bluuebunny/crossref_metadata_2025 huggingface dataset:
The additive analgesia of adrenaline in epidural blockade
Authors: Farquhar-Smith Paul
Published: October 2018

The landmark paper discussed in this chapter is ‘Adrenaline markedly improves thoracic epidural analgesia produced by a low-dose infusion of bupivacaine, fentanyl and adrenaline after major surgery’, published by Niemi and Breivik in 1998. The analgesic potential of neuraxial blockade has long been recognized. The extensive opioid receptor expression in areas germane to pain pathways gave credence to the effective clinical application of lower doses of neuraxial opioids compared with systemic administration. Preclinical data also proposed a potential spinal action of α‎2 agonists in achieving analgesia by a number of mechanisms, including a direct antinociceptive action and by reducing elution of other epidural drugs from the spinal effector site. Early clinical data failed to show a clear benefit from the addition of adrenaline to epidural infusions. Niemi and Breivik’s experiment addressed the methodological flaws of previous studies by using combinations of relatively sub-analgesic doses of each of the combined elements.
Post-operative pain
Authors: Quinlan Jane
Published: October 2018

The landmark paper discussed in this chapter, published in 2002 by Dolin et al., examines the incidence of moderate-to-severe pain and severe pain after major surgery with three analgesic techniques: intramuscular analgesia, patient-controlled analgesia, and epidural analgesia. Up until 1990, intramuscular morphine was the main form of post-operative pain control, with patient-controlled analgesia and epidural analgesia as relatively new techniques. The authors found that the mean incidence of moderate-to-severe pain was more common with intramuscular analgesia (67%) than with patient-controlled analgesia (36%) or epidural analgesia (21%), while the incidence of severe pain was similar, with the incidence of pain with intramuscular analgesia being highest (29%), followed by that associated with patient-controlled analgesia (10%) and epidural (8%). Of note, only patient-controlled analgesia and epidural achieved the Audit Commission’s 1997 standard of no more than 20% of patients experiencing severe pain, while no technique reached their 2002 standard of less than 5%.
The epidemiology of complex regional pain syndrome
Authors: Scott Naomi
Published: October 2018

The landmark paper discussed in this chapter describes a retrospective study examining the epidemiology of complex regional pain syndrome in the Dutch general population. The researchers accessed patient data by means of the Integrated Primary Care Information project, which provided a large representative sample of the general population inclusive of all ages. They found an incidence of 26.2 per 100,000 person-years from a source population of 190,902 people. In those patients diagnosed by a specialist, three contemporaneous diagnostic criteria were applied, one of which was that of the International Association for the Study of Pain (IASP). The authors demonstrated that there were marked differences in the proportions of cases fulfilling different criteria and thus highlighted problems with case diagnosis. When the 1994 IASP criteria were strictly applied, the incidence was found to be 16.8 per 100,000 person-years.
A seminal paper on the epidemiology of cancer pain
Authors: Farquhar-Smith Paul
Published: October 2018

The landmark paper discussed in this chapter is ‘Prevalence of pain in patients with cancer: A systematic review of the past 40 years’, published by van den Beuken et al. in 2007. It is not surprising that this definitive study on cancer pain prevalence is one of the most cited papers in cancer pain. Despite the extent of cancer pain literature, this paper’s 2007 publication is surprisingly recent for the first methodologically sound and major study of cancer pain prevalence. Many previous estimates lacked accuracy, and were prone to bias. What was known was that, despite apparent increasing interest in, research in, and recognition of pain in cancer patients, the prevalence of such pain was still high, even after treatment. This paper attempted to accurately quantify just how high by statistically pooling available high-quality data while avoiding the pitfalls of combining heterogeneous studies, as had plagued previous reports.
Autotomy
Authors: James Nicholas D. , Bradbury Elizabeth J.
Published: October 2018

The landmark paper discussed in this chapter is ‘Autotomy following peripheral nerve lesions: Experimental anaesthesia dolorosa’, published by Wall et al. in 1979. This paper was the culmination of a series of studies in which Wall, together with a number of colleagues, investigated the underlying causes of neuropathic pain following peripheral nerve injury. In this paper, the authors used a variety of nerve injury models to show that the extent of resultant anaesthesia combined with ectopic firing from damaged axons in nerve-end neuromas correlated with the severity of self-mutilation (termed ‘autotomy’) observed in the affected hindlimb. The authors therefore suggested that these simple models might be suitable for studies of the prevention of irritations originating from chronic lesions of peripheral nerves. Indeed, this proved to be the case, sparking the development of numerous animal models of spontaneous pain following nerve injury and spawning a new field of neuropathic pain research.
Risk factors for post-amputation pain
Authors: Phillips Tudor
Published: October 2018

The landmark paper discussed in this chapter is ‘Immediate and long-term phantom limb pain in amputees: Incidence, clinical characteristics and relationship to pre-amputation limb pain’, published by Jensen et al. in 1985. This study examined a cohort of older patients undergoing limb amputation, and carefully related pre-amputation pain to the development and nature of phantom limb pain. The authors demonstrated that a third of patients experienced pain similar to the pre-amputated limb pain immediately after amputation; patients who had experienced pre-amputation pain were more likely to experience phantom limb pain in the first 6 months after the amputation; and persistent phantom limb pain was more likely in patients who experienced stump pain after amputation. The study had clear implications for pain management but, importantly, it also demonstrated that peripheral pain, in the form of pre-amputation and stump pain, was important in determining the development and maintenance of phantom limb pain.
The chronic constriction injury model of neuropathic pain
Authors: Brown Matthew
Published: October 2018

The landmark paper discussed in this chapter is ‘A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man’, published by Bennett and Xie in 1988. This paper, in which the unilateral sciatic nerve chronic constriction injury (CCI) model was first presented, is one of the earliest and most comprehensive descriptions of a specific animal paradigm that was designed to model human neuropathic pain. The authors realized that human neuropathic pain rarely involves nerve transection but instead involves evoked changes in damaged and preserved nerve fibres. Furthermore, they systematically applied a barrage of sensory testing that demonstrated quantifiable hyperalgesia and cold allodynia reflecting some of the clinical observations of human neuropathic pain phenotype. CCI provided a high-quality template for the development of neuropathic pain models that impelled the subsequent development of other animal models striving to replicate the human condition faithfully and accurately.
Botox analgesia for neuropathic pain
Authors: Mowafak Abdelghani
Published: October 2018

The landmark paper discussed in this chapter is ‘Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain’, published by Ranoux et al. in 2008. The muscle-relaxant properties of botulinum toxin type A (BTX-A) have long been known and used therapeutically. However, BTX-A actions independent of those affecting neuromuscular function had previously only been alluded to, via the observation that BTX-A injections alleviated pain more than would have been expected through the treatment of muscle spasm alone. This paper was one of the first to specifically examine the efficacy of BTX-A in neuropathic pain and was a catalyst for further investigation into BTX-A as a novel analgesic.
DNIC and prediction of chronic post-surgical pain
Authors: Anwar Sibtain
Published: October 2018

The landmark paper discussed in this chapter is ‘Prediction of chronic post-operative pain: Pre-operative DNIC testing identifies patients at risk’, published by Yarnitsky et al. in 2008. These authors were the first to report that it was possible to predict persistent post-surgical pain (PPP) before surgery took place, through the use of a laboratory-based assessment of endogenous analgesia: diffuse noxious inhibitory controls (DNIC). Similar peripheral tissue damage at the time of surgery leads to a wide range of PPP intensities and trajectories in different patients. This is likely to be related to individual variations in central pain processing and modulation. A key mechanism in this central modulation is the endogenous analgesic system, which can be assessed via the use of the DNIC platform.
Multidisciplinary cognitive behavioural treatment for chronic pain
Authors: Newton-John Toby
Published: October 2018

The landmark paper discussed in this chapter is ‘Evaluation of a cognitive behavioural programme for rehabilitating patients with chronic pain’, published by Williams et al. in 1993. This article represents the first extensive evaluation of multidisciplinary cognitive behavioural therapy (commonly abbreviated as CBT) for chronic pain conducted in the UK. Back in 1993, evidence was accumulating in the US which supported group-based pain management programmes, but it was not clear whether those results would translate to the different pain populations found in Britain. The study used multiple domains of assessment, including psychometric measures, measures of physical function, and pain medication reduction. As the first of its kind in the UK, this remains an important study, not just for its originality, but for the rigour with which outcomes were evaluated and the novel process and outcome assessments employed.
Congenital insensitivity to pain
Authors: Singh Bhagat , Latremoliere Alban , Costigan Michael
Published: October 2018

The landmark paper discussed in this chapter is ‘Congenital insensitivity to pain. A clinical, genetic and neurophysiological study of four children from the same family’, published by D. C. Thrush in 1973. The study of patients with congenital conditions that result in pain insensitivity has been invaluable in helping define the molecular mechanisms of sensory processing. These patients share a major defining phenotype (they feel little or no pain from birth), although they often have differing subtle symptoms which belie a host of separate conditions that we have now started to recognize with the advent of molecular genetics (e.g. loss-of-function mutations in the gene encoding Nav1.7, and mutations related to nerve growth factor (NGF)); these include congenital insensitivity to pain with anhydrosis (CIPA; thought to be due to mutations in the gene encoding the NGF receptor NTRK1) and hereditary sensory and autonomic neuropathies (HSANs) such as familial dysautonomia.
Polymorphic cytochrome P450 2D6 as the responsible enzyme of activation
Authors: Cascorbi Ingolf
Published: October 2018

The landmark paper discussed in this chapter is ‘Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufI)’, published by Dayer et al. in 1988. Codeine is an old but frequently prescribed drug used for the treatment of mild-to-moderate pain. However, its use is nowadays restricted after observations of partly fatal respiratory repression in children. Codeine itself exhibits no analgesic effect, but is partly activated by O-demethylation to morphine by cytochrome P450 2D6 (CYP2D6). The identification of the polymorphic CYP2D6 as the enzyme responsible for activation was achieved by Dayer et al. in 1998 and was an important milestone contributing to the widely observed inter-individual differences of drug action and side effects of codeine. Translating the pharmacogenetics of codeine into clinical practice is currently underway in clinical trials, to identify ineffective analgesics and, in particular, avoid severe adverse events.
Pioneering use of gene therapy for pain
Authors: Biloshytsky Vadym , Cregg Roman
Published: October 2018

The landmark paper discussed in this chapter is ‘Gene therapy for pain: Results of a Phase I clinical trial’, published by Fink et al. in 2011. In this study, the first of its kind, researchers studied the efficacy and safety of a modified herpes simplex virus (HSV) vector used to deliver PENK, which encodes proenkephalin, which is cleaved into the enkephalin peptides Met-enkephalin and Leu-enkephalin, which induce analgesia by acting on opioid receptors. The development of the HSV vector was based in part on results studies in which adenovirus, adeno-associated virus, or non-viral vectors were used to overexpress genes. Overexpression of a variety of large molecules leads to a reduction in pain-related behaviour in animals. Gene therapy in the treatment of chronic pain seems to offer a promising alternative to systemic or highly invasive therapies. However, additional research is needed to determine the safety, effectiveness, and cost-efficiency of this approach.
Reconciling Practical Knowledge with Self-Deception
Authors: Marcus Eric
Published: October 2018

Is it impossible for a person to do something intentionally without knowing that she is doing it? The phenomenon of self-deceived agency might seem to show otherwise. Here the agent is not (at least in a straightforward sense) lying, yet disavows a correct description of her intentional action. This disavowal might seem expressive of ignorance. However, I show that the self-deceived agent does know what she's doing. I argue that we should understand the factors that explain self-deception as masking rather than negating the practical knowledge characteristic of intentional action. This masking takes roughly the following form: when we are deceiving ourselves about what we are intentionally doing, we don't think about our action because it's painful to do so.
Progress in ENSO prediction and predictability study
Authors: Tang Youmin , Zhang Rong-Hua , Liu Ting , Duan Wansuo , Yang Dejian , Zheng Fei , Ren Hongli , Lian Tao , Gao Chuan , Chen Dake , Mu Mu
Published: October 2018

ENSO is the strongest interannual signal in the global climate system with worldwide climatic, ecological and societal impacts. Over the past decades, the research about ENSO prediction and predictability has attracted broad attention. With the development of coupled models, the improvement in initialization schemes and the progress in theoretical studies, ENSO has become the most predictable climate mode at the time scales from months to seasons. This paper reviews in detail the progress in ENSO predictions and predictability studies achieved in recent years. An emphasis is placed on two fundamental issues: the improvement in practical prediction skills and progress in the theoretical study of the intrinsic predictability limit. The former includes progress in the couple models, data assimilations, ensemble predictions and so on, and the latter focuses on efforts in the study of the optimal error growth and in the estimate of the intrinsic predictability limit.
Self-defining Memories Predict Engagement in Structured Activity in First Episode Psychosis, Independent of Neurocognition and Metacognition
Authors: Wright Abigail C , Davies Geoff , Fowler David , Greenwood Kathryn E
Published: October 2018

Background

Self-defining memories (SDMs) are vivid personal memories, related to narrative identity. Individuals with schizophrenia report less specific, more negative, and extract less meaning from these memories compared to control groups. SDMs have been shown to be predicted by neurocognition, associated with metacognition, and linked to goal outcomes in healthy controls. As neurocognition and metacognition are known predictors of poor functioning in psychosis, SDMs may also be a predictor. No study has assessed the relationship to functioning or pattern of SDMs in first episode psychosis (FEP).

Methods

This was a cross-sectional study involving 71 individuals with FEP and 57 healthy controls who completed an SDM questionnaire. FEP participants completed measures of neurocognition, metacognition (Metacognitive Assessment Interview), functional capacity (The University of California, San Diego [UCSD] Performance-Based Skills Assessment), and functional outcome (Time-Use Survey).

Results

SDMs reported by individuals with FEP were less integrated compared to healthy controls. Within the FEP sample, holding less specific memories was associated with engagement in significantly fewer hours of structured activity per week and specificity of SDMs mediated the relationship between neurocognition and functional outcome, independent of metacognition.

Conclusion

This is the first study to assess SDMs in FEP and to explore the important role of SDMs on clinical outcomes, compared to healthy controls. This study suggests that elaborating on specific SDMs is a valid therapeutic target and may be considered a tool to improve daily functioning in FEP.
Do Information Technologies Improve Teenagers’ Sexual Education? Evidence from a Randomized Evaluation in Colombia
Authors: Chong Alberto , Gonzalez-Navarro Marco , Karlan Dean , Valdivia Martín
Published: October 2018

This study reports results from a randomized evaluation of a mandatory six-month Internet-based sexual education course implemented across public junior high schools in 21 Colombian cities. Six months after finishing the course, the study finds a 0.4 standard deviation improvement in knowledge, a 0.2 standard deviation improvement in attitudes, and a 55 percent increase in the likelihood of redeeming vouchers for condoms as a result of taking the course. The data provide no evidence of spillovers to control classrooms within treatment schools. However, the analysis provides compelling evidence that treatment effects are enhanced when a larger share of a student's friends also takes the course. The low cost of the online course along with the effectiveness the study documents suggests this technology is a viable alternative for improving sexual education in middle-income countries.
Nurse Decision Making and Attitudes About Circuit Disconnection During Ventilator Therapy at a Swedish Neonatal Intensive Care Unit
Authors: Larsson Christina , Karlsson Victoria , Blomqvist Ylva Thernström
Published: October 2018

Background:

There are many challenges to providing care to infants in need of ventilator therapy. Yet, few studies describe the practical handling of the ventilator circuit during nursing care.

Purpose:

To describe neonatal intensive care unit (NICU) nurses' decision making regarding whether or not to disconnect the ventilator circuit when changing the infant's position and to investigate the grounds for their decisions.

Methods:

A descriptive questionnaire study with both quantitative and qualitative elements was conducted. In 2015, a convenience sample of nurses working in an NICU completed a questionnaire including both closed-ended and open-ended, free-text questions. Answers to the closed-ended questions were analyzed with descriptive statistics, whereas answers to the free-text questions were analyzed using qualitative content analysis.

Results:

Nurses' decisions on whether to disconnect or keep the ventilator circuit closed were based on the infant's needs for ventilator support. The nurses gave several reasons and motivations both for why they disconnected the circuit and for why they did not. The handling of the circuit and the reasons and motivations given were inconsistent among the nurses.

Implications for Practice:

This study highlights the need for continuous, repetitive education and training for NICU nurses, as well as demonstrating the importance of clear and distinct guidelines and working methods regarding the care of infants on ventilator support.

Implications for Research:

Future research should continue to find ways of working and handling an infant on ventilator support that are least harmful to the infant.
Risk stratification in early breast cancer in premenopausal and postmenopausal women: integrating genomic assays with clinicopathological features
Authors: Sestak Ivana
Published: October 2018

Purpose of review

There is growing consensus that genomic assays provide useful complementary information to clinicopathological features in oestrogen receptor-positive breast cancers. Here, ongoing research with multigene tests used for postmenopausal breast cancer and new emerging prognostic and predictive markers for pre and postmenopausal women are summarised.

Recent findings

Results of the TAILORx trial have shown that women with an intermediate risk score do not benefit from adjuvant chemotherapy. Prosgina has been further investigated in a contemporary patient population in postmenopausal women and its use has been extended for premenopausal women. The EndoPredict was extensively used in decision-impact studies showing that its use can potentially reduce the need for adjuvant chemotherapy. Several new genomic assays have been developed, with some of them showing promising use for women with early oestrogen receptor-positive breast cancer.

New areas of research for prediction of recurrence and risk stratification involve the development of immune gene signatures that carry modest but significant prognostic value. The recent expansion of high-throughput technology platforms including circulating tumour DNA/RNA and microRNA offer new opportunities to improve prediction models, particularly in women with oestrogen receptor-negative disease and premenopausal women. Genomic assays have clearly improved prognostication of early oestrogen receptor-positive breast cancer but it is clear that standard clinicopathological parameters are still very important when identifying patient for adjuvant chemotherapy.
Impact of ovarian function suppression in premenopausal women with estrogen receptor-positive early breast cancer
Authors: Lambertini Matteo , Viglietti Giulia , de Azambuja Evandro
Published: October 2018

Purpose of review

This manuscript aims at providing an updated overview on the role of adding ovarian function suppression to tamoxifen or an aromatase inhibitor as adjuvant endocrine therapy in premenopausal women with estrogen receptor-positive early breast cancer.

Recent findings

Until recently, tamoxifen alone was the only recommended adjuvant treatment option for premenopausal women with estrogen receptor-positive disease. However, recent important evidence has contributed to significantly modify the endocrine treatment landscape in this setting.

With the only exception of patients with low-risk clinical-pathological features characterized by excellent survival outcomes with tamoxifen alone, the use of ovarian function suppression is to be considered standard of care for most of premenopausal women with estrogen receptor-positive disease. Regarding the choice of its best partner as endocrine agent, the available data suggest that the higher the risk of disease recurrence the larger benefit can be observed with a more profound estrogen deprivation that can be obtained with ovarian function suppression and an aromatase inhibitor as compared to ovarian function suppression and tamoxifen. Despite the significant improvement in our understanding on the role of ovarian function suppression in this setting, several unanswered questions remain and further research efforts are needed in the field.
Filipino Nurses' Use of Smartphones in Clinical Settings
Authors: Bautista John Robert
Published: October 2018

While previous research has examined specific ways that nurses have used smartphones for work purposes in clinical settings, large-sample quantitative studies are limited, particularly in Asia. To address this research gap, this study provided a ranking on how nurses have used their smartphones for work purposes in clinical settings and identified differences based on demographic and organizational factors. In January to June 2017, a pen-and-paper survey was administered to 517 staff nurses employed in 19 tertiary-level general hospitals in Metro Manila, Philippines. Results show that nurses frequently used their smartphones to exchange voice calls and text messages with other nurses and doctors. Results also showed that specific items reflecting the use of smartphones for communication purposes differed according to gender, age, hospital ownership, nursing area, number of patients handled in last shift, and presence of a hospital-provided mobile phone. Next, some items for information-seeking purposes differed according to highest educational attainment and years of clinical experience. Moreover, some items for documentation purposes differed according to age, hospital ownership, and number of patients handled in last shift. Overall, the results of this study can be used to guide policies on the use of smartphones in clinical settings.
Quality of Maternal Height and Weight Data from the Revised Birth Certificate and Pregnancy Risk Assessment Monitoring System
Authors: Deputy Nicholas P. , Sharma Andrea J. , Bombard Jennifer M. , Lash Timothy L. , Schieve Laura A. , Ramakrishnan Usha , Stein Aryeh D. , Nyland-Funke Michael , Mullachery Pricila , Lee Erica
Published: October 2018

Background:

The 2003 revision of the US Standard Certificate of Live Birth (birth certificate) and Pregnancy Risk Assessment Monitoring System (PRAMS) are important for maternal weight research and surveillance. We examined quality of prepregnancy body mass index (BMI), gestational weight gain, and component variables from these sources.

Methods:

Data are from a PRAMS data quality improvement study among a subset of New York City and Vermont respondents in 2009. We calculated mean differences comparing prepregnancy BMI data from the birth certificate and PRAMS (n = 734), and gestational weight gain data from the birth certificate (n = 678) to the medical record, considered the gold standard. We compared BMI categories (underweight, normal weight, overweight, obese) and gestational weight gain categories (below, within, above recommendations), classified by different sources, using percent agreement and the simple κ statistic.

Results:

For most maternal weight variables, mean differences between the birth certificate and PRAMS compared with the medical record were less than 1 kg. Compared with the medical record, the birth certificate classified similar proportions into prepregnancy BMI categories (agreement = 89%, κ = 0.83); PRAMS slightly underestimated overweight and obesity (agreement = 84%, κ = 0.73). Compared with the medical record, the birth certificate overestimated gestational weight gain below recommendations and underestimated weight gain within recommendations (agreement = 81%, κ = 0.69). Agreement varied by maternal and pregnancy-related characteristics.

Conclusions:

Classification of prepregnancy BMI and gestational weight gain from the birth certificate or PRAMS was mostly similar to the medical record but varied by maternal and pregnancy-related characteristics. Efforts to understand how misclassification influences epidemiologic associations are needed.
Maternal Thyroid Function During Pregnancy or Neonatal Thyroid Function and Attention Deficit Hyperactivity Disorder
Authors: Drover Samantha S. M. , Villanger Gro D. , Aase Heidi , Skogheim Thea S. , Longnecker Matthew P. , Zoeller R. Thomas , Reichborn-Kjennerud Ted , Knudsen Gun P. , Zeiner Pål , Engel Stephanie M.
Published: October 2018

Background:

Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in children, yet its etiology is poorly understood. Early thyroid hormone disruption may contribute to the development of ADHD. Disrupted maternal thyroid hormone function has been associated with adverse neurodevelopmental outcomes in children. Among newborns, early-treated congenital hypothyroidism has been consistently associated with later cognitive deficits.

Methods:

We systematically reviewed literature on the association between maternal or neonatal thyroid hormones and ADHD diagnosis or symptoms. We searched Embase, Pubmed, Cinahl, PsycInfo, ERIC, Medline, Scopus, and Web of Science for articles published or available ahead of print as of April 2018.

Results:

We identified 28 eligible articles: 16 studies of maternal thyroid hormones, seven studies of early-treated congenital hypothyroidism, and five studies of neonatal thyroid hormones. The studies provide moderate evidence for an association between maternal thyroid hormone levels and offspring ADHD, some evidence for an association between early-treated congenital hypothyroidism and ADHD, and little evidence for an association between neonatal thyroid hormone levels and later ADHD.

Conclusions:

The reviewed articles suggest an association between maternal thyroid function and ADHD, and possibly between early-treated congenital hypothyroidism and ADHD. Study limitations, however, weaken the conclusions in our systematic review, underlining the need for more research. Importantly, there was much variation in the measurement of thyroid hormone function and of ADHD symptoms. Recommendations for future research include using population-based designs, attending to measurement issues for thyroid hormones and ADHD, considering biologically relevant covariates (e.g., iodine intake), and assessing nonlinear dose–responses.
Attenuation of glutamatergic and nitrergic system contributes to the antidepressant-like effect induced by capsazepine in the forced swimming test
Authors: Sartim Ariandra G. , Brito Bianca M. , Gobira Pedro H. , Joca Sâmia R.L.
Published: October 2018

The transient receptor potential vanilloid 1 (TRPV1) can modulate stress-related behaviours, thus representing an interesting target for new antidepressant drugs. TRPV1 can trigger glutamate release and nitric oxide synthesis in the brain, mechanisms also involved in the neurobiology of depression. However, it is not known if these mechanisms are involved in TRPV1-induced behavioural effects. Therefore, the aim of this study was to verify if the antidepressant-like effect induced by a TRPV1 antagonist in mice submitted to the forced swimming test (FST) would be facilitated by combined treatment with neuronal nitric oxide synthase (nNOS) inhibition and N-methyl-D-aspartate (NMDA) blockade. Male Swiss mice were given (intracerebroventricular) injections of capsazepine (CPZ) (TRPV1 antagonist – 0.05/0.1/0.3/0.6 nmol/µl), and AP7 (NMDA antagonist – 1/3/10 nmol/µl) or N-propyl-l-arginine (NPA, nNOS inhibitor – 0.001/0.01/0.1 nmol/µl), and 10 min later, submitted to an open field test, and immediately afterwards, to the FST. An additional group received coadministration of CPZ and AP7 or CPZ and NPA, in subeffective doses. The results demonstrated that CPZ (0.1 nmol/µl), AP7 (3 nmol/µl) and NPA (0.01/0.1 nmol/µl) induced antidepressant-like effects. Moreover, coadministration of subeffective doses of CPZ and AP7 or CPZ and NPA induced significant antidepressant-like effects. Altogether, the data indicate that blockade of TRPV1 receptors by CPZ induces antidepressant-like effects and that both nNOS inhibition and NMDA blockade facilitate CPZ effects in the FST.
Estimation of Unbound Carboplatin Clearance From Total Plasma Concentrations as a Means of Facilitating Therapeutic Drug Monitoring
Authors: Moeung Sotheara , Chevreau Christine , Poinsignon Vianney , Guitton Jérôme , Lelièvre Bénédicte , Ciccolini Joseph , Gladieff Laurence , Massart Christophe , Fléchon Aude , Delva Rémy , Gravis Gwenaëlle , Lotz Jean-Pierre , Bay Jacques-Olivier , Gross-Goupil Marine , Delahousse Julia , Filleron Thomas , Lochon Isabelle , Chatelut Etienne , Thomas Fabienne
Published: October 2018

Background:

Therapeutic drug monitoring of carboplatin is based on its unbound clearance (CLU) determined by Bayesian analysis on unbound (U) concentrations. However, the ultrafiltration of plasma samples presents technical and time constraints. Therefore, this study aims to estimate CLU using total plasma (P) concentrations.

Methods:

U and P concentration data of 407 patients were obtained from 2 clinical studies in which actual CLU had been determined for each patient. The patients were then split into development (277 patients) and prospective data sets (130 patients). Two approaches were evaluated. PK-model-only approach: a 3-compartment pharmacokinetic (PK) model based on U and P concentrations and taking into account the protein binding process was developed. The model with patient covariates was also evaluated. Linear regression approach: an equation (CLU = aCLP + b) was obtained by linear regression analysis between actual CLU and CLP, which is the total plasma clearance obtained by analyzing P concentrations according to a 2-compartment PK model. Predictive performance was then assessed within the prospective data set by estimating CLU from P concentrations using each approach and computing the relative percentage error (PE) between estimated CLU and actual CLU.

Results:

The linear regression equation was CLU (L/h) = 1.15 CLP (L/h) + 0.13. The mean PE (MPE) between CLU (estimated using the equation) and the actual CLU was +1.2% (ranging from −31% to +33%) and the mean absolute PE (MAPE) was 9.7%. With the 3-compartment PK model, the MPE was +2.3% (ranging from −41% to +31%) and the MAPE was 11.1%. Inclusion of covariates in the 3-compartment model did not improve the estimation of CLU [MPE = +6.3% (from −33% to +37%); MAPE = 11.4%].

Conclusions:

The linear equation gives a relatively good estimation of CLU based on P concentrations, making PK-based carboplatin dose adaptation possible for centers without ultrafiltration facilities.
Pharmacodynamic Monitoring of Biological Therapies in Chronic Inflammatory Diseases
Authors: Dreesen Erwin , Gils Ann
Published: October 2018

Background:

Psoriasis, psoriatic arthritis, spondyloarthritis, rheumatoid arthritis, ulcerative colitis, and Crohn disease share similar underlying pathophysiological processes, providing the opportunity to treat the patients using similar biological therapies. Failure of biological treatments due to underexposure can be managed by therapeutic drug monitoring. Adjusting the treatment based on pharmacokinetic monitoring can be further improved by taking pharmacodynamic parameters such as clinical and molecular markers into account.

Methods:

Here, we critically evaluate the existing evidence, the hurdles to be taken, and the opportunities for a widespread implementation of pharmacodynamic monitoring.

Results:

Pharmacodynamic monitoring typically is the monitoring of biochemical markers. A pharmacodynamic marker preferably is specific for the pharmacological action of a drug, but most of the time nonspecific pharmacodynamic markers are used, such as C-reactive protein and the erythrocyte sedimentation rate. Clinical pharmacodynamic markers typically evaluate physical variables or symptoms. Although physician-reported outcomes have been studied for a longer time and often have been shown to correlate well with molecular pharmacodynamic markers and treatment outcomes, the introduction of mobile health or mHealth technologies caused a shift toward patient-reported outcomes, with the associated challenge to consistently reflect the inflammatory state, thereby preventing undertreatment or unnecessary overdosing of patients.

Conclusions:

The primary goal of pharmacodynamic monitoring is to optimize the response, but it can also have an impact on safety, costs, patient adherence, etc. Ideally, the constant remote monitoring of patient-reported disease activity is expected to become the standard, facilitated by mHealth technologies.
DOCUMENTATION OF A NEW CHOROIDAL NEVUS
Authors: Parikh Ravi , Gal-Or Orly , Sakurada Yoichi , Leong Belinda , Freund K. Bailey
Published: October 2018

Purpose:

To describe the occurrence of an acquired choroidal nevus in a 73-year-old white man.

Methods:

Case report.

Results:

A 73-year-old white man was referred for an evaluation and treatment of macular changes in his left eye consistent with pachychoroid neovasculopathy. Baseline funduscopic examination and color fundus photographs showed two small peripheral choroidal nevi in the right eye and a single small choroidal nevus in the far temporal macula of the left eye. Treatment with intravitreal aflibercept was initiated in the left eye on a treat-and-extend dosing regimen. Approximately 1 year later, a new pigmented choroidal lesion was detected in the left macula in an area where previous high-resolution color fundus photographs had shown no abnormal pigmentation. Swept-source optical coherence tomography of the new pigmented lesion showed flat hyperreflectivity within the inner choroid consistent with a small choroidal nevus. The patient was referred to his internist who found no evidence of an occult malignancy. Over the course of more than 4 additional years of continuous follow-up, the new choroidal nevus remained stable, no new fundus abnormalities were detected in either eye, and the patient remained medically stable.

Conclusion:

To the best of our knowledge, this is the first documented case of a new choroidal nevus. Multimodal imaging performed before lesion detection and over the ensuing 4 years showed its stability, thus allowing for the conclusion that it was a benign choroidal nevus rather than a neoplastic or paraneoplastic process.
Stress, Workplace Violence, and Burnout in Nurses Working in King Abdullah Medical City During Al-Hajj Season
Authors: RAYAN Ahmad , SISAN Mo’men , BAKER Omar
Published: October 2018

Background:

The Hajj pilgrimage to Mecca, one of the largest mass gatherings in the world, is associated with various challenges for nurses. One of these challenges is increased levels of workplace violence. Therefore, handling and mitigating workplace violence against nurses during Hajj, when nurses face a higher risk of violence and most experience stress and burnout, is of particular importance.

Purpose:

The aims of this study were to identify the types and sources of workplace violence, examine the relationship between burnout in nurses and the variables of stress and workplace violence, and identify from the perspective of nurses measures to effectively handle and mitigate these issues during Hajj season.

Methods:

This study used a descriptive correlational design. A convenience sample of 118 nurses completed the Perceived Stress Scale, the Maslach Burnout Inventory, and the modified version of the Joint Programme on Workplace Violence in the Health Sector published by the International Labour Office in Geneva. Data analysis was done using an independent samples t test and Pearson product–moment correlation.

Results:

One hundred eighteen nurses completed the study. Over two thirds (65%) were female, and 56% reported experiencing at least one type of violence, of which bullying/mobbing, racial harassment, threats, and physical violence accounted for 61%, 15%, 12%, and 12%, respectively. Nurse managers displayed violent behaviors against 54% of the participants. Participants reported high levels of stress and burnout. A positive relationship was found between stress and emotional exhaustion (r = .387, p < .01). Providing effective security measures and staff training regarding how to deal with violence at the workplace were the main measures identified to help reduce workplace violence.

Conclusions:

Providing effective security measures and tailored intervention programs addressing how to deal with violence in the workplace may enable nurses to handle violent behaviors more effectively.
Analgesic effects of the cathepsin K inhibitor L-006235 in the monosodium iodoacetate model of osteoarthritis pain
Authors: Nwosu Lilian N. , Gowler Peter R.W. , Burston James J. , Rizoska Biljana , Tunblad Karin , Lindström Erik , Grabowska Urszula , Li Li , McWilliams Dan F. , Walsh David A. , Chapman Victoria
Published: October 2018

Introduction:

The mounting evidence that osteoclasts play an important role in osteoarthritis (OA) pain lead us to investigate the effects of L-006235, a potent and selective inhibitor of cathepsin K, on pain behaviour and joint pathology in a model of OA pain.

Methods:

Effects of preventative (30 and 100 mg/kg) and therapeutic (100 mg/kg) oral dosing with L-006235 on weight-bearing asymmetry, hind paw withdrawal thresholds, cartilage and bone pathology, synovial inflammation, and drug exposure were studied in the monosodium iodoacetate rat model of OA pain.

Results:

Preventative L-006235 inhibited weight-bearing asymmetry from day 14, with this measure nearly abolished by the higher dose. In the same treatment setting, L-006235 prevented lowering of hind paw withdrawal thresholds from day 7. Exposure to L-006235 in plasma was higher for the 100 mg/kg dose, compared with 30 mg/kg. Therapeutic dosing with L-006235 from day 14 significantly inhibited weight-bearing asymmetry, compared with monosodium iodoacetate vehicle rats. Regression analysis revealed a significant interaction coefficient of the effects of L-006235 on weight-bearing asymmetry and synovitis score, but not for cartilage damage nor osteophyte scores.

Conclusion:

Our novel finding that cathepsin K inhibition is analgesic in a clinically relevant model of OA pain provides new evidence for the therapeutic potential of this target.
The ideal patient profile for new beta-lactam/beta-lactamase inhibitors
Authors: Montravers Philippe , Bassetti Matteo
Published: October 2018

Purpose of review

The worldwide spread of extended-spectrum beta-lactamase (ESBL)-producing bacteria, the overuse of carbapenems, the emergence of carbapenemase-producing organisms and the growing importance of multidrug-resistant and/or extended drug-resistant strains have totally changed prescribers’ habits, leading to very few treatment options in many cases. Beta-lactam/beta-lactamase inhibitor (BLBLI) combinations should be considered as an alternative to carbapenems for treating ESBL-producing bacteria and Pseudomonas aeruginosa infections. The purpose of this study was to provide insight concerning the patients who would constitute ideal candidates to receive these new BLBLI combinations.

Recent findings

Ceftolozane/tazobactam and ceftazidime/avibactam are the first drugs constituting the use of new beta-lactamase inhibitors. Ceftolozane/tazobactam is the drug of choice for treating MDR/XDR P. aeruginosa infections. Ceftazidime/avibactam is the best drug available for treating KPC and OXA-48 carbapenemase-producing Enterobacteriaceae. Ceftolozane/tazobactam and ceftazidime/avibactam are both carbapenem-sparing agents for treating ESBL-producing Enterobacteriaceae. The role of carbapenem/inhibitors remains to be clarified.

Each BLBLI combination has distinctive specificities and limitations that need to be investigated cautiously. Randomized trials will play a key role in defining the best strategies. Infection control measures and prompt diagnosis remain fundamental to prevent dissemination of MDR pathogens in healthcare settings and to optimize early antimicrobial treatment.
Antifungal stewardship: developments in the field
Authors: Urbancic Karen F. , Thursky Karin , Kong David C.M. , Johnson Paul D.R. , Slavin Monica A.
Published: October 2018

Purpose of review

To outline key drivers and components of antifungal stewardship (AFS) programmes, the evidence for specific interventions, and methods to assess performance of programmes.

Recent findings

Recent developments in antifungal resistance and breakthrough invasive fungal diseases have increased the urgency for effective AFS. In practice, however, few hospitals have dedicated AFS programmes. To date, AFS programmes have centred around the provision of expert bedside reviews and have reduced costs and consumption of antifungal agents. Incorporating tools such as fungal diagnostics and therapeutic drug monitoring into AFS programme models is recommended. However, the application and impact of these tools in this context have not been adequately assessed. The effectiveness of AFS programmes has been measured in multiple ways but a standardized method of evaluation remains elusive. Few studies have explored the impact of AFS interventions on patient outcomes.

The uptake of formal AFS programmes has been slow. New initiatives integrating AFS tools in programmes, and measuring the impacts on patient outcomes are required given such data are not readily available. A comprehensive approach to evaluate AFS programmes by correlating the quantity and quality of antifungal prescribing with impacts on patient outcomes is needed. Consensus definitions for core AFS metrics are required to benchmark performance and are essential to the resourcing and sustainability of these programmes.
Whole-Exome Sequencing of Adult and Pediatric Cohorts of the Rare Vascular Disorder Systemic Capillary Leak Syndrome
Authors: Pierce Richard , Ji Weizhen , Chan Eunice C. , Xie Zhihui , Long Lauren M. , Khokha Mustafa , Lakhani Saquib , Druey Kirk M.
Published: October 2018

Objective:

Systemic capillary leak syndrome (SCLS) is a rare disorder that presents with episodes of hypovolemic shock. The extent to which genetic abnormalities contribute to SCLS is unknown. We identified pediatric and adult cohorts with characteristic clinical courses. We sought to describe the clinical characteristics of both cohorts, identify a possible genetic contribution to SCLS, and demonstrate that whole-exome sequencing (WES) may be conducted by critical care providers.

Design:

Prospective observational study of WES of nine adult and eight pediatric SCLS patients and available unaffected first-degree relatives.

Setting:

Tertiary children's hospitals and referral research laboratory.

Patients:

Children and adults with SCLS.

Interventions:

None.

Measurements:

Patients and available first-degree relatives underwent WES. Data were analyzed for rare homozygous, biallelic, de novo, and heterozygous variants with allelic enrichment and metabolic pathway analyses.

Main Results:

Children with SCLS presented at a younger age with episodes similar to those experienced by adults. All patients and available relatives underwent satisfactory WES. No overlapping gene variants or metabolic pathways were identified across all SCLS patients. Multiple candidate genes with homozygous or biallelic mutations were identified in individual subjects with SCLS. There was no significant enrichment of genes with rare heterozygous variants.

Conclusions:

The clinical characteristics of children and adults with SCLS are similar. We did not identify a uniform germline exomic genetic etiology for SCLS. WES identified several candidate genes in individual patients for future research. WES is a viable way for critical care providers to investigate the etiology of diseases with presumed genetic contributions.