Investing in antibiotics to alleviate future catastrophic outcomes: What is the value of having an effective antibiotic to mitigate pandemic influenza?
Over 95% of post-mortem samples from the 1918 pandemic, which caused 50 to 100 million deaths, showed bacterial infection complications. The introduction of antibiotics in the 1940s has since reduced the risk of bacterial infections, but growing resistance to antibiotics could increase the toll from future influenza pandemics if secondary bacterial infections are as serious as in 1918, or even if they are less severe. We develop a valuation model of the option to withhold wide use of an antibiotic until significant outbreaks such as pandemic influenza or foodborne diseases are identified. Using real options theory, we derive conditions under which withholding wide use is beneficial, and calculate the option value for influenza pandemic scenarios that lead to secondary infections with a resistant Staphylococcus aureus strain. We find that the value of withholding an effective novel oral antibiotic can be positive and significant unless the pandemic is mild and causes few secondary infections with the resistant strain or if most patients can be treated intravenously. Although the option value is sensitive to parameter uncertainty, our results suggest that further analysis on a case-by-case basis could guide investment in novel agents as well as strategies on how to use them.


CRISPR/Cas9-mediated knockout of p22phox leads to loss of Nox1 and Nox4, but not Nox5 activity.
The NADPH oxidases are important transmembrane proteins producing reactive oxygen species (ROS). Within the Nox family, different modes of activation can be discriminated. Nox1-3 are dependent on different cytosolic subunits, Nox4 seems to be constitutively active and Nox5 is directly activated by calcium. With the exception of Nox5, all Nox family members are thought to depend on the small transmembrane protein p22phox. With the discovery of the CRISPR/Cas9-system, a tool to alter genomic DNA sequences has become available. So far, this method has not been widely used in the redox community. On such basis, we decided to study the requirement of p22phox in the Nox complex using CRISPR/Cas9-mediated knockout. Knockout of the gene of p22phox, CYBA, led to an ablation of activity of Nox4 and Nox1 but not of Nox5. Production of hydrogen peroxide or superoxide after knockout could be rescued with either human or rat p22phox, but not with the DUOX-maturation factors DUOXA1/A2. Furthermore, different mutations of p22phox were studied regarding the influence on Nox4-dependent H2O2 production. P22phox Q130* and Y121H affected maturation and activity of Nox4. Hence, Nox5-dependent O2•- production is independent of p22phox, but native p22phox is needed for maturation of Nox4 and production of H2O2.


Hospitalisation costs of cystic fibrosis.
To calculate per-case hospital costs for patients with cystic fibrosis under routine conditions from a healthcare provider's perspective; identify the impact of different cost categories; investigate whether cases with cystic fibrosis can be grouped into homogenous cost groups according to defined severity levels; and determine the value of specific factors as predictors of hospital cost variations. All data were collected from cases (n = 131) admitted to an inpatient cystic fibrosis unit under routine conditions during a period of 6 months in 2004. All costs were calculated for the year 2004 and divided into categories with high and low impact on variation in hospitalisation costs between patients. Staff costs for patient care, laboratory costs and drug costs were defined as categories with high impact, thus the individual resource utilisation for each case was measured. Cost categories that were classified as having a low impact were measured as overhead costs. Cases were classified according to two different severity models; within each model, patients were classified according to three severity levels. The diagnosis-related model classifies patients with pulmonary hypertension and global respiratory insufficiency as having severe disease, patients with Pseudomonas aeruginosa as having moderate disease, and patients with no colonisation of the lungs as having mild disease. The lung-function-related model differentiates patients as having mild, moderate and severe disease when patients have forced expiratory volumes in 1 second (FEV(1)) that are > or =70%, between > or =40% and <70%, and <40%, respectively. Analysis of variance tests were performed to investigate the differences of mean costs between the groups. Ordinary least squares regression analysis was used to determine predictors for cost variation. The mean total costs per case were 7326 euro. Almost one-third of the total mean costs were attributable to drug costs (28% of total costs), while shares of staff costs for patient care and laboratory costs (both 9% of total costs) were relatively small. Most of the difference in costs between severity levels was attributable to the variation in overhead costs and drug costs. For both severity models differences in mean total costs of mild and severe cases were statistically significant (p < 0.01 and p < 0.05, respectively) when compared with the mean costs of non-mild and non-severe cases. However, in moderate cases, significant differences compared with cases that were not of moderate severity were only seen for certain cost categories. In the multiple regression model the variables 'diagnosis-related severity' and 'FEV(1)' explained 31% of the variance of 'Ln (total costs per case)' between severity levels (p < or = 0.01). This study shows that to a large extent hospitalisation costs for patients with cystic fibrosis vary according to the severity of their disease; drug costs play a major role in these differences. In the light of this variation it seems plausible to create separate reimbursement rates for two or three severity groups. Diagnoses as well as FEV(1) seem suitable criteria for such a classification.


Immunohistopathologic demonstration of deleterious effects on growing rat testes of radiofrequency waves emitted from conventional Wi-Fi devices.
To investigate effects on rat testes of radiofrequency radiation emitted from indoor Wi-Fi Internet access devices using 802.11.g wireless standards. Ten Wistar albino male rats were divided into experimental and control groups, with five rats per group. Standard wireless gateways communicating at 2.437 GHz were used as radiofrequency wave sources. The experimental group was exposed to radiofrequency energy for 24 h a day for 20 weeks. The rats were sacrificed at the end of the study. Intracardiac blood was sampled for serum 8-hydroxy-2'-deoxyguanosine levels. Testes were removed and examined histologically and immunohistochemically. Testis tissues were analyzed for malondialdehyde levels and prooxidant-antioxidant enzyme activities. We observed significant increases in serum 8-hydroxy-2'-deoxyguanosine levels and 8-hydroxyguanosine staining in the testes of the experimental group indicating DNA damage due to exposure (p < 0.05). We also found decreased levels of catalase and glutathione peroxidase activity in the experimental group, which may have been due to radiofrequency effects on enzyme activity (p < 0.05). These findings raise questions about the safety of radiofrequency exposure from Wi-Fi Internet access devices for growing organisms of reproductive age, with a potential effect on both fertility and the integrity of germ cells.


rs4771122 Predicts Multiple Measures of Long-Term Weight Loss After Bariatric Surgery.
We examined the association of 34 single nucleotide polymorphisms with weight loss up to 9.5 years after Roux-en-Y surgery. Participants were enrollees in the NUgene biobank with stored DNA and linked electronic health records. Ninety-five self-identified white participants underwent surgery and had follow-up weights obtained between 1 and 9.5 years after surgery. SNP rs4771122 was the variant most significantly associated with long-term weight loss after surgery in a repeated linear mixed model (p = .004) of long-term weight loss. In this model, each additional copy of the minor allele was associated with nearly 5 % greater percentage weight loss. This same SNP was also nominally significantly (p < .05) associated with weight loss trajectories, weight loss nadir, and weight loss 2 years after surgery.


Using a time-geographical diary method in order to facilitate reflections on changes in patterns of daily occupations.
Time-use methodologies have been proposed to be established research techniques when exploring aspects of daily occupations. In this study, two graphs illustrating the time arrangement of occupations as they appear in a continuous sequence were used in order to encourage individuals to reflect on their everyday life. The aim was to investigate the usefulness of a time-geographical diary method (using illustrative graphs) in combination with stimulated-recall interviews, to facilitate reflections on how patterns of daily occupations change over time and the causes that lie behind these changes. The study had a qualitative design. The participants were two working, married mothers, i.e. individuals considered to have highly complex patterns of daily occupations. The data analysis was performed by using thematic content analysis. The results showed that the stimulated-recall interviews, based on the graphs, facilitated new insights that came to light concerning the scope of the participants' daily life. The method enabled the participants to reflect on their patterns of daily occupations and become aware of changes relevant to explain the causes for engaging in occupations the way they did. The method thus seems useful in research and practice for occupational therapists working with individuals with a need to change lifestyle.


Hidden in plain sight-highly abundant and diverse planktonic freshwater Chloroflexi.
Representatives of the phylum Chloroflexi, though reportedly highly abundant in the extensive deep water habitats of both marine (SAR202 up to 30% of total prokaryotes) and freshwater (CL500-11 up to 26% of total prokaryotes), remain uncultivated and uncharacterized. There are few metagenomic studies on marine Chloroflexi representatives, while the pelagic freshwater Chloroflexi community is largely unknown except for a single metagenome-assembled genome of CL500-11. Here, we provide the first extensive examination of the community composition of this cosmopolitan phylum in a range of pelagic habitats (176 datasets) and highlight the impact of salinity and depth on their phylogenomic composition. Reconstructed genomes (53 in total) provide a perspective on the phylogeny, metabolism, and distribution of three novel classes and two family-level taxa within the phylum Chloroflexi. We unraveled a remarkable genomic diversity of pelagic freshwater Chloroflexi representatives that thrive not only in the hypolimnion as previously suspected, but also in the epilimnion. Our results suggest that the lake hypolimnion provides a globally stable habitat reflected in lower species diversity among hypolimnion-specific CL500-11 and TK10 clusters in distantly related lakes compared to a higher species diversity of the epilimnion-specific SL56 cluster. Cell volume analyses show that the CL500-11 are among the largest prokaryotic cells in the water column of deep lakes and with a biomass to abundance ratio of two they significantly contribute to the deep lake carbon flow. Metabolic insights indicate participation of JG30-KF-CM66 representatives in the global cobalamin production via cobinamide to cobalamin salvage pathway. Extending phylogenomic comparisons to brackish and marine habitats suggests salinity as the major influencer of the community composition of the deep-dwelling Chloroflexi in marine (SAR202) and freshwater (CL500-11) habitats as both counterparts thrive in intermediate brackish salinity; however, freshwater habitats harbor the most phylogenetically diverse community of pelagic Chloroflexi representatives that reside both in epi- and hypolimnion.


Dose-Dependent Effects of the Myosin Activator Omecamtiv Mecarbil on Cross-Bridge Behavior and Force Generation in Failing Human Myocardium.
Omecamtiv mecarbil (OM) enhances systolic function in vivo by directly binding the myosin cross-bridges (XBs) in the sarcomere. However, the mechanistic details governing OM-induced modulation of XB behavior in failing human myocardium are unclear. The effects of OM on steady state and dynamic XB behavior were measured in chemically skinned myocardial preparations isolated from human donor and heart failure (HF) left ventricle. HF myocardium exhibited impaired contractile function as evidenced by reduced maximal force, magnitude of XB recruitment (Pdf), and a slowed rate of XB detachment (krel) at submaximal Ca2+ activations. Ca2+ sensitivity of force generation (pCa50) was higher in HF myocardium when compared with donor myocardium, both prior to and after OM incubations. OM incubation (0.5 and 1.0 μmol/L) enhanced force generation at submaximal Ca2+ activations in a dose-dependent manner. Notably, OM induced a slowing in krel with 1.0 μmol/L OM but not with 0.5 μmol/L OM in HF myocardium. Additionally, OM exerted other differential effects on XB behavior in HF myocardium as evidenced by a greater enhancement in Pdf and slowing in the time course of cooperative XB recruitment (Trec), which collectively prolonged achievement of peak force development (Tpk), compared with donor myocardium. Our findings demonstrate that OM augments force generation but also prolongs the time course of XB transitions to force-bearing states in remodeled HF myocardium, which may extend the systolic ejection time in vivo. Optimal OM dosing is critical for eliciting enhanced systolic function without excessive prolongation of systolic ejection time, which may compromise diastolic filling.


Predicting Lower Quarter Y-Balance Test Performance From Foot Characteristics.
The lower quarter Y-Balance Test (YBT-LQ) is associated with injury risk; however, ankle range of motion impacts YBT-LQ. Arch height and foot sensation impact static balance, but these characteristics have not yet been evaluated relative to YBT-LQ. Determine if arch height index (AHI), forefoot sensation (SEN), and ankle dorsiflexion predict YBT-LQ composite score (CS). Descriptive cohort. Athletic training laboratory. Twenty general population (14 females and 6 males; mean [SD]: age 35 [18] y, weight 70.02 [16.76] kg, height 1.68 [0.12] m) participated in this study. AHI measurement system assessed arch height in 10% (AHI10) and 90% (AHI90) weight-bearing. Two-point discrim-a-gon discs assessed sensation (SEN) at the plantar great toe, third and fifth metatarsal heads. Biplane goniometer and weight-bearing lunge tests were used to measure static and weight-bearing dorsiflexion, respectively. The YBT-LQ assessed dynamic single-leg balance. For right-limb dynamic single-leg balance, AHI90 and SEN were included in the final sequential prediction equation; however, neither model significantly (P = .052 and .074) predicted variance in YBT-LQ CS. For left-limb dynamic single-leg balance, both SEN and weight-bearing lunge test were included in the final sequential prediction equation. The regression model (SEN and weight-bearing lunge test) significantly (P = .047) predicted 22% of the variance in YBT-LQ CS. This study demonstrates that foot characteristics may play a role in YBT-LQ CS. The authors did not assess limb dominance in this study; therefore, the authors are unable to determine which limb would be the stance versus kicking limb. However, altered SEN and weight-bearing dorsiflexion appear to be contributing factors to YBT-LQ CS.


Origin and migration of the Alpine Iceman.
The Alpine Iceman provides a unique window into the Neolithic-Copper Age of Europe. We compared the radiogenic (strontium and lead) and stable (oxygen and carbon) isotope composition of the Iceman's teeth and bones, as well as 40Ar/39Ar mica ages from his intestine, to local geology and hydrology, and we inferred his habitat and range from childhood to adult life. The Iceman's origin can be restricted to a few valleys within approximately 60 kilometers south(east) of the discovery site. His migration during adulthood is indicated by contrasting isotopic compositions of enamel, bones, and intestinal content. This demonstrates that the Alpine valleys of central Europe were permanently inhabited during the terminal Neolithic.


Inhibitory Effects of Helianthus tuberosus Ethanol Extract on Dermatophagoides farina body-induced Atopic Dermatitis Mouse Model and Human Keratinocytes.
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by complex symptoms. To treat AD without adverse effects, alternative therapeutic agents are required. The tubers of Helianthus tuberosus L. (Jerusalem artichoke) have been used in folk remedies for diabetes and rheumatism. However, its effect on AD development remains unknown. Therefore, this study examined the inhibitory effect of H. tuberosus (HT) on AD skin symptoms using an NC/Nga mouse model and HaCaT keratinocytes. The effect of HT and associated molecular mechanisms were evaluated in Dermatophagoides farina body (Dfb)-induced AD mice and tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated HaCaT keratinocytes by ELISA, western blot, and histological analysis. Topical HT administration attenuated AD skin symptoms in Dfb-induced AD mice, with a significant reduction in the dermatitis score and production of inflammatory mediators. HT also decreased epidermal thickness and mast cell infiltration. Moreover, HT restored filaggrin expression and inhibited adhesion molecules in the mice. These effects were confirmed in vitro. Furthermore, HT suppressed the activation of NF-κB, Akt, and mitogen-activated protein kinase (MAPK) signaling pathways induced by TNF-α/IFN-γ. These results suggest that HT is a potential therapeutic agent or supplement for skin allergic inflammatory diseases such as AD.


Lifelong chronic psychosocial stress induces a proteomic signature of Alzheimer's disease in wildtype mice.
Late onset, sporadic Alzheimer's disease (AD) accounts for the vast majority of cases. Unlike familial AD, the factors that drive the onset of sporadic AD are poorly understood, although aging and stress play a role. The early onset/severity of neuropathology observed in most genetic mouse models of AD hampers the study of the role of aging and environmental factors; thus alternate strategies are necessary to understand the contributions of these factors to sporadic AD. We demonstrate that mice acquiring a low social status (subordinate) in a lifelong chronic psychosocial stress (CPS) model, accrue widespread proteomic changes in the frontal/temporal cortex during aging. To better understand the significance of these stress-induced changes, we compared the differentially expressed proteins (DEPs) of subordinate mice to those of patients at varying stages of dementia. Sixteen and fifteen DEPs upregulated in subordinate mice were also upregulated in patients with mild cognitive impairment (MCI) and AD, respectively. Six of those upregulated proteins (CPE, ERC2, GRIN2B, SLC6A1, SYN1, WFS1) were shared by subordinate mice and patients with MCI or AD. Finally, comparison with a spatially detailed transcriptomic database revealed that the superior frontal gyrus and hippocampus had the greatest overlap between mice subjected to lifelong CPS and AD patients. Overall, most of the overlapping proteins were functionally associated with enhanced NMDA receptor mediated glutamatergic signaling, an excitotoxicity mechanism known to affect neurodegeneration. These findings support the association between stress and AD progression and provide valuable insight into potential early biomarkers and protein mediators of this relationship.


Treating anxiety while minimizing abuse and dependence.
Anxiety is common and often disabling. Although effective treatments are available, the use of antianxiety medication remains controversial. Some of the controversy involves the relative benefits of psychological versus pharmacologic interventions. Much of the expressed concern, however, relates to the risks of abuse and dependence associated with standard antianxiety drugs. In some instances, concern about these risks prevents patients from receiving potentially effective treatment. In other instances, failure to recognize possible abuse and dependence results in a clinical dilemma. This presentation will address the factors involved in anxiolytic drug dependence and abuse, including patient characteristics and the pharmacologic profiles of anxiolytic drugs. Specific recommendations about how to minimize abuse and dependence through such measures as diagnostic assessment, patient education, drug selection, and treatment planning will be offered.


Contribution of Wastewater Irrigation to Soil Transmitted Helminths Infection among Vegetable Farmers in Kumasi, Ghana.
Wastewater irrigation is associated with several benefits but can also lead to significant health risks. The health risk for contracting infections from Soil Transmitted Helminths (STHs) among farmers has mainly been assessed indirectly through measured quantities in the wastewater or on the crops alone and only on a limited scale through epidemiological assessments. In this study we broadened the concept of infection risks in the exposure assessments by measurements of the concentration of STHs both in wastewater used for irrigation and the soil, as well as the actual load of STHs ova in the stool of farmers and their family members (165 and 127 in the wet and dry seasons respectively) and a control group of non-farmers (100 and 52 in the wet and dry seasons, respectively). Odds ratios were calculated for exposure and non-exposure to wastewater irrigation. The results obtained indicate positive correlation between STH concentrations in irrigation water/soil and STHs ova as measured in the stool of the exposed farmer population. The correlations are based on reinfection during a 3 months period after prior confirmed deworming. Farmers and family members exposed to irrigation water were three times more likely as compared to the control group of non-farmers to be infected with Ascaris (OR = 3.9, 95% CI, 1.15-13.86) and hookworm (OR = 3.07, 95% CI, 0.87-10.82). This study therefore contributes to the evidence-based conclusion that wastewater irrigation contributes to a higher incidence of STHs infection for farmers exposed annually, with higher odds of infection in the wet season.


Facial Erosive Pustular Dermatosis After Cosmetic Resurfacing.
Erosive pustular dermatosis (EPD) is a rare condition that typically affects actinically damaged skin of the scalp. Characterized by sterile pustules, erosions, and crusts, EPD is difficult to treat and heals slowly. The exact cause of EPD is unknown, although trauma is an inciting factor. To describe 3 women who presented with prolonged facial erosions after cosmetic resurfacing procedures, specifically fully ablative carbon dioxide laser or medium-depth chemical peel. This case series describes the clinical features, histopathological findings, laboratory results, and treatment of 3 patients with an ultimate diagnosis most consistent with facial EPD. Patients were evaluated between September 10, 2010, and May 6, 2016, in a dermatology clinic in an academic medical center. The patients were 3 women seeking diagnostic evaluation and therapeutic options for nonhealing facial erosions occurring after ablative procedures (carbon dioxide laser resurfacing or Jessner solution/trichloroacetic acid chemical peel). Histologic examination and wound culture from initial presentation as well as clinical follow-up documenting improvement with therapeutic interventions. All 3 patients were women in their 50s or 60s for whom EPD was deemed to be the best diagnosis, after infection, immunobullous disorders, and other pustular dermatoses were considered. Histologic features were nonspecific. Treatment included a combination of topical and systemic therapies, such as corticosteroids, dapsone, isotretinoin, and/or antibiotics. Watchful waiting (tincture of time) appeared to be central to the healing process. After cosmetic resurfacing, patients may develop EPD isolated to the face. As a diagnosis of exclusion that should be considered in patients who have nonhealing wounds following ablative procedures, EPD is challenging to treat and may require the use of anti-inflammatory agents. Recognizing this condition is important, especially as cosmetic procedures become more widespread.


A comprehensive meta-analysis of common genetic variants in autism spectrum conditions.
Autism spectrum conditions (ASC) are a group of neurodevelopmental conditions characterized by difficulties in social interaction and communication alongside repetitive and stereotyped behaviours. ASC are heritable, and common genetic variants contribute substantial phenotypic variability. More than 600 genes have been implicated in ASC to date. However, a comprehensive investigation of candidate gene association studies in ASC is lacking. In this study, we systematically reviewed the literature for association studies for 552 genes associated with ASC. We identified 58 common genetic variants in 27 genes that have been investigated in three or more independent cohorts and conducted a meta-analysis for 55 of these variants. We investigated publication bias and sensitivity and performed stratified analyses for a subset of these variants. We identified 15 variants nominally significant for the mean effect size, 8 of which had P values below a threshold of significance of 0.01. Of these 15 variants, 11 were re-investigated for effect sizes and significance in the larger Psychiatric Genomics Consortium dataset, and none of them were significant. Effect direction for 8 of the 11 variants were concordant between both the datasets, although the correlation between the effect sizes from the two datasets was poor and non-significant. This is the first study to comprehensively examine common variants in candidate genes for ASC through meta-analysis. While for majority of the variants, the total sample size was above 500 cases and 500 controls, the total sample size was not large enough to accurately identify common variants that contribute to the aetiology of ASC.


Exposure of iron foundry workers to polycyclic aromatic hydrocarbons: benzo(a)pyrene-albumin adducts and 1-hydroxypyrene as biomarkers for exposure.
Exposure to polycyclic aromatic hydrocarbons (PAHs) in foundry workers has been evaluated by determination of benzo(a)pyrene-serum albumin adducts and urinary 1-hydroxypyrene. Benzo(a)pyrene binding to albumin and 1-hydroxypyrene were quantitatively measured by enzyme linked immunosorbent assay (ELISA) and reverse phase high performance liquid chromatography (HPLC), respectively. 70 male foundry workers and 68 matched controls were investigated. High and low exposure groups were defined from breathing zone hygienic samples, consisting of 16 PAH compounds in particulate and gaseous phase. Mean total PAH was 10.40 micrograms/m3 in the breathing zone, and mean dust adsorbed PAH was 0.15 microgram/m. All carcinogenic PAH was adsorbed to dust. Median benzo(a)pyrene-albumin adduct concentrations (10-90% percentiles) were similar in foundry workers (smokers 0.55 (0.27-1.00) and non-smokers 0.58 (0.17-1.15)) pmol/mg albumin and age matched controls (smokers 0.57 (0.16-1.45) and non-smokers 0.70 (0.19-1.55) pmol/mg albumin). Median 1-hydroxypyrene concentrations were significantly higher (P < 0.0001) in smoking and non-smoking foundry workers (0.022 (0.006-0.075) and 0.027 (0.006-0.164)) mumol/mol creatinine than in smoking and non-smoking controls (0 (0-0.022) and 0 (0-0.010) mumol/mol creatinine). Dose-response relations between total PAH, pyrene, carcinogenic PAHs, and 1-hydroxypyrene for smokers, and polycyclic aromatic hydrocarbons adsorbed to dust for non-smokers are suggested. Exposure to PAHs adsorbed to dust showed an additive effect. There was no correlation between the concentrations of 1-hydroxypyrene and benzo(a)pyrene-albumin adducts. The change in 1-hydroxypyrene over a weekend was also studied. Friday morning median 1-hydroxypyrene concentrations were significantly higher in both smokers and non-smokers (0.021 (0-0.075) and 0.027 (0.06-0.164)) mumol/mol creatinine than Monday morning median concentrations (0.007 (0-0.021) and 0.008 (0-0.021) mumol/mol creatinine). Smoking did not affect the concentrations of 1-hydroxypyrene or benzo(a)pyrene-albumin adducts. These data suggest that 1-hydroxypyrene is a sensitive biomarker for low dose PAH exposure. Exposure to PAHs may be aetiologically related to increased risk of lung cancer in foundry workers.


Targeting Glioma Initiating Cells with A combined therapy of cannabinoids and temozolomide.
Glioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor due, at least in part, to its poor response to current anticancer treatments. These features could be explained, at least partially, by the presence within the tumor mass of a small population of cells termed Glioma Initiating Cells (GICs) that has been proposed to be responsible for the relapses occurring in this disease. Thus, the development of novel therapeutic approaches (and specifically those targeting the population of GICs) is urgently needed to improve the survival of the patients suffering this devastating disease. Previous observations by our group and others have shown that Δ9-Tetrahydrocannabinol (THC, the main active ingredient of marijuana) and other cannabinoids including cannabidiol (CBD) exert antitumoral actions in several animal models of cancer, including gliomas. We also found that the administration of THC (or of THC + CBD at a 1:1 ratio) in combination with temozolomide (TMZ), the benchmark agent for the treatment of GBM, synergistically reduces the growth of glioma xenografts. In this work we investigated the effect of the combination of TMZ and THC:CBD mixtures containing different ratios of the two cannabinoids in preclinical glioma models, including those derived from GICs. Our findings show that TMZ + THC:CBD combinations containing a higher proportion of CDB (but not TMZ + CBD alone) produce a similar antitumoral effect as the administration of TMZ together with THC and CBD at a 1:1 ratio in xenografts generated with glioma cell lines. In addition, we also found that the administration of TMZ + THC:CBD at a 1:1 ratio reduced the growth of orthotopic xenografts generated with GICs derived from GBM patients and enhanced the survival of the animals bearing these intracranial xenografts. Remarkably, the antitumoral effect observed in GICs-derived xenografts was stronger when TMZ was administered together with cannabinoid combinations containing a higher proportion of CBD. These findings support the notion that the administration of TMZ together with THC:CBD combinations - and specifically those containing a higher proportion of CBD - may be therapeutically explored to target the population of GICs in GBM.


Enhancing tissue integration in cartilage repair procedures.
Arguably, the gold standard of biological repair of articular cartilage lesions is autologous chondrocyte transplantation. Although the clinical outcomes appear to range between good and excellent in most cases, there are, nevertheless, both clinical and biological challenges that remain to improve rehabilitation and clinical outcome. One of the major biological problems relates to tissue integration of the reparative tissue into the host tissue at a predictable level. Often within a single lesion, varying degrees of integration can be observed from total integration through to non-integration as one passes through the defect. Here we briefly review some of the literature relating to this problem and include some of our own data drawn from questions we have posed about the biological nature of cartilage/cartilage integration. The nature and status of the tissue that comprises the wound lesion edge is central to tissue integration, and controlling aspects of trauma and free-radical-induced cell death together with matrix synthesis are identified as two components that require further investigation. Interestingly, there appears to be a limited ability of chondrocytes to be able to infiltrate existing cartilage matrices and even to occupy empty chondrocyte lacunae. Proliferation as a result of blunt and sharp trauma shows differential responses. As expected, blunt trauma induces a greater proliferative burst than sharp trauma and is more widespread from the lesion edge. However, in the case of sharp trauma, the basal cells enter proliferation before surface zone chondrocytes, which is not the case in blunt wounds. Regulation of these and associated processes will be necessary in order to devise strategies that can predict successful integration in biological repair procedures.


Clinical significance of the KRAS mutation.
The challenge of translational medicine is to translate very complex scientific data into the clinical setting so that medical management can be better guided towards the ultimate goal of better patient outcome. Physicians now have the opportunity to use specific biomarkers to personalize therapeutic options in various settings. Recent research has demonstrated that presence of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation may directly influence medical decisions in patients with colon and lung cancer. Use of KRAS oncogene as a selection marker for specific treatment is a good example of individualized medicine approach to cancer treatment.


Priority medicines for maternal and child health: a global survey of national essential medicines lists.
In April 2011, the World Health Organization (WHO) published a list of "priority medicines" for maternal and child health based on 1) the global burden of disease and 2) evidence of efficacy and safety. The objective of this study was to examine the occurrence of these priority medicines on national essential medicines lists. All essential medicines lists published since 1999 were selected from the WHO website collection. The most-up-to date list for each country was then selected, resulting in 89 unique country lists. Each list was evaluated for inclusion of medicines (chemical entity, concentration, and dosage form) on the Priority Medicines List. There was global variation in the listing of the Priority Medicines. The most frequently listed medicine was paracetamol, on 94% (84/89) of lists. Sodium chloride, gentamicin and oral rehydration solution were on 93% (83/89) of lists. The least frequently listed medicine was the children's antimalarial rectal artesunate, on 8% of lists (7/89); artesunate injection was on 16% (14/89) of lists. Pediatric artemisinin combination therapy, as dispersible tablets or flexible oral solid dosage form, appeared on 36% (32/89) of lists. Procaine benzylpenicillin, for treatment of pediatric pneumonia and neonatal sepsis, was on 50% (45/89) of the lists. Zinc, for treatment of diarrhoea in children, was included on only 15% (13/89) of lists. For prevention and treatment of postpartum hemorrhage in women, oxytocin was more prevalent on the lists than misoprostol; they were included on 55 (62%) and 31 (35%) of lists, respectively. Cefixime, for treatment of uncomplicated anogenital gonococcal infection in woman was on 26% (23/89) of lists. Magnesium sulfate injection for treatment of severe pre-eclampsia and eclampsia was on 50% (45/89) of the lists. The findings suggest that countries need to urgently amend their lists to provide all priority medicines as part of the efforts to improve maternal and child health.


Chemical Genetic Analysis and Functional Characterization of Staphylococcal Wall Teichoic Acid 2-Epimerases Reveals Unconventional Antibiotic Drug Targets.
Here we describe a chemical biology strategy performed in Staphylococcus aureus and Staphylococcus epidermidis to identify MnaA, a 2-epimerase that we demonstrate interconverts UDP-GlcNAc and UDP-ManNAc to modulate substrate levels of TarO and TarA wall teichoic acid (WTA) biosynthesis enzymes. Genetic inactivation of mnaA results in complete loss of WTA and dramatic in vitro β-lactam hypersensitivity in methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE). Likewise, the β-lactam antibiotic imipenem exhibits restored bactericidal activity against mnaA mutants in vitro and concomitant efficacy against 2-epimerase defective strains in a mouse thigh model of MRSA and MRSE infection. Interestingly, whereas MnaA serves as the sole 2-epimerase required for WTA biosynthesis in S. epidermidis, MnaA and Cap5P provide compensatory WTA functional roles in S. aureus. We also demonstrate that MnaA and other enzymes of WTA biosynthesis are required for biofilm formation in MRSA and MRSE. We further determine the 1.9Å crystal structure of S. aureus MnaA and identify critical residues for enzymatic dimerization, stability, and substrate binding. Finally, the natural product antibiotic tunicamycin is shown to physically bind MnaA and Cap5P and inhibit 2-epimerase activity, demonstrating that it inhibits a previously unanticipated step in WTA biosynthesis. In summary, MnaA serves as a new Staphylococcal antibiotic target with cognate inhibitors predicted to possess dual therapeutic benefit: as combination agents to restore β-lactam efficacy against MRSA and MRSE and as non-bioactive prophylactic agents to prevent Staphylococcal biofilm formation.


Juvenile granulosa cell tumors of the testis: a clinicopathologic study of 70 cases with emphasis on its wide morphologic spectrum.
The clinical and pathologic features of 70 juvenile granulosa cell tumors (JGCTs) of the testis are presented. The patients were from 30 weeks gestational age to 10 years old; 60 of 67 (90%) whose ages are known to us were 6 months old or younger. Sixty-two underwent gonadectomy, 6 wedge excision, and 2 only biopsy. Twenty-six tumors were left sided and 22 right sided. Six occurred in an undescended testis and 2 in dysgenetic gonads. The most common presentation was a testicular mass (65%), followed by an "enlarging testis" (25%). Six of 14 patients in whom it was measured had "elevated" serum α-fetoprotein (AFP), likely physiologically, and 1 had gynecomastia. The tumors measured 0.5 to 5 cm (mean, 1.7 cm; median, 1.5 cm) and were most commonly well circumscribed and typically yellow-tan; approximately 2/3 had a cystic component, whereas 1/3 were entirely solid. Microscopic examination typically showed a lobular growth, punctuated in 67 cases by variably sized and shaped follicles containing material that was basophilic (21%), eosinophilic (44%), or of both characters (35%); 3 lacked follicles. In nonfollicular areas, the tumor cells typically grew diffusely but occasionally had a corded arrangement (26%) or reticular appearance (29%). The stroma was either fibrous or fibromyxoid; hemorrhage associated with hemosiderin-laden macrophages was focally seen in 16%. The tumor cells were mostly small to medium sized with round to oval nuclei containing inconspicuous nucleoli and moderate to abundant, but occasionally scant, pale to lightly eosinophilic, sometimes vacuolated, cytoplasm; nuclear grooves were infrequent (6%). Focal columnar morphology was seen in 27% of the tumors. Mitoses were plentiful in 37%, and apoptosis was prominent in 46%. Intratubular tumor was seen in 43% and entrapped seminiferous tubules in 70%. Lymphovascular invasion was present in 2 cases, rete testis involvement in 4, and necrosis in 1. Rare features/patterns included: regressed tumor with hyalinization and prominent blood vessels (13%), papillary growth (4%), basaloid morphology (1%), spindle cell predominance (1%), microcystic foci (1%), adult granulosa cell-like (1%) patterns, and hyaline globules (1%). Inhibin (16/18), calretinin (8/9), WT1 (6/7), FOXL2 (12/12), SF-1 (12/12), and SOX9 (6/11) were positive, whereas SALL4 and glypican-3 were consistently negative in the neoplastic granulosa cells. Only 1 of 10 tumors was focally positive for α-fetoprotein. JGCT is a rare neoplasm with a wide morphologic spectrum that also occurs rarely in undescended testes and dysgenetic gonads. The solid and reticular patterns may pose diagnostic challenges, but the lobular appearance and follicular differentiation are characteristic. Immunohistochemical stains may aid in its distinction from other tumors of young male individuals, particularly yolk sac tumor, a neoplasm that peaks at a somewhat later age. Twenty-four patients with follow-up, including 4 of 6 patients treated with wedge resection/biopsy, had no evidence of disease (2 to 348 mo; mean, 83 mo; median, 61 mo). One additional patient was alive at 260 months, but the disease status is unknown. The benign clinical course of all cases of JGCT with follow-up, despite often frequent mitotic activity, supports testis sparing surgery when technically feasible.


Use of aminoglutethimide as second-line endocrine therapy in metastatic breast cancer.
Sixty-five patients with advanced breast cancer, progressive despite prior endocrine therapy in all cases and prior chemotherapy in most cases, were treated with aminoglutethimide, 250 mg four times a day. At present, 52 are evaluable for response assessment, and of these 10 (19%) showed an overall objective response, major sites of response being soft tissue and lung. A further 12 patients (23%) had stable disease during aminoglutethimide therapy, while a total of 9 patients with bone metastases reported marked relief of pain without objective evidence of response. Forty-nine patients had received prior treatment with tamoxifen, and of the 10 tamoxifen responders 4 (40%) responded to subsequent aminoglutethimide, while of the 20 tamoxifen failures only 2 (10%) responded to subsequent aminoglutethimide. Aminoglutethimide was reasonably well tolerated, although 6 patients (0%) discontinued treatment because of intolerable side effects. Six of the 10 responding patients have subsequently relapsed, with a mean duration of response of 17 weeks, but 4 continued to respond at 24, 32, 55, and 111 weeks, respectively. The median survival from the start of aminoglutethimide therapy is in excess of 41 weeks for responders and 11 weeks for nonresponders, while the median survival from first relapse is 48 months for aminoglutethimide responders and 28 months for aminoglutethimide nonresponders. These results confirm that aminoglutethimide can offer a useful alternative form of endocrine therapy for advanced breast cancer, but the response rates obtained in heavily pretreated patients are inferior to those obtained when aminoglutethimide is used earlier in sequential treatment. For optimal results, particularly in terms of quality of life, aminoglutethimide should generally be used prior to chemotherapy.


The role of traditional healers in the diagnosis and management of Burkitt lymphoma in Cameroon: understanding the challenges and moving forward.
Burkittlymphoma(BL) is the most common childhood cancer in Cameroon with a reported incidence of 3 per 100,000 children under 15 years in the Northwest region. Treatment at three Baptist mission hospitals has a recorded cure rate of over 50%. Traditional medicine(TM) is recognized by the national health system, but its scope is undefined and entraps children with BL. The aim of this study was to investigate the attitudes and practices of parents and traditional healers (TH) towards TM in children with BL in order to develop recommendations for an integrative approach and improved access to life-saving treatment for children with BL. This is a descriptive case series of children diagnosed with BL treated at Banso, Mbingo, and Mutengene Baptist Hospitals between 2003 and 2014. A questionnaire was used to obtain the following information: demographic information, religion, the rate of use of TM, reasons why guardians chose to use TM, the diagnoses made by the TH, treatment offered, and the type of payment requested, based on the accounts of patient caregivers. Data was analyzed using Center for Disease Control Epi Info 7. Three hundred eighty-seven questionnaires were completed by parents/guardians. 55% had consulted a TH, of whom 76.1% consulted the TH as first choice. Common diagnoses provided by TH included liver problem, abscess, witchcraft, poison, hernia, side pain, mushroom in the belly and toothache. Methods of management included massage, cuts, concoctions, and incantations. The fee for these services included chickens, farm tools, and cash ranging from 200FCFA (0.4USD) to 100,000FCFA(200USD). The choice of TM was based on accessibility, failed clinic/hospital attendance, recommendation of relatives, and belief in TM. TH are involved in BL management in Cameroon. TH are ignorant about BL, resulting in non-referral, and thus delay in diagnosis and treatment. Collaboration with TH could reduce late diagnosis and improve cure rates of BL and other childhood cancers.


Membrane interactions of mutated forms of the influenza fusion peptide.
We have studied a group of fusion peptides of influenza hemagglutinin in which the N-terminal amino acid, Gly (found in the wild-type peptide), has been systematically substituted with Ala, Ser, Val, or Glu. The activity of the intact hemagglutinin protein with these same substitutions has already been reported. As a measure of the extent of modulation of intrinsic membrane curvature by these peptides, we determined their effects on the polymorphic phase transition of dipalmitoleoylphosphatidylethanolamine. The wild-type peptide is the only one that, at pH 5, can substantially decrease the temperature of this transition. This is also the only form in which the intact protein promotes contents mixing in cells. The Ala and Ser mutant hemagglutinins exhibit a hemifusion phenotype, and their fusion peptides have little effect on lipid polymorphism at low pH. The two mutant proteins that are completely fusion inactive are the Val and Glu mutant hemagglutinins. The fusion peptides from these forms significantly increase the polymorphic phase transition temperature at low pH. We find that the effect of the fusion peptides on membrane curvature, as monitored by a shift in the temperature of this polymorphic phase transition, correlates better with the fusogenic activities of the corresponding protein than do measurements of the isotropic (31)P NMR signals or the ability to induce the fusion of liposomes. The inactivity of the hemagglutinin protein with the hydrophobic Val mutation can be explained by the change in the angle of membrane insertion of the helical fusion peptide as measured by polarized FTIR. Thus, the nature of the interactions of the fusion peptides with membranes can, in large part, explain the differences in the fusogenic activity of the intact protein.


Demonstration of a Coherent Electronic Spin Cluster in Diamond.
An obstacle for spin-based quantum sensors is magnetic noise due to proximal spins. However, a cluster of such spins can become an asset, if it can be controlled. Here, we polarize and readout a cluster of three nitrogen electron spins coupled to a single nitrogen-vacancy spin in diamond. We further achieve sub-nm localization of the cluster spins. Finally, we demonstrate coherent spin exchange between the species by simultaneous dressing of the nitrogen-vacancy and the nitrogen states. These results establish the feasibility of environment-assisted sensing and quantum simulations with diamond spins.


Home medicines reviews following acute coronary syndrome: study protocol for a randomized controlled trial.
Despite continual improvements in the management of acute coronary syndromes, adherence to guideline-based medications remains suboptimal. We aim to improve adherence with guideline-based therapy following acute coronary syndrome using an existing service that is provided by specifically trained pharmacists, called a Home Medicines Review. We have made two minor adjustments to target the focus of the existing service including an acute coronary syndrome specific referral letter and a training package for the pharmacists providing the service. We will be conducting a randomized controlled trial to compare the directed home medicines review service to usual care following acute coronary syndromes. All patients aged 18 to 80 years and with a working diagnosis of acute coronary syndrome, who are admitted to two public, acute care hospitals, will be screened for enrolment into the trial. Exclusion criteria will include: not being discharged home, documented cognitive decline, non-Medicare eligibility, and presence of a terminal malignancy. Randomization concealment and sequence generation will occur through a centrally-monitored computer program. Patients randomized to the control group will receive usual post-discharge care. Patients randomized to receive the intervention will be offered usual post-discharge care and a directed home medicines review at two months post-discharge. The study endpoints will be six and twelve months post-discharge. The primary outcome will be the proportion of patients who are adherent to a complete, guideline-based medication regimen. Secondary outcomes will include hospital readmission rates, length of hospital stays, changes in quality of life, smoking cessation rates, cardiac rehabilitation completion rates, and mortality. As the trial is closely based on an existing service, any improvements observed should be highly translatable into regular practice. Possible limitations to the success of the trial intervention include general practitioner approval of the intervention, general practitioner acceptance of pharmacists' recommendations, and pharmacists' ability to make appropriate recommendations. A detailed monitoring process will detect any barriers to the success of the trial. Given that poor medication persistence following acute coronary syndrome is a worldwide problem, the findings of our study may have international implications for the care of this patient group. Australian New Zealand Clinical Trials Registry ACTRN12611000452998.


Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene.
We screened 100 patients with inherited and sporadic lower motor neuron degeneration and identified three novel missense mutations in the glycyl-tRNA synthetase (GARS) gene. One mutation was in the anticodon binding domain and associated with onset in early childhood and predominant involvement of the lower limbs, thus extending the phenotype associated with GARS mutations.


Mechanisms of thyroid hormone action on the insulin-like growth factor system: all thyroid hormone effects are not growth hormone mediated.
Normal somatic growth requires that both the thyroid hormone axis and GH axis be intact. Thyroid hormone stimulates GH secretion, and many thyroid hormone actions on the insulin-like growth factor (IGF) system can be explained by this mechanism. We have previously described distinct changes in IGF binding protein (IGFBP) expression in experimental hypothyroidism in the rat; these changes could be completely corrected by thyroid hormone replacement. To see if the effects of thyroid hormone on IGFBP expression are, in fact, indirect GH effects, we rendered both newborn and adult rats hypothyroid with methimazole treatment, and investigated whether we could correct the resulting IGF and IGFBP changes with GH replacement. The prolonged high expression of serum IGFBP-2 and liver IGFBP-2 messenger RNA (mRNA) during the perinatal period in hypothyroid rat pups could not be normalized by GH therapy, although serum IGF-I values (reduced to 54% of control levels in the hypothyroid animals) were brought up to control level. In adult hypothyroid rats, serum IGF-I concentrations (51% of control levels), were increased up to 79% of control levels, but not totally corrected, by GH therapy. Reduced IGFBP-3 expression (80% of control serum and 50% of control liver mRNA levels) in adult hypothyroid animals was normalized by GH, but there was no correction of the reduced IGFBP-4 serum levels (50% of control levels). Hepatic mRNA levels for the type 1 and 2 IGF receptors were not altered by hypothyroidism, or by thyroid or GH replacement. Somatic growth in hypothyroid pups and adults was only partially corrected by GH therapy. We conclude that GH treatment of hypothyroid animals normalized serum IGF-I levels in the hypothyroid rat pup, but did not correct their prolonged IGFBP-2 expression. In the mature animal, serum IGF-I levels were partially corrected and IGFBP-3 levels were normalized by GH, but no change could be induced in the reduced serum IGFBP-4 levels. All the above changes were normalized by thyroid hormone replacement. Thus, the effects of thyroid hormone on serum IGF levels and IGFBP-3 expression seem to be mediated indirectly via GH. The effects on IGFBP-2 ontogeny, and IGFBP-4 expression in the mature animal, however, are either direct thyroid hormone effects, or mediated by some other route, independent of GH, IGFs, or IGF receptors.


Nonmedical Use of Stimulants Is Associated With Riskier Sexual Practices and Other Forms of Impulsivity.
This study sought to examine the occurrence of the nonmedical use of prescription stimulants (amphetamines and methylphenidate) in a university sample and their associated physical and mental health correlates, including potential relationships with risky sexual practices. A 156-item anonymous online survey was distributed via e-mail to a sample of 9449 university students. Current use of alcohol and drugs, psychological and physical status, and academic performance were assessed, along with questionnaire-based measures of impulsivity and compulsivity. A total of 3421 participants (59.7% female) were included in the analysis. 6.7% of the sample reported current/recent nonmedical use of prescription stimulants, while an additional 5.8% reported misuse in the past. Nonmedical use of prescription stimulants was associated with lower grade point averages, and with taking a broad range of other drugs (including alcohol, nicotine, illicit substances, and consumption of caffeinated soft drinks). Nonmedical use of stimulants was also significantly associated with impulsivity (Barratt scale), prior treatment for substance use problems, and elevated occurrence of disordered gambling, post-traumatic stress disorder, and anxiety; but not depression symptoms or binge-eating disorder (though it was associated with using drugs to lose weight). The relationship with probable attention-deficit/hyperactivity disorder (ADHD) on screening was not significant but was numerically elevated. Finally, those using nonmedical prescribed stimulants were significantly more sexually active (including at a younger age), and were less likely to use barrier contraception. Nonmedical use of prescription stimulants is common in young adults and has profound public health associations including with a profundity of other drug use (licit and illicit), certain mental health diagnoses (especially gambling, anxiety, and post-traumatic stress disorder ), worse scholastic performance, and riskier sexual practices. The majority of people with nonmedical use of prescription stimulants do not have ADHD, and its link with current ADHD symptoms was less marked than for certain other disorders. Clinicians should screen for the misuse of prescription stimulants as they may be associated with a range of problematic behaviors. Risk of diversion (which may be higher for those living in shared accommodation and those with substance use disorder history) merits careful assessment before prescribing stimulant medication.


The unique pharmacology of the scorpion alpha-like toxin Lqh3 is associated with its flexible C-tail.
The affinity of scorpion alpha-toxins for various voltage-gated sodium channels (Na(v)s) differs considerably despite similar structures and activities. It has been proposed that key bioactive residues of the five-residue-turn (residues 8-12) and the C-tail form the NC domain, whose topology is dictated by a cis or trans peptide-bond conformation between residues 9 and 10, which correlates with the potency on insect or mammalian Na(v)s. We examined this hypothesis using Lqh3, an alpha-like toxin from Leiurus quinquestriatus hebraeus that is highly active in insects and mammalian brain. Lqh3 exhibits slower association kinetics to Na(v)s compared with other alpha-toxins and its binding to insect Na(v)s is pH-dependent. Mutagenesis of Lqh3 revealed a bi-partite bioactive surface, composed of the Core and NC domains, as found in other alpha-toxins. Yet, substitutions at the five-residue turn and stabilization of the 9-10 bond in the cis conformation did not affect the activity. However, substitution of hydrogen-bond donors/acceptors at the NC domain reduced the pH-dependency of toxin binding, while retaining its high potency at Drosophila Na(v)s expressed in Xenopus oocytes. Based on these results and the conformational flexibility and rearrangement of intramolecular hydrogen-bonds at the NC domain, evident from the known solution structure, we suggest that acidic pH or specific mutations at the NC domain favor toxin conformations with high affinity for the receptor by stabilizing the bound toxin-receptor complex. Moreover, the C-tail flexibility may account for the slower association rates and suggests a novel mechanism of dynamic conformer selection during toxin binding, enabling alpha-like toxins to affect a broad range of Na(v)s.


Prevalence and clinical correlates of insomnia in adults with attention-deficit hyperactivity disorder.
To investigate the prevalence of insomnia in adults with Attention-deficit hyperactivity disorder (ADHD) and its association with clinical subtypes, current ADHD symptoms, and stimulant treatment. We obtained diagnostic information, symptom rating scales and treatment history from clinically ascertained adult ADHD patients diagnosed according to DSM-IV criteria (n = 268, mean age 38.1 years) and randomly selected population controls (n = 202, mean age 36.5 years). The Bergen Insomnia Scale (BIS) was used to measure insomnia. ADHD symptom domains were self-rated using the Adult ADHD Self-Rating Scale. Insomnia was far more frequent among adults with ADHD (66.8%) than in the population controls (28.8%) (P < 0.001). Insomnia was more common in adults with the combined subtype than in those with the inattentive subtype (79.7% and 55.6%, respectively) (P = 0.003). For self-reported current ADHD symptoms, inattention was strongly correlated to insomnia. Patients currently using stimulant treatment for ADHD reported a lower total insomnia score compared to patients without medication (P < 0.05). Insomnia was highly prevalent among adults with ADHD. The lower insomnia score in patients on current stimulant treatment suggests that stimulant treatment is not associated with worsening of insomnia symptoms in adult ADHD patients.


Human telomeres and telomere biology disorders.
Telomeres consist of long nucleotide repeats and a protein complex at chromosome ends essential for chromosome stability. Telomeres shorten with each cell division and thus are markers of cellular age. Dyskeratosis congenita (DC) is a cancer-prone inherited bone marrow failure syndrome caused by germ-line mutations in key telomere biology genes that result in extremely short telomeres. The triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia is diagnostic of DC but highly variable. Patients with DC may also have but numerous other medical problems, including pulmonary fibrosis, liver abnormalities, avascular necrosis of the hips, and stenosis of the esophagus, lacrimal ducts, and/or urethra. All modes of inheritance have been reported in DC and de novo mutations are common. Broad phenotypic heterogeneity occurs within DC. Clinically severe variants of DC are Hoyeraal-Hreidarsson syndrome and Revesz syndrome. Coats plus syndrome joined the spectrum of DC with the discovery that it is caused by mutations in a telomere-capping gene. Less clinically severe variants, such as subsets of apparently isolated aplastic anemia or pulmonary fibrosis, have also been recognized. These patients may not have the DC-associated mucocutaneous triad or complicated medical features, but they do have the same underlying genetic etiology. This has led to the use of the descriptive term telomere biology disorder (TBD). This chapter will review the connection between telomere biology and human disease through the examples of DC and its related TBDs.


Complementary and alternative medicine use among outpatients during the 2015 MERS outbreak in South Korea: a cross-sectional study.
The 2015 MERS outbreak in South Korea was the largest event outside of the Middle East. Under such circumstances, individuals tend to resort to non-conventional solutions such as complementary and alternative medicine (CAM) to manage health. Thus, this study aims to examine characteristics of CAM use among outpatients in a community hospital setting during the 2015 MERS outbreak and to assess potential predictors of CAM use during the epidemic. A cross-sectional study was conducted among 331 patients (response rate: 82.75%) at a community hospital located in Seoul, South Korea. The survey instrument included 36 questions on the use of CAM, demographic characteristics, health status, and respondents' perceptions and concerns about MERS infection. Chi-square test and logistic regression were conducted for data analysis using SPSS ver. 21.0., and a p-value of less than 0.05 was considered statistically significant for all analyses. 76.1% of respondents used one or more types of CAM modalities during the MERS outbreak. Consumption of easily accessible modalities such as multivitamin (51.2%) and food products (32.1%) was most popular, and the majority of CAM users relied on mass media (52.4%) and the internet (27.4%) to obtain information on CAM. The use of CAM was associated with age between 40 and 49, age over 50, prior CAM use, and dissatisfaction with the government response to the MERS outbreak. CAM was commonly used by outpatients during the 2015 MERS outbreak in Korea, and mass media was the main source of information. Establishing a media platform is of paramount importance to provide reliable information and ensure the safety of its use.


Multi-sensor super-resolution for hybrid range imaging with application to 3-D endoscopy and open surgery.
In this paper, we propose a multi-sensor super-resolution framework for hybrid imaging to super-resolve data from one modality by taking advantage of additional guidance images of a complementary modality. This concept is applied to hybrid 3-D range imaging in image-guided surgery, where high-quality photometric data is exploited to enhance range images of low spatial resolution. We formulate super-resolution based on the maximum a-posteriori (MAP) principle and reconstruct high-resolution range data from multiple low-resolution frames and complementary photometric information. Robust motion estimation as required for super-resolution is performed on photometric data to derive displacement fields of subpixel accuracy for the associated range images. For improved reconstruction of depth discontinuities, a novel adaptive regularizer exploiting correlations between both modalities is embedded to MAP estimation. We evaluated our method on synthetic data as well as ex-vivo images in open surgery and endoscopy. The proposed multi-sensor framework improves the peak signal-to-noise ratio by 2 dB and structural similarity by 0.03 on average compared to conventional single-sensor approaches. In ex-vivo experiments on porcine organs, our method achieves substantial improvements in terms of depth discontinuity reconstruction.


Optical isolation of portions of a wave front.
A criterion is established for determining when portions of a wave front can be said to be optically isolated from the rest of the wave front in the sense that they can subsequently be treated separately when one is considering the formation of images. The subarea of the wave front is treated as a separate aperture, and it is said to be isolated if diffraction maxima for the majority of the wave front fall at or beyond the first minima for the subarea. An illustrative example employing two circular unequal-diameter apertures is presented. A method is given for identifying portions of wave front that may be optically isolated; the method uses the technique of fitting a reference surface to the actual wave front and then finding what is defined as the differential deflection of the actual surface with respect to the reference surface at all locations. Subpopulations of locations with similar differential deflection values, sufficient numbers, and sufficient differential deflection are candidates for area of optical isolation.


Oxygen consumption and usage during physical exercise: the balance between oxidative stress and ROS-dependent adaptive signaling.
The complexity of human DNA has been affected by aerobic metabolism, including endurance exercise and oxygen toxicity. Aerobic endurance exercise could play an important role in the evolution of Homo sapiens, and oxygen was not important just for survival, but it was crucial to redox-mediated adaptation. The metabolic challenge during physical exercise results in an elevated generation of reactive oxygen species (ROS) that are important modulators of muscle contraction, antioxidant protection, and oxidative damage repair, which at moderate levels generate physiological responses. Several factors of mitochondrial biogenesis, such as peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), mitogen-activated protein kinase, and SIRT1, are modulated by exercise-associated changes in the redox milieu. PGC-1α activation could result in decreased oxidative challenge, either by upregulation of antioxidant enzymes and/or by an increased number of mitochondria that allows lower levels of respiratory activity for the same degree of ATP generation. Endogenous thiol antioxidants glutathione and thioredoxin are modulated with high oxygen consumption and ROS generation during physical exercise, controlling cellular function through redox-sensitive signaling and protein-protein interactions. Endurance exercise-related angiogenesis, up to a significant degree, is regulated by ROS-mediated activation of hypoxia-inducible factor 1α. Moreover, the exercise-associated ROS production could be important to DNA methylation and post-translation modifications of histone residues, which create heritable adaptive conditions based on epigenetic features of chromosomes. Accumulating data indicate that exercise with moderate intensity has systemic and complex health-promoting effects, which undoubtedly involve regulation of redox homeostasis and signaling.


In vivo muscle fibre behaviour during counter-movement exercise in humans reveals a significant role for tendon elasticity.
Six men performed a single ankle plantar flexion exercise in the supine position with the maximal effort with counter movement (CM, plantar flexion preceded by dorsiflexion) and without counter movement (NoCM, plantar flexion only) produced by a sliding table that controlled applied load to the ankle (40 % of the maximal voluntary force). The reaction force at the foot and ankle joint angle were measured using a force plate and a goniometer, respectively. From real-time ultrasonography of the gastrocnemius medialis muscle during the movement, the fascicle length was determined. The estimated peak force, average power, and work at the Achilles' tendon during the plantar flexion phase in CM were significantly greater than those in NoCM. In CM, in the dorsiflexion phase, fascicle length initially increased with little electromyographic activity, then remained constant while the whole muscle-tendon unit lengthened, before decreasing in the final plantar flexion phase. In NoCM, fascicle length decreased throughout the movement and the fascicle length at the onset of movement was longer than that of the corresponding phase in CM. It was concluded that during CM muscle fibres optimally work almost isometrically, by leaving the task of storing and releasing elastic energy for enhancing exercise performance to the tendon.


Chemically Functionalized Conjugated Oligoelectrolyte Nanoparticles for Enhancement of Current Generation in Microbial Fuel Cells.
Water-soluble conjugated oligoelectrolyte nanoparticles (COE NPs), consisting of a cage-like polyhedral oligomeric silsesquioxanes (POSS) core equipped at each end with pendant groups (oligo(p-phenylenevinylene) electrolyte, OPVE), have been designed and demonstrated as an efficient strategy in increasing the current generation in Escherichia coli microbial fuel cells (MFCs). The as-prepared COE NPs take advantage of the structure of POSS and the optical properties of the pendant groups, OPVE. Confocal laser scanning microscopy showed strong photoluminescence of the stained cells, indicating spontaneous accumulation of COE NPs within cell membranes. Moreover, the electrochemical performance of the COE NPs is superior to that of an established membrane intercommunicating COE, DSSN+ in increasing current generation, suggesting that these COE NPs thus hold great potential to boost the performance of MFCs.


Testosterone reduces functional connectivity during the 'Reading the Mind in the Eyes' Test.
Women on average outperform men in cognitive-empathic abilities, such as the capacity to infer motives from the bodily cues of others, which is vital for effective social interaction. The steroid hormone testosterone is thought to play a role in this sexual dimorphism. Strikingly, a previous study shows that a single administration of testosterone in women impairs performance on the 'Reading the Mind in Eyes' Test (RMET), a task in which emotions have to be inferred from the eye-region of a face. This effect was mediated by the 2D:4D ratio, the ratio between the length of the index and ring finger, a proxy for fetal testosterone. Research in typical individuals, in individuals with autism spectrum conditions (ASC), and in individuals with brain lesions has established that performance on the RMET depends on the left inferior frontal gyrus (IFG). Using functional magnetic resonance imaging (fMRI), we found that a single administration of testosterone in 16 young women significantly altered connectivity of the left IFG with the anterior cingulate cortex (ACC) and the supplementary motor area (SMA) during RMET performance, independent of 2D:4D ratio. This IFG-ACC-SMA network underlies the integration and selection of sensory information, and for action preparation during cognitive empathic behavior. Our findings thus reveal a neural mechanism by which testosterone can impair emotion-recognition ability, and may link to the symptomatology of ASC, in which the same neural network is implicated.


Focus issue: noncoding RNAs in cancer.
Through various means, noncoding RNAs regulate the expression of genes, many of which are associated with cellular homeostasis. Noncoding RNAs--especially microRNAs--are critical regulators of the mechanisms underlying numerous processes in cell biology, particularly those involved in the development and progression of cancer. This special issue of Science Signaling sheds light on the physiological and pathophysiological functions of this distinct class of molecules.


Seeking out SARI: an automated search of electronic health records.
The definition of severe acute respiratory infection (SARI) - a respiratory illness with fever and cough, occurring within the past 10 days and requiring hospital admission - has not been evaluated for critically ill patients. Using integrated electronic health records data, we developed an automated search algorithm to identify SARI cases in a large cohort of critical care patients and evaluate patient outcomes. We conducted a retrospective cohort study of all admissions to a medical intensive care unit from August 2009 through March 2016. Subsets were randomly selected for deriving and validating a search algorithm, which was compared with temporal trends in laboratory-confirmed influenza to ensure that SARI was correlated with influenza. The algorithm was applied to the cohort to identify clinical differences for patients with and without SARI. For identifying SARI, the algorithm (sensitivity, 86.9%; specificity, 95.6%) outperformed billing-based searching (sensitivity, 73.8%; specificity, 78.8%). Automated searching correlated with peaks in laboratory-confirmed influenza. Adjusted for severity of illness, SARI was associated with more hospital, intensive care unit and ventilator days but not with death or dismissal to home. The search algorithm accurately identified SARI for epidemiologic study and surveillance.


Seasonal and geographic differences in treatment-seeking and household cost of febrile illness among children in Malawi.
Households in malaria endemic countries experience considerable costs in accessing formal health facilities because of childhood malaria. The Ministry of Health in Malawi has defined certain villages as hard-to-reach on the basis of either their distance from health facilities or inaccessibility. Some of these villages have been assigned a community health worker, responsible for referring febrile children to a health facility. Health facility utilization and household costs of attending a health facility were compared between individuals living near the district hospital and those in hard-to-reach villages. Two cross-sectional household surveys were conducted in the Chikhwawa district of Malawi; one during each of the wet and dry seasons. Half the participating villages were located near the hospital, the others were in areas defined as hard-to-reach. Data were collected on attendance to formal health facilities and economic costs incurred due to recent childhood febrile illness. Those living in hard-to-reach villages were less likely to attend a formal health facility compared to those living near the hospital (Dry season: OR 0.35, 95%CI0.18-0.67; Wet season: OR 0.46, 95%CI0.27-0.80). Analyses including community health workers (CHW) as a source of formal health-care decreased the strength of this relationship, and suggested that consulting a CHW may reduce attendance at health facilities, even if indicated. Although those in hard-to-reach villages were still less likely to attend in both the dry (OR 0.53, 95%CI 0.25-1.11) and wet (OR 0.60, 95%CI 0.37-0.98) seasons. Household costs for those who attended a health facility were greater for those in HTR villages (Dry: USD5.24; Wet: USD5.60) than for those living near the district hospital (Dry: USD3.45; Wet: USD4.46). Those living in hard-to-reach areas were less likely to attend a health facility for a childhood febrile event and experienced greater associated household costs. Consulting CHWs was infrequent, but appeared to reduce attendance at a health facility, even when indicated. Health service planners must consider geographic and financial barriers to accessing public health facilities in designing appropriate interventions.


A method for treating wastewater containing formaldehyde.
Many industrial activities utilise formaldehyde as a key chemical in organic synthesis including: synthesis of special chemicals such as pentaerythritol and ethylene glycol, synthetic resins, paper products, medicinal products and drugs and others, too numerous to mention. Therefore, effluents arising from these applications may contain significant amounts of formaldehyde. In a biodegradation experiments of a wastewater sample containing formaldehyde ranging from 31.5 to 125 mg/l, residual formalin (a solution of formaldehyde gas in water) ranging from 40% to 85%, respectively, was found at the end of the run (16 d) showing the inhibition effect of formalin which increased with the increase in formalin concentration. The biodegradation of formalin decreased significantly at concentrations higher than 300 mg/l. A method to convert formaldehyde to an easily biodegradable substance is herein described. In the commercial manufacture of resins from phenol and formalin the reaction is never completely quantitative. As a result during the dehydration stage phenol and formalin are distilled from the wastewater. Phenol is toxic to several biochemical reactions. However, biological transformation of phenol to a non-toxic entity is possible through specialized microbes. Transformation of phenol is inhibited by the presence of formaldehyde. Biotransformation of phenol in a wastewater containing high concentrations of formaldehyde started shortly after treating the wastewater with calculated amounts of sodium sulphite. Sodium sulphite is believed to react with formaldehyde forming sodium formaldehyde bisulphite, which is not only non-toxic to microorganisms but also a biodegradable substance. From the DO measurements before and after the addition of sodium sulphite, the authors noticed that the dissolved oxygen in a wastewater containing formaldehyde is not affected by the addition of the calculated amount of sodium sulphite, which is just enough to consume the measured amount of formaldehyde in that wastewater.


Effect of dibenzopyrene measurement on assessing air quality in Beijing air and possible implications for human health.
Size fractionated particulate matter (PM) was collected in summer and winter from Beijing, China for the characterization of an expanded list of PAHs and evaluation of air pollution metrics. Summertime ΣPAHs on PM was 14.6 ± 29(PM 1.5), 0.88 ± 0.49(PM 1.5-7.2) and 0.29 ± 0.076(PM 7.2) ng m(-3) air while wintertime concentrations were 493 ± 206(PM 1.5), 26.7 ± 14(PM 1.5-7.2) and 5.3 ± 2.5(PM 7.2) ng m(-3) air. Greater than 90% of the carcinogenic PAHs were concentrated on PM(1.5). Dibenzopyrene isomers made up a significant portion (∼30%) of the total carcinogenic PAH load during the winter. To our knowledge, this is the first report of dibenzopyrenes in the Beijing atmosphere and among the few studies that report these highly potent PAHs in ambient particulate matter. Lifetime risk calculations indicated that 1 out of 10,000 to over 6 out of 100 Beijing residents may have an increased risk of lung cancer due to PAH concentration. Over half of the lifetime risk was attributed to Σdibenzopyrenes. The World Health Organization and Chinese daily PM(10) standard was exceeded on each day of the study, however, PAH limits were only exceeded during the winter. The outcomes of the air pollution metrics were highly dependent on the individual PAHs measured and seasonal variation.


Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8(+) T cells and activating Foxp3(+) regulatory T cells.
Allergic contact dermatitis is the most frequent occupational disease in industrialized countries. It is caused by CD8(+) T cell-mediated contact hypersensitivity (CHS) reactions triggered at the site of contact by a variety of chemicals, also known as weak haptens, present in fragrances, dyes, metals, preservatives, and drugs. Despite the myriad of potentially allergenic substances that can penetrate the skin, sensitization is relatively rare and immune tolerance to the substance is often induced by as yet poorly understood mechanisms. Here we show, using the innocuous chemical 2,4-dinitrothiocyanobenzene (DNTB), that cutaneous immune tolerance in mice critically depends on epidermal Langerhans cells (LCs), which capture DNTB and migrate to lymph nodes for direct presentation to CD8(+) T cells. Depletion and adoptive transfer experiments revealed that LCs conferred protection from development of CHS by a mechanism involving both anergy and deletion of allergen-specific CD8(+) T cells and activation of a population of T cells identified as ICOS(+)CD4(+)Foxp3(+) Tregs. Our findings highlight the critical role of LCs in tolerance induction in mice to the prototype innocuous hapten DNTB and suggest that strategies targeting LCs might be valuable for prevention of cutaneous allergy.


A decision framework for coordinating bioterrorism planning: lessons from the BioNet program.
Effective disaster preparedness requires coordination across multiple organizations. This article describes a detailed framework developed through the BioNet program to facilitate coordination of bioterrorism preparedness planning among military and civilian decision makers. The authors and colleagues conducted a series of semistructured interviews with civilian and military decision makers from public health, emergency management, hazardous material response, law enforcement, and military health in the San Diego area. Decision makers used a software tool that simulated a hypothetical anthrax attack, which allowed them to assess the effects of a variety of response actions (eg, issuing warnings to the public, establishing prophylaxis distribution centers) on performance metrics. From these interviews, the authors characterized the information sources, technologies, plans, and communication channels that would be used for bioterrorism planning and responses. The authors used influence diagram notation to describe the key bioterrorism response decisions, the probabilistic factors affecting these decisions, and the response outcomes. The authors present an overview of the response framework and provide a detailed assessment of two key phases of the decision-making process: (1) pre-event planning and investment and (2) incident characterization and initial responsive measures. The framework enables planners to articulate current conditions; identify gaps in existing policies, technologies, information resources, and relationships with other response organizations; and explore the implications of potential system enhancements. Use of this framework could help decision makers execute a locally coordinated response by identifying the critical cues of a potential bioterrorism event, the information needed to make effective response decisions, and the potential effects of various decision alternatives.


Histone deacetylase 1 and p300 can directly associate with chromatin and compete for binding in a mutually exclusive manner.
Lysine acetyltransferases (KATs) and histone deacetylases (HDACs) are important epigenetic modifiers and dynamically cycled on active gene promoters to regulate transcription. Although HDACs are recruited to gene promoters and DNA hypersensitive sites through interactions with DNA binding factors, HDAC activities are also found globally in intergenic regions where DNA binding factors are not present. It is suggested that HDACs are recruited to those regions through other distinct, yet undefined mechanisms. Here we show that HDACs can be directly recruited to chromatin in the absence of other factors through direct interactions with both DNA and core histone subunits. HDACs interact with DNA in a non-sequence specific manner. HDAC1 and p300 directly bind to the overlapping regions of the histone H3 tail and compete for histone binding. Previously we show that p300 can acetylate HDAC1 to attenuate deacetylase activity. Here we have further mapped two distinct regions of HDAC1 that interact with p300. Interestingly, these regions of HDAC1 also associate with histone H3. More importantly, p300 and HDAC1 compete for chromatin binding both in vitro and in vivo. Therefore, the mutually exclusive associations of HDAC1/p300, p300/histone, and HDAC1/histone on chromatin contribute to the dynamic regulation of histone acetylation by balancing HDAC or KAT activity present at histones to reorganize chromatin structure and regulate transcription.


Genes regulating the remote wing margin enhancer in the Drosophila cut locus.
The mechanisms that allow enhancers to activate promoters from thousands of base pairs away are disrupted by the suppressor of Hairy-wing protein (SUHW) of Drosophila. SUHW binds a DNA sequence in the gypsy retrotransposon and prevents enhancers promoter-distal to a gypsy insertion in a gene from activating without affecting promoter-proximal enhancers. Several observations indicate that SUHW does not affect enhancer-binding activators. Instead, SUHW may interfere with factors that structurally facilitate interactions between an enhancer and promoter. To identify putative enhancer facilitators, a screen for mutations that reduce activity of the remote wing margin enhancer in the cut gene was performed. Mutations in scalloped, mastermind, and a previously unknown gene, Chip, were isolated. A TEA DNA-binding domain in the Scalloped protein binds the wing margin enhancer. Interactions between scalloped, mastermind and Chip mutations indicate that mastermind and Chip act synergistically with scalloped to regulate the wing margin enhancer. Chip is essential and also affects expression of a gypsy insertion in Ultrabithorax. Relative to mutations in scalloped or mastermind, a Chip mutation hypersensitizes the wing margin enhancer in cut to gypsy insertions. Therefore, Chip might encode a target of SUHW enhancer-blocking activity.


Psychometric properties of the 25-item NEI-VFQ in a Hispanic population: Proyecto VER.
To assess the psychometric properties of the NEI-VFQ-25 in a population-based study of older Hispanic persons living in the United States, explore other demographic factors that affect participant response, and observe the comparability of the Spanish and English versions of the instrument. A sample of randomly selected block groups in Tucson and Nogales, Arizona, were selected for study. Participants were interviewed at home; a majority of the interviews were conducted in Spanish. The home interview included questions from the NEI-VFQ-25 and HHANES: Presenting acuity was done using ETDRS methodology, followed by a standardized eye examination by an ophthalmologist. The authors analyzed the internal consistency of the NEI-VFQ-25 responses using Cronbach's alpha coefficient and the construct validity by assessing the relationship between presenting acuity and scale scores, adjusting for age and gender. A second model was also explored to determine whether other demographic variables affected scale scores; differences in reporting between the Spanish and English versions was observed in this model, used in a subset of the population that minimized interviewer effect. Of the 4774 participants in the study, 99.7% had completed questionnaires, not completed by proxy. The highest nonresponse rate occurred in the Driving scale, with 25% of participants not driving for reasons other than problems with vision. Internal consistency was high, with Cronbach alpha ranging between 0.65 and 0.86 for scales with multiple items. Adjusting for age and gender, those with presenting acuity worse than 20/40 scored significantly lower than those with presenting acuity 20/40 or better, for all scales. The demographic variables with the most consistent association across the NEI-VFQ-25 scales were presenting acuity, income, and gender. No significant differences in reporting were found between the Spanish and English versions of the questionnaire in the subset of the population. In this study of Hispanic people age 40 years or older, the NEI-VFQ-25 was sensitive to presenting acuity and other demographic variables, such as age, gender, and income. The findings from this psychometric analysis provide evidence of the reliability and validity of some of the scales in the 25-item NEI-VFQ when used among people with a range of visual acuity level, providing other explanatory variables are also considered.


"Coming from a different place": Partnerships between consumers and health services for system change.
The aim of the current study is to explore whether and how the expectations of consumers to be "representative" influences consumers' ability to contribute to health services partnerships. Health standards call for services to partner with consumers in service development and governance. While existing research criticises the assumption that individual mental health consumers working with mental health services must be representative of consumers more broadly, research has yet to explore whether this requirement exists for consumers of other health services. Requiring individual consumers to be representative of consumers more broadly marginalises and limits consumer involvement. A qualitative, exploratory design was employed. Consumers (n = 6), clinicians (n = 7) and health managers (n = 5) were interviewed about consumer participation in health services. Data analysis was conducted through the lens of social exchange theory and informed by discursive psychological principles. The current study extends the existing literature within mental health, finding that consumers of other health services are also held responsible for representing broader communities. Data also suggested that a requirement to be representative would marginalise consumers with a passion to bring about change in health systems. The findings suggest that organisations might need a culture change so that individual consumers are not expected to be representative of consumers more broadly and that participation be made more accessible for diverse groups of consumers. Given the role that nurses might play as allies to consumers within health services, the findings of this study contribute to knowledge about the expectations placed on consumers and the ways that nurses might advocate for better partnerships.


Breast cancer patients' insurance status and residence zip code correlate with early discontinuation of endocrine therapy: An analysis of the ECOG-ACRIN TAILORx trial.
Early discontinuation is a substantial barrier to the delivery of endocrine therapies (ETs) and may influence recurrence and survival. The authors investigated the association between early discontinuation of ET and social determinants of health, including insurance coverage and the neighborhood deprivation index (NDI), which was measured on the basis of patients' zip codes, in breast cancer. In this retrospective analysis of a prospective randomized clinical trial (Trial Assigning Individualized Options for Treatment), women with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer who started ET within a year of study entry were included. Early discontinuation was calculated as stopping ET within 4 years of its start for reasons other than distant recurrence or death via Kaplan-Meier estimates. A Cox proportional hazards joint model was used to analyze the association between early discontinuation of ET and factors such as the study-entry insurance and NDI, with adjustments made for other variables. Of the included 9475 women (mean age, 55.6 years; White race, 84%), 58.0% had private insurance, whereas 11.7% had Medicare, 5.8% had Medicaid, 3.8% were self-pay, and 19.1% were treated at international sites. The early discontinuation rate was 12.3%. Compared with those with private insurance, patients with Medicaid (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.23-1.92) and self-pay patients (HR, 1.65; 95% CI, 1.25-2.17) had higher early discontinuation. Participants with a first-quartile NDI (highest deprivation) had a higher probability of discontinuation than those with a fourth-quartile NDI (lowest deprivation; HR, 1.34; 95% CI, 1.11-1.62). Patients' insurance and zip code at study entry play roles in adherence to ET, with uninsured and underinsured patients having a high rate of treatment nonadherence. Early identification of patients at risk may improve adherence to therapy. In this retrospective analysis of 9475 women with breast cancer participating in a clinical trial (Trial Assigning Individualized Options for Treatment), Medicaid and self-pay patients (compared with those with private insurance) and those in the highest quartile of neighborhood deprivation scores (compared with those in the lowest quartile) had a higher probability of early discontinuation of endocrine therapy. These social determinants of health assume larger importance with the expected increase in unemployment rates and loss of insurance coverage in the aftermath of the coronavirus disease 2019 pandemic. Early identification of patients at risk and enrollment in insurance optimization programs may improve the persistence of therapy.


Retention of alkali, alkaline earth and transition metals on an itaconic acid cation-exchange column. Eluent pH, ionic strength and temperature effects upon selectivity.
The unusual selectivity of a methylene succinic (itaconic) acid modified polymeric column was investigated for the separation of alkali, alkaline earth, transition and heavy metals employing non-chelating inorganic eluents. The retention of selected metal ions on the column was investigated with simple HNO3 eluents and eluents prepared from KNO3 and KCl salts of varying pH (adjusted using HNO3). From these studies both the effect of eluent ionic strength and pH upon retention was evaluated for the itaconic acid stationary phase. The results obtained showed that despite slow exchange kinetics causing poor efficiencies, acceptable baseline separations of selected alkaline earth and transitions could be obtained under optimum conditions (the baseline separation of Mg(II), Ca(II), Mn(II), Cd(II), Zn(II) and Co(II) was possible using a 15 mM KNO3-5 mM KCl eluent at pH 3.50 in under 25 min). The use of an simple ionic strength step gradient was shown that facilitated the addition of Pb(II) to the above group of metal ions. An investigation into the effect of temperature upon peak efficiency and retention showed increased column temperature could be used to improve the resolution of closely eluting metal ions such as Ca(II) and Sr(II) and Ca(II) and Mn(II).


Freedom from rejection and stable kidney function are excellent criteria for steroid withdrawal in tacrolimus-treated kidney transplant recipients.
This prospective, randomized, multicentre study investigated the efficacy and safety of two tacrolimus-based regimens and their potential to withdraw steroids. In total 489 patients were randomised to receive either tacrolimus and MMF (n = 243) or tacrolimus and azathioprine (n = 246) concomitantly with steroids in both treatment groups. The initial oral dose of tacrolimus was 0.2 mg/kg/day, MMF dose was 1 g/day, azathioprine was administered at 1-2 mg/day. Steroids were tapered from 20 mg/day to 5 mg/day. From month 3 onwards, steroids were withdrawn in patients who were free from steroid-resistant rejection and who had serum creatinine concentrations < 160 mumol/L. Study duration was 6 months. Patient survival at month 6 was 98.3% (Tac/MMF/S) and 98.4% (Tac/Aza/S), graft survival at 6 month was 95.0% (Tac/MMF/S) and 93.5% (Tac/Aza/S). The 6-month incidences of biopsy-proven acute rejection were 18.9% (Tac/MMF/S) compared with 26.8% (Tac/Aza/S), p = 0.038. The 6-month incidences of steroid-resistant acute rejection were 2.1% (Tac/MMF/S) and 4.9% (Tac/Aza/S), p = ns. At the end of month 3, steroid withdrawal was performed in 60.5% (Tac/MMF/S) and 48.8% (Tac/Aza/S) of patients, p < 0.01. During months 4-6, 2.7% of patients in the Tac/MMF group had a biopsy-confirmed acute rejection compared with 0.8% of patients in the Tac/Aza group. In patients who continued to receive steroids, the incidences of biopsy-proven acute rejections during months 4-6 were 3.5% (Tac/MMF/S) and 7.1% (Tac/Aza/S). At study end, the steroid-free patients had an excellent kidney function, the median serum creatinine concentration was 119.5 mumol/L (Tac/MMF) and 115.1 mumol/L (Tac/Aza); the median serum creatinine of the total study group was 130.5 mumol/L (Tac/MMF/S) and 132.8 mumol/L (Tac/Aza/S). Both tacrolimus regimens are efficacious and safe. The combination of Tacrolimus and MMF achieved a lower rejection rate and permitted a higher proportion of steroid-free patients. The overall incidence of acute rejection was low and kidney function was good.


Double outlet right ventricle: aetiologies and associations.
Double outlet right ventricle (DORV), a clinically significant congenital heart defect, occurs in 1-3% of individuals with congenital heart defects. In contrast to other major congenital heart defects, there are no systematic or comprehensive data regarding associations, aetiologies, and pathogenesis of DORV. We analysed reported cases in the medical literature to address these issues. We queried the PubMed database using key words "double outlet right ventricle" and "DORV" for case reports, epidemiologic analyses and animal studies with this cardiac anomaly. The anatomic subtype of DORV was classified according to criteria of Van Praagh. Chromosomal abnormalities were present in 61 of the 149 cases of DORV. Trisomies 13 and 18, and del 22q11 were the most commonly associated cytogenetic lesions; different anatomic subtypes of DORV were noted in trisomies 13 and 18 versus del 22q11. DORV was reported in many uncommon or rare non-chromosomal syndromes. Mutations and non-synonymous sequence variants in the CFC1 and CSX genes were the most commonly reported monogenic loci associated with DORV in humans; numerous genes are reported in murine models of DORV. Animal studies implicate maternal diabetes and prenatal exposure to ethanol, retinoids, theophylline, and valproate in DORV teratogenesis. The large number of genes associated with DORV in both humans and animal models and the different anatomic subtypes seen in specific aetiologies indicate the likelihood of several distinct pathogenetic mechanisms for DORV, including impairment of neural crest derivative migration and impairment of normal cardiac situs and looping.