the operation, length of hospital stay, time to return to normal activities and quality of life. A systematic review of the literature identified 37 randomised controlled trials (RCTs) that compared laparoscopic with open mesh repair of inguinal hernias in a total of 5560 participants. The effectiveness of laparoscopic surgery compared with different methods of open surgery (OFM, OPPM and OPM) was presented separately for the TAPP and TEP laparoscopic methods of repair. The best available data (individual patient data, or aggregate data from studies) were used to generate a meta-analysis of the effectiveness of TAPP and TEP procedures for different outcomes of effectiveness. Laparoscopic surgery was associated with a statistically significant increase in operation time compared with open methods of hernia repair. Meta-analysis of 16 RCTs of TAPP repair demonstrated an overall increase of 13.33 minutes (95% CI 12.08 to 14.57) compared with open repair. Meta-analysis of eight RCTs of TEP repair demonstrated an overall increase of 7.89 minutes (95% CI 6.22 to 9.57) compared with open repair. Laparoscopic surgery was associated with a significantly shorter time to return to usual activities in all of the studies that measured this outcome. Meta-analysis of seven RCTs of TAPP repair reported a hazard ratio (HR) of 0.66 (95% CI 0.58 to 0.75; p < 0.00001), corresponding to a return to normal activities approximately 3 days earlier than after open repair. Meta-analysis of five RCTs of TEP repair reported an HR of 0.49 (95% CI 0.42 to 0.56; p < 0.00001), approximating to a return to usual activities 4 days earlier than after open repair. Both TAPP and TEP procedures demonstrated a statistically significant reduction in persistent numbness compared with open repair. Meta-analysis of eight RCTs comparing TAPP and open repair reported a relative risk (RR) of numbness of 0.26 (95% CI 0.17 to 0.40; p < 0.00001) in favour of TAPP repair. Meta-analysis of four RCTs comparing TEP with open repair reported an RR of 0.67 (95% CI 0.53 to 0.86; p < 0.002) in favour of TEP. One trial (n = 160) that randomised patients to TAPP or OPM repair reported no significant difference (RR 1.00, 95% CI 0.06 to 15.71 for TAPP) between the two techniques. Another trial that randomised 254 patients to TEP or OPM repair reported no significant difference (RR 2.57, 95% CI 0.11 to 62.38) between the two techniques. One RCT of TAPP compared with open repair showed that the reduction in numbness was maintained at 5-year follow-up (3% persistent numbness with TAPP compared with 23% with OFM repair). Overall, there were fewer cases of persistent pain at 1 year post-operation after laparoscopic repair, compared with open repair, in both TAPP and TEP studies. Meta-analysis of eight RCTs of TAPP repair reported an RR of 0.72 (95% CI 0.58 to 0.88; p = 0.001) in favour of TAPP. Meta-analysis of four RCTs of TEP repair reported an RR of 0.77 (95% CI 0.64 to 0.92; p = 0.004) in favour of TEP repair. One RCT of TAPP compared with open repair showed that the reduction in pain was maintained at 5-year follow-up (2% persistent pain with TAPP compared with 10% with OFM repair). The rates of recurrence were similar for laparoscopic and open repair. Meta-analysis of 15 TAPP RCTs reported a total of 26 recurrences out of 1052 TAPP procedures (2.5%) compared with 22 recurrences out of 1062 open repair procedures (2.1%; RR 1.18, 95% CI 0.69 to 2.02). Thirteen RCTs of TEP repair reported a total of 23 recurrences out of 1007 TEP repairs (2.3%), compared with 13 recurrences out of 1002 open repair procedures (1.3%; RR 1.61, 95% CI 0.87 to 2.98). A number of studies reported the incidence of adverse events (complications such as haematoma, seroma, wound-related infection, mesh infection, vascular or visceral injuries and port-site hernia). Laparoscopic repair (both TAPP and TEP) was associated with fewer cases of wound-related infection and haematoma. However, TAPP repair was associated with a higher incidence of vascular and visceral injuries compared with open repair (0.13% vascular injuries with TAPP compared with 0% with TEP and open repair; 0.79% visceral injuries with TAPP compared with 0.16% with TEP and 0.14% with open repair). One RCT randomised 52 patients with unilateral inguinal hernia to TAPP (n=28) or TEP (n=24) repair. There were no statistically significant differences between the procedures in terms of the duration of operation, intra-operative complications, incidence of haematoma, recurrence at 3-month follow-up, or time to return to usual activities. There were no direct comparisons of TAPP and TEP methods of laparoscopic repair in patients with bilateral or recurrent hernia. Trials that evaluated the effectiveness of laparoscopic surgery compared with various forms of open surgery (OFM, OPPM and OPM) in the repair of recurrent inguinal hernias (six trials of TAPP and five trials of TEP) and bilateral inguinal hernias (six trials of TAPP and six trials of TEP) were consistent with the overall results for primary surgery of unilateral inguinal hernias. The Assessment Group evaluated the effect of surgeons' experience on the duration of operation for laparoscopic repair (the 'learning effect'). Inexperienced surgeons (up to 20 procedures) were estimated to perform TAPP procedures in 70 minutes and TEP procedures in 95 minutes, compared with experienced surgeons, who were estimated to perform TAPP procedures in 40 minutes and TEP procedures in 55 minutes. A recent study, published after the Assessment Group's initial review, randomised 2164 patients to laparoscopic surgery (10% TAPP, 90% TEP) or to OFM repair. Many of the results of this study were broadly consistent with the findings of the systematic review and did not affect the pooled results when they were incorporated into meta-analysis. This study reported a statistically significant increase in the recurrence rate with laparoscopic surgery (10.1% for TAPP and TEP combined compared with 4.9% after open repair at 2-year follow up, odds ratio 2.2, 95% CI 1.5 to 3.2). When the recurrence rates from the recent study were incorporated into meta-analysis of TEP compared with OFM repair, the RR of recurrence associated with laparoscopic surgery was increased from 1.61 (95% CI 0.57 to 4.60), in the original report, to 2.0 (95% CI 1.43 to 2.81). The incidence of serious complications was also significantly higher with laparoscopic repair (1.1%; TAPP and TEP combined) compared with open repair (0.1%; OR 11.2, 95% CI 1.3 to 1.7), although this had little effect on the results when incorporated into the meta-analysis. This study also reported a reduction in persistent pain after laparoscopic compared with open repairs (9.8% after laparoscopic surgery compared with 14.3% after open repair). # Cost effectiveness The literature review identified seven economic evaluations of laparoscopic surgery for inguinal hernia repair – three based on economic models and four based on primary studies. Only two studies (submitted by Ethicon Endo-Surgery and BARD Ltd) were relevant to the UK setting. Ethicon Endo-Surgery provided a re-analysis of data from the MRC Laparoscopic Groin Hernia Trial, taking into consideration the repair of occult bilateral hernias. This model was based on the assumption that bilateral repairs in 30% of people with occult hernias would prevent the need for subsequent operation, and reduced the incremental cost effectiveness ratio (ICER) for laparoscopic surgery from £55,549 per quality-adjusted life year (QALY), as reported in the MRC Laparoscopic Groin Hernia Trial, to £15,000 per QALY. However, the model did not take into account the possibility that some people with occult hernias would not develop a clinically significant hernia. The BARD submission compared the cost effectiveness of the Perfix plug (used in OPM repairs) with that of laparoscopic surgery on the basis of data presented in the previous guidance, issued in 2001 (see Section 8). BARD estimated that open plug and mesh repairs may be cost saving on the basis of assumptions that the additional device cost may be offset by reductions in the recurrence rate (0.5% Perfix plug compared with 2.2% with laparoscopic surgery reported in the previous guidance) and an increase in the number of perfix plug repairs undertaken as less costly day cases (91% perfix plug and 60% laparoscopic repairs undertaken as day cases). The Assessment Group developed a Markov model that updates the paper by Vale l, Grant A and McCormack K (unpublished data 2003). The cost and outcome of various laparoscopic (TAPP and TEP) and open (OFM, OPPM and OPM) techniques were assessed in 1-year cycles over 5- and 25-year time horizons. All individuals entered the model at the point of initial hernia repair. In the first year, survivors were assumed to undergo a 3-month period of convalescence and then to return to full health. In subsequent years, individuals could be in a health state of no recurrence (with or without persistent pain or numbness), recurrent hernia proceeding to re-operation, recurrence without re-operation (at risk of emergency surgery for complications), or death (operative and all-cause mortality). Inputs to the economic model on the costs and EQ5D utility estimates for the different health states were based on data from the MRC Laparoscopic Groin Hernia Trial. Theatre costs (£6.40 per minute) and in-hospital costs (£236 per day) were similar for open and laparoscopic procedures. The additional equipment and consumable costs of laparoscopic surgery were £167 per procedure when using predominantly reusable equipment (assuming all reusable devices are used on average 250 times a year for 5 years), or £788 per procedure when predominantly disposable equipment is used. Baseline estimates for operation length, hospital stay, operative mortality, recurrence, re-operation, persistent pain and numbness, time away from usual activities and health state utilities were taken from the best available data identified during this systematic review. Relative differences in the effectiveness of the different methods of open and laparoscopic repair were based on the meta-analysis results for the various outcomes, which were applied to these baseline parameters. Probabilities, costs and utilities were not considered to be fixed but were assigned a probability distribution to reflect uncertainty about their values. The same annual risk of recurrence, pain, numbness and relative effect sizes was used for primary and subsequent procedures. A constant annual risk for persistent pain, numbness and recurrence was assumed when extrapolating from years 6 to 25 of the model. The results from the model showed that laparoscopic surgery (using reusable equipment) was associated with an increased cost of between £100 and £400 per procedure. Also, QALY differences between all of the techniques were small. Incremental analysis found the OPM method to be the most cost-effective method of open repair, driven by the duration of operation and hospital stay, which was the shortest with this procedure. However, when the same duration of operation and of hospital stay were assumed for all open procedures, the costs of OPM and OPPM techniques increased compared with OFM, and OFM became the most cost-effective method of open repair. TEP dominated TAPP, as it was less costly and more effective than the TAPP method of repair. The incremental cost of laparoscopic surgery compared with OFM was between £5000 and £12,000 per QALY at 5 years and between £2000 and £5000 per QALY at 25 years for TEP and TAPP, respectively. When the cost effectiveness of laparoscopic surgery was compared with OPM repair, laparoscopic surgery was not cost effective (with an ICER of £46,000–£606,000), and TEP was only cost effective (£20,000 per QALY) if the benefits extended for 25 years. Sensitivity analysis for differences in the costs, utility and relative effectiveness of different methods of open and laparoscopic repair was undertaken to evaluate the effect of uncertainty in these areas; most of these had little effect on the cost effectiveness of laparoscopic surgery. However, the cost effectiveness of laparoscopic repair was shown to be highly dependent on the cost of the open repair comparator. Sensitivity analysis that assumed that laparoscopic surgery did not improve the level of persistent numbness compared with OFM, increased the ICER of TEP from £2000 per QALY at baseline to £4000 per QALY at 25 years. Sensitivity analysis that assumed that laparoscopic surgery did not improve the level of persistent pain, increased the ICER of TEP from £2000 per QALY at baseline to £8000 per QALY at 25 years. Assumptions that laparoscopic surgery did not confer any benefits of reduced persistent pain or numbness increased the ICER of TEP to approximately £100,000 per QALY at 25 years. The use of reusable (approximately £170 per procedure) or disposable (approximately £790 per procedure) equipment in laparoscopic surgery had a huge impact on the cost effectiveness of surgery. Laparoscopic surgery using disposable equipment increased the ICER of TEP from £2000 per QALY at baseline to £14,000 per QALY at 25 years. In a separate analysis, the Assessment Group modelled the effect of repairing occult bilateral hernias on the cost effectiveness of laparoscopic surgery. This led to an increase in the cost of laparoscopic surgery compared with OFM, and a reduction in the probability of recurrence (as it has already been repaired) in the first year, increasing the ICER of TEP from £5000 per QALY at baseline to up to £10,000 per QALY at 5 years, depending on the prevalence and rate of progression of occult hernia. A supplementary analysis was undertaken by the Assessment Team in order to evaluate the effect of inclusion of new data from the study published after completion of the original report (4.1.12). This also incorporated a number of sensitivity analyses evaluating the cost effectiveness of laparoscopic surgery, using data from the most recent trial, which led to more conservative estimates of the reduction in persistent pain and an increased RR of hernia recurrence with laparoscopic repair. Thus when the baseline recurrence rate for all laparoscopic surgery was increased from a cumulative rate of approximately 3% in the original base-case analysis to 10% at 2 years (based on the recent paper), the ICER of TEP compared with OFM was £6500 per QALY at a 25-year time horizon. When the RR of persistent pain was reduced from 0.77 in the original model, to 0.69 based on the results of the recent study, the ICER of TEP compared with OFM repair was £4000 per QALY at a 25-year time horizon. With these scenarios TAPP and TEP were associated with costs and effects that were increasingly similar. # Consideration of the evidence The Committee reviewed the data available on the clinical and cost effectiveness of laparoscopic surgery for inguinal hernia repair, having considered evidence on the nature of the condition and the value placed on the benefits of laparoscopic surgery for inguinal hernia repair by people with the condition, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources. The Committee heard evidence from experts that the incision resulting from open hernia repair may cause damage to the tissues and nerves, leaving some people with long-term pain and numbness. Experts further advised that all the open methods of repair (OFM, OPPM and OPM) would be expected to have similar incidences of persistent pain and numbness. The Committee considered carefully the evidence from the RCTs on the potentially higher incidences of visceral and vascular injuries associated with laparoscopic hernia repair compared with open procedures. In addition, the evidence from the RCTs suggests that the incidences of these important adverse events may be different between the two laparoscopic procedures. Experts advised that this may have been a result of the relative lack of experience of surgeons in some of these early studies, and advised that there is currently no significant difference in the rate of adverse events between the two laparoscopic procedures when performed by experienced surgeons. The Committee considered carefully the recent study (4.1.12), which reported a significantly higher incidence of serious complications with laparoscopic repair compared with open repair (although this was not reported separately for TAPP and TEP repairs). Many of the adverse events may have been related to the effects of the general anaesthetic used in the patients undergoing laparoscopic repair coupled with the relatively poorer general health of patients recruited into this study (that is, two-thirds in ASA groups II and III) compared with patients included in the original systematic review. However, the Committee were persuaded that the patients in this trial were probably representative of the unselected patients undergoing operations for inguinal hernia in the NHS and therefore considered that inclusion of the data from this study in the overall analysis was appropriate. The Committee appreciated that differences in the outcomes and adverse events of laparoscopic surgery, which may occur in practice and are apparent in the recent study (4.1.12), could result from differences in surgical experience. The Committee were persuaded that ongoing evaluation and review of the results of laparoscopic hernia repair was important and that this should be established at a national level to ensure that potentially serious events are identified and recorded in individual centres. The Committee considered the uncertainty over the recurrence rate associated with laparoscopic surgery, which was statistically significantly higher than that associated with open repair when data from the recent study were incorporated. The Committee concluded that the risk of recurrence which was relatively low with both procedures, and that the increased risk of recurrence with laparoscopic surgery may be acceptable for some patients when the benefits (reduced pain and numbness, and earlier return to normal activities) are taken into consideration. In summary, the Committee considered that laparoscopic repair of inguinal hernia was likely to result in considerably less postoperative pain and numbness than open repair. However, there was uncertainty over the rates of recurrence and of serious complications associated with laparoscopic surgery for primary repairs, which may be higher than those associated with the open procedure. On balance, the Committee concluded that laparoscopic surgery would be the preferred technique for the repair of recurrent hernias (as scar tissue from previous open repairs may be avoided) and bilateral hernias (repaired during the same operation and should also be an option for primary repair of unilateral hernias because of the reduced incidence of long-term pain and numbness and the potential for earlier return to normal activities. The Committee considered that current evidence did not suggest which of the two available laparoscopic methods should be preferred for routine surgery, and noted the importance of the individual surgeon's experience in each method as a factor in determining the best choice. The Committee was advised that the TAPP approach enabled the surgeon to both view, and if required, effect a repair of an occult hernia on the contralateral side during a primary repair procedure. The TEP approach also allowed an occult hernia on the contralateral side to be seen, but required more dissection to facilitate repair. The Committee was aware that laparoscopic (TAPP and TEP) methods of repair are technically more demanding than open repair, and that the clinical and the cost effectiveness of laparoscopic hernia repair are closely linked to the experience of the surgeon in the technique. The Committee heard evidence from experts that whilst surgeons are being trained in laparoscopic surgery, there is likely to be an increase in the duration of the operation, but were persuaded that this would not affect the overall longer-term cost effectiveness of the procedure. The Committee was persuaded of the importance of ensuring appropriate standards of training for laparoscopic hernia repair. They considered that, in light of the relatively small number of surgeons currently proficient in laparoscopic techniques (as compared with those undertaking open repair procedures), further training of surgeons in laparoscopic methods of repair will be required before this procedure can be more widely adopted. The Committee considered it important that individuals be advised of the potential risk of complications associated with laparoscopic surgery. Laparoscopic surgery would not be appropriate for all, particularly those people unable to undergo or at higher risk from general anaesthesia, or in situations where the size or location of the hernia defect does not lend itself to laparoscopic surgery. Experts advised that individual surgeons tend to have a favoured method of open or laparoscopic repair. The Committee concluded that individuals should be given impartial advice as to the relative risks and benefits of laparoscopic repair compared with open repair during discussions with the surgeon at the time of referral, in order to facilitate an informed choice. The Committee reviewed the data on the cost effectiveness of laparoscopic repair compared with the different methods of open repair, and considered the OFM technique to be the most clinically relevant comparator because it is the most common method of open repair and because of the absence of long-term data on the costs and outcomes of newer techniques (OPPM and OPM). The Committee considered that, taking all data reviewed into account, laparoscopic surgery (TAPP and TEP) is a cost-effective alternative to OFM repair. However, they noted that the choice of disposable or reusable equipment for use in laparoscopic hernia repairs had a significant effect on the ICER of the procedure. The Committee were therefore persuaded that, wherever possible, the use of reusable equipment was to be preferred.# Recommendations for further research The Institute recommends that further trials be undertaken to evaluate the utility of individuals undergoing laparoscopic surgery at 1 year and longer follow-up (where possible, up to 25 years) to provide long-term data on the cost effectiveness of this technique. The issue of chronic pain and numbness after inguinal hernia repair should be addressed prospectively in future studies, using standard definitions to allow for assessment of the degree of pain. It is recommended that a registry be set up to monitor the incidence of serious adverse events (specifically the rates of visceral and vascular injury) associated with laparoscopic hernia repair and recurrence rates.# Implications for the NHS Approximately 70,000 surgical inguinal hernia repairs are performed in England each year, at a cost to the NHS of £56 million a year. In the year 2001/02, 95.9% of mesh repairs were performed by open surgery, and 4.1% of repairs were performed by laparoscopic surgery. The anticipated costs of adopting laparoscopic surgery are based on the degree of diffusion of this technique. However, experts advised that, for the foreseeable future, it is unlikely that the uptake of laparoscopic surgery would exceed 40% of all surgical hernia repairs. If the annual percentage of laparoscopic repairs increased to 20%, the additional cost to the NHS in England would be approximately £1 million (based on the number and cost of hernia repairs in 2001/02 of £1078 for laparoscopic and £987 for open mesh repairs). The cost effectiveness of laparoscopic surgery for inguinal hernia repair is influenced by: the number of laparoscopic procedures performed per annum and the experience of the operating surgeon the use of disposable or reusable laparoscopic equipment the rates of hernia recurrence, serious complications and persistent pain (and its severity). The duration of surgery is directly linked to the experience of the surgeon: the duration of laparoscopic surgery decreases as the operating surgeon's experience increases, and this should reduce the costs attributable to theatre time. Operating costs for open and laparoscopic repairs done by experienced surgeons are likely to be similar. Hospital policy as to the use of reusable or disposable consumables will also have a significant impact on the cost of laparoscopic surgery. Reusable equipment for laparoscopic surgery costs about £170 per procedure compared with disposable equipment, which costs about £790 per procedure. Regional variations in the implementation costs of this guidance are likely, depending on the degree to which laparoscopic surgery is taken up locally, and on variations in hospital policy towards, for example, the use of reusable or disposable equipment.# Related guidance The Institute issued the original guidance on the use of laparoscopic repair of inguinal hernia in January 2001. National Institute for Clinical Excellence (2001) Guidance on the use of laparoscopic surgery for inguinal hernia. NICE Technology Appraisal Guidance No. 18. London: National Institute for Clinical Excellence.# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review. The guidance on this technology will be reviewed in September 2007. Andrew DillonChief ExecutiveSeptember 2004# Appendix C. Detail on criteria for audit of the use of laparoscopic surgery for inguinal hernia repair # Possible objectives for an audit An audit could be carried out on the appropriateness of the use of laparoscopic surgery for inguinal hernia to ensure the following. Laparoscopic surgery is considered as one of the treatment options for the repair of inguinal hernia. Individuals are fully informed of the risks and benefits of alternative procedures. Surgeons carry out laparoscopic surgery for the repair of inguinal hernia only after receiving appropriate training and experience. # Possible patients to be included in the audit An audit could be carried out on all people referred for repair of inguinal hernia in a reasonable time period for audit, for example, 6 months or 1 year. # Measures that could be used as a basis for an audit The measures that could be used in an audit of laparoscopic surgery for inguinal hernia are as follows. Criterion Standard Exception Definition of terms . Laparoscopic surgery is considered as one of the treatment options for the repair of inguinal hernia % of the people referred for repair of inguinal hernia None Surgeons will need to agree locally on how consideration of laparoscopic surgery as a treatment option is recorded for audit purposes. In choosing between open and laparoscopic surgery, the following are considered: (a) the individual's suitability for general anaesthesia; (b) the nature of the presenting hernia; (c) the suitability of the particular hernia for laparoscopic or open approach; (d) the experience of the surgeon in open and laparoscopic procedures. 'Laparoscopic surgery' means the TEP or the TAPP procedure. 'Nature of the presenting hernia' means primary repair, recurrent hernia or bilateral hernias. 'Experience of the surgeon' refers to all three techniques, open surgery and the TEP or TAPP laparoscopic procedures. . The individual undergoing repair of inguinal hernia is fully informed of all the risks and benefits associated with open and laparoscopic surgery through the informed consent process % of people referred for repair of inguinal hernia None 'Risks' include immediate serious complications, post-operative pain or numbness and long-term recurrence. 'Laparoscopic surgery' means either the TEP or the TAPP procedure. Clinicians will need to agree locally on how an individual is determined to be 'fully informed' of risks and benefits for audit purposes. . Laparoscopic repair of inguinal hernia is performed only by a surgeon who: a. has received appropriate training and b. regularly carries out the procedure % of people having laparoscopic repair of inguinal hernia None Clinicians will need to agree locally on what constitutes 'appropriate training' and how many procedures are needed in a given time period to count as 'regularly' carrying out the procedure. # Calculation of compliance Compliance (%) with each measure described in the table above is calculated as follows. Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed x 100 Number of patients to whom the measure applies Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.# Changes after publication March 2014: implementation section updated to clarify that laparoscopic surgery is recommended as a treatment option for repair of inguinal hernia. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance replaces 'Laparoscopic surgery for hernia' (NICE Technology Appraisal Guidance 18) issued in January 2001. The Institute reviews each piece of guidance it issues. The review and re-appraisal of the use of laparoscopic surgery for inguinal hernia repair has resulted in changes in the guidance. Specifically there has been: a recommendation that laparoscopic surgery is one of the treatment options for the repair of inguinal hernia a recommendation that patients should be fully informed of all the risks and benefits of open and laparoscopic surgery by either the TAPP or TEP approaches, to enable them to choose between the procedures. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence . All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. 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