Search

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility; however, whether women with PCOS and spontaneous or drug-induced ovulatory cycles have the same reproductive potential as non-PCOS controls is a matter of debate. In the present opinion paper, the author takes the opportunity to summarize the collective evidence supporting the hypothesis of reduced fertility potential in women with PCOS, regardless of ovulatory status, and speculate that reduced reproductive potential may be caused by altered oocytes, embryo and endometrial competence, and infertility-related co-morbidities as well as an increased risk of pregnancy complications. [ABSTRACT FROM AUTHOR]

To determine the safety of hydromorphone delivered by continuous intrathecal infusion via implanted delivery systems in sheep. Sheep implanted with intrathecal infusion systems were randomly assigned to receive either 1.5, 3, or 6 mg/day hydromorphone HCl or saline control (3 sheep/dose level) at a fixed infusion rate of 1.92 mL/day for 28–31 days. Infusions were initiated approximately 5 days after surgical implantation of the delivery systems (pumps and intrathecal catheters), and investigators were blinded to doses administered. An additional group of sheep (N=3) received hydromorphone (open label) at a dose of 12 mg/day. All animals were examined daily during drug infusion for changes in behavior and neurologic function. Cerebrospinal fluid was analyzed for protein, cytology, and hydromorphone concentration in samples collected prior to and at the end of drug infusion. The spinal cord with the catheter in situ was removed en bloc and fixed in formalin for microscopic analysis. All sheep receiving intrathecal hydromorphone exhibited gaiting deficits and biting behavior over the caudal lumbar area above the infusion site. Animals treated with 12 mg/day were sedate and lethargic, and exhibited repeated biting behavior over the caudal lumbar area during the study. No lesions were noted in any animal upon gross evaluation of the spinal cord. Microscopic changes were comparable between hydromorphone- and saline-treated animals with one exception. Mild inflammation 5 cm cranial to the catheter tip was present in two of three sheep receiving 12 mg/day and in one of three sheep receiving 1.5 mg/day. Mild chronic inflammation hydromorphone in the vicinity of the catheter was also presented in saline-treated animals. Hydromorphone was not associated with inflammatory mass formation in the sheep model. Further studies are necessary to determine whether hydromorphone is a safer alternative to morphine for continuous intrathecal infusion for the treatment of chronic pain. [ABSTRACT FROM AUTHOR]

Background Persons with HIV and tuberculosis (TB) co-infection require transaminase monitoring while on hepatotoxic medications. A novel paper-based, point-of-care transaminase test is in development at an anticipated cost of $1 per test. Methods To project long-term clinical outcomes and estimate the cost-effectiveness of using a paper-based fingerstick test to monitor for drug-induced liver injury (DILI), as compared with automated testing and with no laboratory monitoring. The design was a decision analytic model, including deterministic and probabilistic sensitivity analyses. Data sources were observational cohorts and a validation study of the paper-based test. The target population was HIV/TB co-infected persons in South Africa on antiretroviral therapy who were initiating TB therapy. Interventions: (1) clinical (no laboratory) monitoring; (2) monitoring using the paper-based test with a ≥120 IU/mL threshold for positivity; (3) monitoring using the paper-based test with a ≥200 IU/mL threshold for positivity; (4) monitoring using the paper-based test using 1 of 3 categories: <120 IU/mL, 120 to 200 IU/mL, and >200 IU/mL (“bin placement”); (5) monitoring using automated ALT testing using the same 3 categories (“automated testing”). The outcome measures were discounted quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Results The ICER of automated testing was $5180/QALY. Use of the paper-based test with the bin placement strategy was cost-effective compared with clinical monitoring alone. Conclusion At its current performance, monthly DILI monitoring by bin placement using the paper-based test was cost-effective, compared with clinical monitoring, in HIV/TB co-infected persons in South Africa. [ABSTRACT FROM AUTHOR]

Background Lenvatinib plus pembrolizumab significantly improved efficacy compared with chemotherapy in patients with advanced endometrial cancer (aEC) regardless of microsatellite instability status or histologic subtype, who had disease progression following prior platinum-based therapy, in Study-309/KEYNOTE-775. The safety profile of the combination was generally consistent with that of each monotherapy drug and of the combination in patients with endometrial cancer and other solid tumors. Given the medical complexity of patients with aEC, this paper aims to characterize key adverse reactions (ARs) of the combination treatment and review management strategies, providing a guide for AR management to maximize anticancer benefits and minimize treatment discontinuation. Materials and Methods In Study-309/KEYNOTE-775, patients received lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously every 3 weeks) or chemotherapy (doxorubicin or paclitaxel). The incidence and median time to the first onset of ARs, dose modifications, and concomitant medications are described. Key ARs characterized include hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight decreased, proteinuria, and palmar-plantar erythrodysesthesia syndrome. Results As expected, the most common any-grade key ARs included: hypothyroidism, hypertension, fatigue, diarrhea, and musculoskeletal disorders. Grades 3-4 key ARs with incidence ≥10% included: hypertension, fatigue, and weight decreased. Key ARs first occurred within approximately 3 months of treatment initiation. AR management strategies consistent with the prescribing information and the study protocol are discussed. Conclusion Successful AR management strategies for lenvatinib plus pembrolizumab include education of the patient and entire treatment team, preventative measures and close monitoring, and judicious use of dose modifications and concomitant medications. Clinicaltrials.gov ID NCT03517449 [ABSTRACT FROM AUTHOR]

Introduction In 2018, a unique maculopathy associated with chronic pentosan polysulfate sodium (PPS) use for the treatment of interstitial cystitis (IC) was described, where the authors detailed macular retinal pigment epithelial abnormalities in six patients. In this paper, a retrospective study of a larger patient pool at one large tertiary retina practice was undertaken to evaluate patients taking PPS and their macular findings. Materials and methods A retrospective chart review was performed on all patients presenting to a single large retina practice between 2011 and 2019. Patient's macular diagnosis, findings, optical coherence tomography scans, and macular auto-fluorescent scans were assessed. This project was Institutional Review Board (IRB) approved by the St Luke's Hospital IRB board (St Louis, MO, USA). Results Fifty-five patients were identified as taking PPS for IC. Fifty-three patients were found to have a diagnosis consistent with changes attributable to known macular diseases to include macular degeneration and pattern dystrophies. Two (4%) of fifty-five patients had macular findings suggestive of PPS toxicity. The first was a 58-year-old female with subtle retinal pigment epithelium (RPE) deposits on optical coherence tomography that exhibited hyper-autofluorescence. The second was a 72-year-old female with 14 years of PPS use who exhibited RPE excrescences and parafoveal areas of atrophy. Conclusions Pentosan polysulfate sodium may be the cause of macular findings in a small percentage of patients referred to a tertiary retina practice. Although causation of macular changes with PPS use has yet to be elucidated, clinicians should be aware of this possibility when assessing patients with atypical macular findings. Future longitudinal studies are necessary to evaluate a definitive relationship. This paper should remind all clinicians of the importance of a throughout review of the patient's medication list as novel toxicities may become apparent years after initial FDA trials. The strength of this study is the larger patient population compared to earlier studies, and the main weaknesses include the retrospective nature of the study, lack of family and genetic testing, and lack of multimodal imaging for all patients. [ABSTRACT FROM AUTHOR]

Drug-induced enteritis is an inflammatory disease changing in the morphology and function of the intestine as a result of medicine damage. With the increase in drug abuse in recent years, the incidence of drug-associated enteritis accordingly rises and becomes an important disease affecting the health and life quality of patients. Hence, elucidating the pathogenesis of drug-induced enteritis and finding cost-effective diagnostic and therapeutic tools have become current research focuses. The gut microbiota and metabolites regulate the immune response, playing a key role in the maintenance of homeostasis in the intestine. Numerous studies have found that many medicines can induce intestinal flora disorders, which are closely related to the development of drug-induced enteritis. Therefore, this paper analyses the role of gut microbiota and metabolites in regulating the immune response, and provides basic research direction and clinical reference strategies for drug-induced enteritis, taking into account the existing applications and perspectives. [ABSTRACT FROM AUTHOR]

The discovery of immune checkpoint inhibition (ICI) sparked a revolution in the era of targeted anticancer therapy. However, although monoclonal antibodies targeting the cytotoxic T‐lymphocyte antigen‐4 and programmed death‐1 axes have improved survival in patients with advanced cancers, these immunotherapies are associated with a wide spectrum of dermatological immune‐related adverse events (irAEs), ranging from mild to life‐threatening. Several publications have addressed the clinical and histopathological classification of these skin‐directed irAEs, their impact on anti‐tumour immunity and survival, and the critical role of supportive oncological dermatology in their management. In this paper, we review the current understanding of the mechanistic drivers of immune‐related skin toxicities with a focus on inflammatory, immunobullous and melanocyte/pigment‐related reactions. We detail the specific immune‐based mechanisms that may underlie different cutaneous reactions. We also discuss potential mechanisms as they relate to extracutaneous irAEs and the lessons learned from these, the potential overlap with cutaneous irAEs, techniques to study differences in immune‐related vs. de novo skin reactions, and how treatment of these AEs impacts cancer treatment, patient quality of life and overall survival. An improved understanding of the mechanistic basis of cutaneous irAEs will allow clinicians to develop and use blood‐based biomarkers that could help ultimately predict onset and/or severity of these irAEs, and to implement rational mechanistic‐based treatment strategies that are targeted to the irAEs while potentially avoiding reducing the anti‐tumour effect of ICIs. [ABSTRACT FROM AUTHOR]

Background the prevalence of adverse drug reactions (ADRs) in hospitalised older patients, their clinical presentations, causative drugs, severity, preventability and measurable outcomes are unclear, ADRs being an increasing challenge to older patient safety. Methods we systematically searched PubMed, Embase, EBSCO-CINAHL, the Cochrane Library, 'rey' literature and relevant systematic review bibliographies, published from database inception to March 2020. We included any study reporting occurrence of in-hospital ADRs as primary or secondary outcomes in hospitalised older adults (mean age ≥ 65 years). Two authors independently extracted relevant information and appraised studies for bias. Study characteristics, ADR clinical presentations, causative drugs, severity, preventability and clinical outcomes were analysed. Study estimates were pooled using random-effects meta-analytic models. Results from 2,399 abstracts, we undertook full-text screening in 286, identifying 27 studies (29 papers). Final analysis yielded a pooled ADR prevalence of 16% (95%CI 12–22%, I 2 98%, τ 2 0.8585), in a population of 20,153 hospitalised patients aged ≥65 years of whom 2,479 patients experienced ≥ one ADR. ADR ascertainment was highly heterogeneous. Almost 48.3% of all ADRs involved five presentations: fluid/electrolyte disturbances (17.3%), gastrointestinal motility/defaecation disorders (13.3%), renal disorders (8.2%), hypotension/blood pressure dysregulation disorders/shock (5.5%) and delirium (4.1%). Four drug classes accounted for 57.8% of causative medications i.e. diuretics (19.8%), anti-bacterials (14.8%), antithrombotic agents (12.2%) and analgesics (10.9%). Pooled analysis of severity was not feasible. Four studies reported the majority of ADRs as preventable (55–95%). Conclusions on average, 16% of hospitalised older patients experience significant ADRs, varying in severity and mostly preventable, with commonly prescribed drug classes accounting for most ADRs. [ABSTRACT FROM AUTHOR]

Adverse drug reactions (ADRs) is a challenge in modern healthcare, particularly given the increasing complexity of drug therapy, an ageing population, rising multimorbidity, and a high patient turnover. The core activity of detecting potential ADRs over the last half century has been spontaneous reporting systems. A recent Norwegian regulation commits healthcare professionals other than physicians and dentists to report serious ADRs. In this discussion paper, we share our preliminary experience with a training programme using nurses as ADR advocates to stimulate ADR reporting among the clinical staff in a hospital department. Central Illustration: Central Illustration Nurses as adverse drug reaction (ADR) reporting advocates participating in pharmacovigilance (PV) at the Department of Heart Disease, Haukeland University Hospital, Bergen, Norway. The department is a 'lighthouse' (inspiring other departments) in PV in the hospital, and cooperates with the drug committee and the regional PV centre. Commitment is achieved through the department manager and the medical director in the hospital. In addition, a new national regulation commits healthcare professionals other than physicians and dentists to report serious ADRs. [ABSTRACT FROM AUTHOR]

Objectives: The objectives of this study were to identify the amikacin dosage regimens and drug concentrations consistent with good outcomes and to determine the drug exposures related to nephrotoxicity and ototoxicity.Methods: A literature review was conducted in Medline, EMBASE and the Cochrane Central Register of Controlled Trials. Full journal articles reporting randomized controlled trials, controlled clinical trials, interrupted time series trials, and controlled before and after studies involving amikacin therapeutic drug monitoring (TDM) and dose adjustment were considered for inclusion.Results: Seventeen studies for inclusion were identified, comprising 1677 participants. Amikacin doses ranged from 11 to 15 mg/kg/day with 13 studies using 15 mg/kg/day. Studies were generally designed to compare different aminoglycosides rather than to assess concentration-effect relationships. Only 11 papers presented data on target concentrations, rate of clinical cure and toxicity. Target peak concentrations ranged from 15 to 40 mg/L and target troughs were typically <10 or <5 mg/L. It was not clear whether these targets were achieved. Measured peaks averaged 28 mg/L for twice-daily dosing and 40-45 mg/L for once-daily dosing; troughs averaged 5 and 1-2 mg/L, respectively. Fifteen of the included studies reported rates of nephrotoxicity; auditory and vestibular toxicities were reported in 12 and 8 studies.Conclusions: This systematic review found little published evidence to support an optimal dosage regimen or TDM targets for amikacin therapy. The use of alternative approaches, such as consensus opinion and a review of current practice, will be required to develop guidelines to maximize therapeutic outcomes and minimize toxicity with amikacin. [ABSTRACT FROM AUTHOR]

Objective To establish the efficacy of medications, incidence of adverse events (AEs), and withdrawal rates associated with the pharmacological management of chronic spinal cord injury pain. Methodology PubMed, MEDLINE, Embase, CINAHL, Web of Science, CENTRAL, and PsycINFO were searched (November 2017) and updated (January 2020). Two independent review authors screened and identified papers for inclusion. Results Twenty-one studies met inclusion requirements for efficacy analysis and 17 for AE and withdrawal rate analysis; no additional papers were included from the updated 2020 search. Treatments were divided into six categories: anticonvulsants (n = 6), antidepressants (n = 3), analgesics (n = 8), anti-spasticity medications (n = 2), cannabinoids (n = 1), and other (n = 2). Trials of anticonvulsants, antidepressants, and cannabinoids included long-term follow-up trials (2 weeks to 4 months), and trials of analgesics and anti-spasticity medications, among others, were short-term trials (0–2 days). Effectiveness for neuropathic pain was found for pregabalin (3/3 studies) and lidocaine (2/3 studies). Studies using ketamine also reported effectiveness (2/2), but the quality of these papers was rated as poor. The most frequently reported AEs included dizziness, dry mouth, nausea, and constipation. Pregabalin was associated with a higher risk of somnolence (risk ratio [RR] 3.15, 95% confidence interval [CI]: 2.00–4.98) and dizziness (RR 2.9, 95% CI: 1.58–5.30). Ketamine was associated with a higher risk of reduced vision (RR 9.00, 95% CI: 0.05–146.11), dizziness (RR 8.33, 95% CI: 1.73–40.10), and somnolence (RR 7.00, 95% CI: 1.73–40.1). Withdrawal rates ranged from 18.4% for antidepressants to 0–30% for anticonvulsants, 0–10% for anti-spasticity medications, 0–48% for analgesics, 28.6% for cannabinoids, and 0–22.2% for other medications. Conclusion Pregabalin was found to be effective for neuropathic pain vs placebo. Cannabinoids were ineffective for neuropathic pain. AEs are a common cause for withdrawal. The nature of AEs was poorly reported, and AE reporting should be improved in future randomized controlled trials. [ABSTRACT FROM AUTHOR]

The side effects of drugs present growing concern attention in the healthcare system. Accurately identifying the side effects of drugs is very important for drug development and risk assessment. Some computational models have been developed to predict the potential side effects of drugs and provided satisfactory performance. However, most existing methods can only predict whether side effects will occur and cannot determine the frequency of side effects. Although a few existing methods can predict the frequency of drug side effects, they strongly depend on the known drug-side effect relationships. Therefore, they cannot be applied to new drugs without known side effect frequency information. In this paper, we develop a novel similarity-based deep learning method, named SDPred, for determining the frequencies of drug side effects. Compared with the existing state-of-the-art models, SDPred integrates rich features and can be applied to predict the side effect frequencies of new drugs without any known drug-side effect association or frequency information. To our knowledge, this is the first work that can predict the side effect frequencies of new drugs in the population. The comparison results indicate that SDPred is much superior to all previously reported models. In addition, some case studies also demonstrate the effectiveness of our proposed method in practical applications. The SDPred software and data are freely available at https://github.com/zhc940702/SDPred , https://zenodo.org/record/5112573 and https://hub.docker.com/r/zhc940702/sdpred. [ABSTRACT FROM AUTHOR]

Objectives This scoping review aims to systematically map the empirical evidence on publicly funded medication reviews provided by community pharmacists in Canada and identify gaps that could inform future research directions. Methods We used a scoping review framework and PRISMA guidelines for Scoping Reviews to conduct the study. Three electronic databases were searched for papers published between January 2000 until August 2020. Data was charted on study characteristics, and a thematic synthesis was performed. Key findings Of 41 original studies included, most were conducted in Ontario (n = 21). Majority of the studies employed quantitative designs (70%). Five major themes identified were program uptake, patient health outcomes, stakeholder beliefs and attitudes, processes and collaboration and pharmacy workplace culture, which varied considerably. At the individual, organizational and policy levels, many factors were interrelated and influenced the implementation of reimbursed medication reviews by community pharmacists. Gaps in eligibility policy highlighted some patients who may have complex needs are excluded. Variation in clinical outcomes may relate to different types of medication review and pharmacist practice across Canada. Few researchers evaluated eligibility criteria, the impact of policy changes, strategies to engage patients and healthcare professionals, patient–pharmacist communication or compared practice models of medication reviews. About 12% of the research applied a theoretical framework. Summary Publicly funded medication reviews in Canadian community pharmacies reduce medication-related problems and potentially improve patient health outcomes. Future research and policies could consider addressing barriers and exploring models for sustainable delivery of high-quality medication reviews internationally. [ABSTRACT FROM AUTHOR]

Counselling by pharmacy staff plays a key role in ensuring the quality use of medications in community settings. Information gathering is the first step and an essential part of counselling. Yet, data on information gathering during counselling in Indonesia is lacking. Objective: To identify pharmacy staff's practice of counselling and information gathered during counselling in an East Javan district, Indonesia. Methods: A survey questionnaire was conducted in community-based health facilities in the district (i.e. 3 hospital outpatient clinics, 69 community pharmacies and 24 Community Health Centres [CHCs]); one health facility was represented by one pharmacy staff. Quantitative content analysis was used to summarise data regarding information gathering. Key findings: Sixty-six pharmacy staff responded, giving a 69% response rate. Almost all staff reported providing counselling; those at CHCs and outpatient clinics mostly provided prescription medicine counselling (95.5% and 100.0%, respectively), while those at community pharmacies mostly provided non-prescription medicine counselling (symptom-based versus product-based requests: 94.9% versus 71.8%, respectively). For non-prescription counselling, the most frequent information gathered was details of symptoms (symptoms-based versus product-based requests: 97.3% versus 75.0%, respectively). While for prescription medication counseling, pharmacy staff mostly asked the patient's identity (76.2%). Less than 20% of the pharmacy staff for non-prescription/prescription medication counselling gathered information on concurrent medications or history of allergies or adverse drug reactions. Conclusions: Pharmacy staff in these Indonesian settings provided prescription/non-prescription counselling to some extent. Improved information gathering skills are required for effective counselling, especially for prescription medications, thus ensuring rational drug use among Indonesians. [ABSTRACT FROM AUTHOR]

There is increasing evidence for the role of the microbiome in various mental health disorders. Moreover, there has been a growing understanding of the importance of the microbiome in mediating both the efficacy and side effects of various medications, including psychotropics. In this issue, Tomizawa and colleagues report on the effect of psychotropic drugs on the gut microbiome of 40 patients with depression and/or anxiety disorders. In their longitudinal cohort, the authors find that antipsychotics, but not anxiolytics, decrease microbiome alpha diversity. They further find that antipsychotics dosage was negatively correlated with alpha diversity in these patients. The health consequences of these microbiome alterations remain to be fully understood. In this commentary, we will discuss such findings through the lens of several recent studies on the microbiota-gut-brain axis. We also use the paper as a backdrop to discuss directionality and, by extension, causality in relation to microbiota-gut-brain-brain signaling. [ABSTRACT FROM AUTHOR]

Objectives In view of their biodegradability, biocompatibility, encapsulation efficiency and targeted release, as well as low toxicity, liposomes are being widely used in the context of drug delivery. However, the efficiency of such drug delivery systems might face limitations by macrophagemediated clearance (CL), which reduces circulation half-life (T½). This problem can be resolved through surface functionalization via poly (ethylene glycol) (PEG) in the process of PEGylation. However, the use of PEG might have its own disadvantages. Accordingly, the main purpose of this study was to produce novel stealth nanoliposomes using CD47 mimicry peptide [namely selfpeptide (SP)] as an alternative to PEG for minimizing macrophage-mediated CL and enhancing circulation T½. Methods At first, doxorubicin (Dox)-containing liposomes [i.e.liposomal Dox (LD)] were coated with different concentrations of SP (viz. SP-LD) (0.5%, 1% and 2%). In addition, PEG-functionalized LD (i.e. PLD) was fabricated as a standard control group. Then, various types of liposomal formulae were injected into a population of mice, assigned to six groups (four mice per group) for biodistribution. After sacrificing these animals in prespecified time points (namely 0.5, 6, 12, 24, 48, 72, 96 and 168 h), serum, liver, spleen, heart, kidney and lung samples were collected to estimate the encapsulated drug content in different groups through measuring intrinsic autofluorescence signal of Dox. Key findings The tissue distribution results in the liver, spleen, heart, kidney and lung samples indicated a significant difference between the SP-LD and the PLD groups. Furthermore, the examination of Dox content, 6 h after administration, showed a growth rate of 28% in Dox content in the SP group compared with the PLD one. Subsequently, these values were, respectively, 63% and 75% at 24 and 48 h. Conclusions The results of tissue distribution and serum kinetic analysis correspondingly revealed that the use of the SP could augment the circulation time of Dox in comparison with PEG, and it could additionally minimize the tissue accumulation of the drug, which is normally the cause of drug-induced toxicity. The use of the SP on nanoliposomes could prolong the circulation of T½ and diminish the tissue accumulation of LD. These findings are relevant for improving therapeutic efficacy and reducing the toxicity of liposomal drugs. [ABSTRACT FROM AUTHOR]

Adverse outcome pathways have shown themselves to be useful ways of understanding and expressing knowledge about sequences of events that lead to adverse outcomes (AOs) such as toxicity. In this paper we use the building blocks of adverse outcome pathways—namely key events (KEs) and key event relationships—to construct networks which can be used to make predictions of the likelihood of AOs. The networks of KEs are augmented by data from and knowledge about assays as well as by structure activity relationship predictions linking chemical classes to the observation of KEs. These inputs are combined within a reasoning framework to produce an information-rich display of the relevant knowledge and data and predictions of AOs both in the abstract case and for individual chemicals. Illustrative examples are given for skin sensitization, reprotoxicity and non-genotoxic carcinogenicity. [ABSTRACT FROM AUTHOR]

Motivation Adverse drug reaction (ADR) or drug side effect studies play a crucial role in drug discovery. Recently, with the rapid increase of both clinical and non-clinical data, machine learning methods have emerged as prominent tools to support analyzing and predicting ADRs. Nonetheless, there are still remaining challenges in ADR studies. Results In this paper, we summarized ADR data sources and review ADR studies in three tasks: drug-ADR benchmark data creation, drug–ADR prediction and ADR mechanism analysis. We focused on machine learning methods used in each task and then compare performances of the methods on the drug–ADR prediction task. Finally, we discussed open problems for further ADR studies. Availability Data and code are available at https://github.com/anhnda/ADRPModels. [ABSTRACT FROM AUTHOR]

Motivation When phase III clinical drug trials fail their endpoint, enormous resources are wasted. Moreover, even if a clinical trial demonstrates a significant benefit, the observed effects are often small and may not outweigh the side effects of the drug. Therefore, there is a great clinical need for methods to identify genetic markers that can identify subgroups of patients which are likely to benefit from treatment as this may (i) rescue failed clinical trials and/or (ii) identify subgroups of patients which benefit more than the population as a whole. When single genetic biomarkers cannot be found, machine learning approaches that find multivariate signatures are required. For single nucleotide polymorphism (SNP) profiles, this is extremely challenging owing to the high dimensionality of the data. Here, we introduce RAINFOREST (tReAtment benefIt prediction using raNdom FOREST), which can predict treatment benefit from patient SNP profiles obtained in a clinical trial setting. Results We demonstrate the performance of RAINFOREST on the CAIRO2 dataset, a phase III clinical trial which tested the addition of cetuximab treatment for metastatic colorectal cancer and concluded there was no benefit. However, we find that RAINFOREST is able to identify a subgroup comprising 27.7% of the patients that do benefit, with a hazard ratio of 0.69 (P  = 0.04) in favor of cetuximab. The method is not specific to colorectal cancer and could aid in reanalysis of clinical trial data and provide a more personalized approach to cancer treatment, also when there is no clear link between a single variant and treatment benefit. Availability and implementation The R code used to produce the results in this paper can be found at github.com/jubels/RAINFOREST. A more configurable, user-friendly Python implementation of RAINFOREST is also provided. Due to restrictions based on privacy regulations and informed consent of participants, phenotype and genotype data of the CAIRO2 trial cannot be made freely available in a public repository. Data from this study can be obtained upon request. Requests should be directed toward Prof. Dr. H.J. Guchelaar (h.j.guchelaar@lumc.nl). Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

AbstractThe major burden of illness in bipolar disorder (BD) is in the depressive pole. Lamotrigine has been shown to be useful in the long-term prophylaxis of depressive episodes in BD. Current guidelines recommend discontinuing lamotrigine in patients who develop rash. Our objective in this paper is to review literature to identify possible predictors of serious vs. benign rash that might help guide clinical decision-making and recommend titration strategy for re-introduction of lamotrigine, if indicated. We performed a search of the literature between 1966 and July 2008 to investigate the phenomenon of lamotrigine-induced rash and rechallenge procedures. The search identified six reports, and we were able to identify another case series from reviewing the bibliography of all of the above papers. We reviewed all the papers of lamotrigine rash rechallenge that resulted from the literature search. These papers describe 44 cases of lamotrigine rechallenge. Currently, there are 39 reported cases in the literature of successful lamotrigine rechallenge after a rash and five cases with rash recurrence. There are some characteristics of the rash that can help identify serious cases from benign ones. In addition, very slow titration of lamotrigine is crucial to the reduction of rash recurrence rate. Several cases that develop benign rash on lamotrigine can be rechallenged without adverse consequences. We believe that lamotrigine rechallenge in bipolar depression is an under-utilized option in our clinical armamentarium, and further studies are needed to guide us in this area. [ABSTRACT FROM AUTHOR]

The efficient management of the continuously increasing number of chemical substances used in today's society is assuming greater importance than ever before. Toxicity testing plays a key role in the regulatory decisions of agencies and governments that aim to protect the public and the environment from the potentially harmful or adverse effects of these multitudinous chemicals. Therefore, there is a critical need for reliable toxicity-testing methods to identify, assess and interpret the hazardous properties of any substance. Traditionally, toxicity-testing approaches have been based on studies in experimental animals. However, in the last 20 years, there has been increasing concern regarding the sustainability of these methodologies. This has created a real need for the development of new approach methodologies (NAMs) that satisfy the regulatory requirements and are acceptable and affordable to society. Numerous initiatives have been launched worldwide in attempts to address this critical need. However, although the science to support this is now available, the legislation and the pace of NAMs acceptance is lagging behind. This review will consider some of the various initiatives in Europe to identify NAMs to replace or refine the current toxicity-testing methods for pharmaceuticals. This paper also presents a novel systematic approach to support the desired toxicity-testing methodologies that the 21st century deserves. [ABSTRACT FROM AUTHOR]

Internet of Things (IoT) is a growing technology that widely applied to interconnect available medical resources and provide reliable, effective and smart healthcare service to patients. The quality of healthcare is measured by the potential of occurrence of medical errors, cost shrinkage and high speed. This paper proposes a new system to prevent Adverse Drug Events (ADEs) which is a kind medical errors very propagated in health facilities. The proposed system focus on ADE in prescription stage called Prescription ADE system (PrescADE). It improves patient safety, reduces ADE and optimizes the healthcare process. It based on ADE ontology, on IoT and a set of rules to analyze prescription and help doctors. For experimentations, a platform is developed to test rules using 20 patients and three doctors. We compared our proposed system to Computerized Prescriber Order Entry system (CPOE) which is a system to detect ADE of prescription and widely used in hospitals. The results show that PrescADE system has better performance than CPOE system in terms of prescription time and ADE detected. PrescADE detects 314% of ADEs higher than CPOE and 82% of prescription time lower than CPOE. [ABSTRACT FROM AUTHOR]

Drug-induced nephrotoxicity is a common problem in clinical medicine and the frequency of drug-related acute and chronic kidney dysfunction worldwide. One of them is anti-tuberculosis (TB) drugs that cause renal function impairment during TB treatment. Medicinal plants contain bioactive compounds that are capable for treating drug or toxin-induced renal disorders. The aim of the present study was to assess the protective effect of the ethanolic extract of Nigella sativa seeds (NS) against anti-TB drugs (ATDs) induced nephrotoxicity in Wistar albino rats. Rats were treated with ATDs for 12weeks (3 alternative days in a week). Supplementation with 125mg NS/kg, p.o. was administered to the experimental rats for 12weeks (3 alternative days in a week considering next day of ATDs treatment). The results demonstrated that NS treatment protected against renal damage induced by ATDs, as evidenced by the reduction in serum urea, creatinine, uric acid, urea nitrogen levels, pro-inflammatory markers (TNF-α and IL-6), whereas improvement in histological tubular and glomerular damage. In addition, NS enhanced the antioxidant enzyme activity (superoxide dismutase and catalase) and decreased the lipid peroxidation and glutathione level in the kidney. In conclusion, NS could reduce chronic nephritis in ATDs treated group through suppressing inflammation and oxidative stress. It suggests that NS can be used as supplementary preventive and protective drug against kidney injury during anti-TB treatment. [ABSTRACT FROM AUTHOR]

Summary: The paper analyses health consequences of forced civilian displacement that occurred during the war in Croatia 1991–1995 which accompanied the demise of Yugoslavia. During the Serbo‐Croatian conflict a quarter of Croatian territory was ceded, 22000 people were killed and more than 500000 individuals were displaced. Using the Croatian Adult Health Survey 2003 we identify the causal effect of forced migration on various dimensions of measured and self‐assessed health. To circumvent the self‐selection into displacement, we adopt an instrumental variable approach where civilian casualties per county are used as an instrument for displacement. We find robust adverse effects on probability of suffering hypertension and tachycardia as well as on self‐assessed health and ‘Short form health survey’ health dimensions. Comparing ordinary least squares with instrumental variable estimates yields a conclusion of a positive selection into displacement with respect to latent health. Given the likely violation of the exclusion restriction, we use a method which allows the instrument to affect health outcomes directly and conclude that, even with substantial departures from the exclusion restriction, displacement still adversely affects health. [ABSTRACT FROM AUTHOR]

In the past few decades, great conceptual and technological advances have been made in the field of toxicology, but animal model-based research still remains one of the most widely used and readily available tools for furthering our current knowledge. However, animal models are not perfect in predicting all systemic toxicity in humans. Extrapolating animal data to accurately predict human toxicities remains a challenge, and researchers are obligated to question the appropriateness of their chosen animal model. This paper provides an assessment of the utility of the methionine- and choline-deficient (MCD) diet fed animal model in reflecting human nonalcoholic steatohepatitis (NASH) and the potential risks of adverse drug reactions and toxicities that are associated with the disease. As a commonly used NASH model, the MCD model fails to exhibit most metabolic abnormalities in a similar manner to the human disease. The MCD model, on the other hand, closely resembles human NASH histology and reflects signatures of drug transporter alterations in humans. Due to the nature of the MCD model, it should be avoided in studies of NASH pathogenesis, metabolic parameter evaluation, and biomarker identification. But it can be used to accurately predict altered drug disposition due to NASH-associated transporter alterations. [ABSTRACT FROM AUTHOR]

Introduction older adults are at risk of adverse outcomes due to a high prevalence of polypharmacy and potentially inappropriate medications (PIMs). Deprescribing interventions have been demonstrated to reduce polypharmacy and PIMs. However, deprescribing is not performed routinely in long-term care facilities (LTCFs). This qualitative evidence synthesis aims to identify the factors which limit and enable health care workers' (HCWs) engagement with deprescribing in LTCFs. Methods the 'best-fit' framework approach was used to synthesise evidence by using the Theoretical Domains Framework (TDF) as the a priori framework. Included studies were analysed qualitatively to identify LTCF barriers and enablers of deprescribing and were mapped to the TDF. Constructs within domains were refined to best represent the LTCF context. A conceptual model was created, hypothesising relationships between barriers and enablers. Results of 655 records identified, 14 met the inclusion criteria. The 'best-fit' framework included 17 barriers and 16 enablers, which mapped to 11 of the 14 TDF domains. Deprescribing barriers included perceptions of an 'established hierarchy' within LTCFs, negatively affecting communication and insufficient resources which limited HCWs' engagement with deprescribing. Enablers included tailored deprescribing guidelines, interprofessional support and working with a patient focus, allowing the patients' condition to influence decisions. Discussion this study identified that education, interprofessional support and collaboration can facilitate deprescribing. To overcome deprescribing barriers, change is required to a patient-centred model and HCWs need to be equipped with necessary resources and adequate reimbursement. The LTCF organisational structure must support deprescribing, with communication between health care systems. [ABSTRACT FROM AUTHOR]

Background Ribociclib is approved for hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) advanced breast cancer (ABC) treatment, in combination with endocrine therapy. Hematological, hepatic, and cardiac adverse events (AEs) emerged from pivotal trials, but little is known about cutaneous adverse events (CAEs). Patients and Methods We report data from a retrospective cohort study of all patients with HR+/HER2− ABC treated with ribociclib at Humanitas Cancer Center between June 2017 and December 2022. We recorded clinical-pathological data, the incidence, and treatment of ribociclib-related CAEs. These were evaluated according to the NCI-CTCAE v5.0 classification. Progression-free survival (PFS) was estimated by Kaplan-Meier method and the log-rank test was used to analyze differences between groups. Results Thirteen of 91 patients (14.3%) experienced treatment-related CAEs (mean time to the occurrence: 3.9 months). The most frequent CAEs were eczematous dermatitis (53.8%) and maculo-papular reaction (15.4%). Itch was reported by all 13 patients. The grade was G3 in 8 cases, G2 in 4, and G1 in 1. An integrated approach based on ribociclib dose modulation and dermatological interventions (oral antihistamine, moisturized cream, topical, and/or systemic steroids) could prevent ribociclib discontinuation in most patients. At a median follow-up of 20 months, the median PFS was 13 months (range, 1-66) with a better PFS curves for patients experiencing CAEs (P  = .04). Conclusion We mapped frequency and types of ribociclib-induced CAEs. An interdisciplinary management of CAEs incorporated into routine care may reduce the rate of drug discontinuation thus potentially contributing to better long-term outcomes. [ABSTRACT FROM AUTHOR]

MEK signaling pathway targeting has emerged as a valuable addition to the options available for the treatment of advanced cancers including melanoma and non-small cell lung cancer. Ophthalmologic monitoring of patients taking part in clinical trials of MEK inhibitors has shown that while ocular effects are common, generally emerging during the first days to weeks of treatment, the majority are either asymptomatic or have minimal visual impact and are benign, resolving without intervention or the need to reduce or stop MEK inhibitor therapy. However rare cases of serious, potentially vision-threatening ocular toxicities have been reported during MEK inhibitor therapy. There is currently no recommendation for routine ophthalmologic screening or monitoring of patients with advanced cancer who are initiating MEK inhibitor therapy. However, baseline ophthalmologic examination may be useful for all patients initiating MEK inhibitor therapy to allow the differentiation of preexisting pathology versus the development of MEK inhibitor-associated retinopathy in the event of the emergence of symptomatic ocular events. Regular ophthalmologic examination may be appropriate for patients at increased risk for ocular events, such as patients with a history of ocular inflammation, infection, or underlying macular/retinal disease. All patients reporting visual disturbance should be referred for prompt ophthalmologic review to determine the potential seriousness of any underlying abnormalities and whether there is a need for treatment modification or specific intervention. Understanding the potential consequences of ocular toxicities is of particular importance in the context of decision-making for the continuation of potentially life-prolonging medications such as MEK inhibitors. [ABSTRACT FROM AUTHOR]

Two recent Supreme Court decisions (PLIVA, Inc. v. Mensing (2011), and Mutual Pharmaceutical v. Bartlett (2013)), have essentially removed the threat of liability from generic drug manufacturers. In this paper, we consider four possible liability regimes in a simple model of drug market competition and safety research. Specifically, we compare a baseline regime of No Liability (NL) with the Everyone Liable (EL) regime (generics face the same liability as branded manufacturers), the No Liability for Generics (NLG) regime, resulting from PLIVA and Mutual (generics face no liability), and a novel Brand Fully Liable (BFL) regime (branded developer faces liability from injuries caused by a generic version of a drug it has developed). We find that the BFL regime typically provides the most efficient incentives to identify side effects and develop an efficient warning. However, the BFL regime can lead to overconsumption of the generic drug by patients who should not take the drug at all. For this reason, the EL regime may be preferable for a drug where the danger of side effects may outweigh the clinical value, as was alleged in Mutual Pharmaceutical v. Bartlett. We find that the NLG regime that resulted from the recent Supreme Court decisions is unlikely to be optimal, because it is dominated by BFL when the consumption decision is not important, and inferior to EL when it is very important. [ABSTRACT FROM AUTHOR]

Background: Physicians can come across patients who are exposed to certain prescription drugs or toxins that can result in adverse effects and complications which have high rates of morbidity and mortality.Objective: To summarise the key clinical features and management of the common movement disorder toxidromes relevant to physicians (with an interest in neurology).Methods: We searched PUBMED from 1946 to 2016 for papers relating to movement toxidromes and their treatment. The findings from those studies were then summarised and are presented here.Results: The key features of 6 of the common movement disorder toxidromes and their treatment are tabulated and highlighted. The management of toxidromes with the highest mortality like neuroleptic malignant syndrome and serotonin syndrome are discussed in detail.Conclusion: There are several toxidromes that have the potential to become a serious life-threatening emergency if there is a delay in recognition of key clinical features and instituting the appropriate treatment at the earliest is crucial. [ABSTRACT FROM AUTHOR]

This article is a response to a previous paper that discussed the intensive care requirements of patients treated with immune checkpoint inhibitors (ICIs). The authors of this response emphasize the importance of detailing the diverse reasons for ICU admission in ICI-treated patients and argue that ICU admission can be beneficial regardless of whether patients present with ICI-related adverse events. They also acknowledge the challenges faced by emergency care systems, such as shortage of ICU beds and the heterogeneity of emergency cancer services. The authors conclude that early recognition and aggressive treatment of high-risk immune-related adverse events are crucial for good outcomes, while also recognizing the need to identify patients who are unlikely to benefit from intensive care interventions. [Extracted from the article]

Background Immune checkpoint inhibitors (ICIs) have demonstrated efficacy over previous cytotoxic chemotherapies in clinical trials among various tumors. Despite their favorable outcomes, they are associated with a unique set of toxicities termed as immune-related adverse events (irAEs). Among the toxicities, ICI-related pneumonitis has poor outcomes with little understanding of its risk factors. This retrospective study aimed to investigate whether pre-existing interstitial lung abnormality (ILA) is a potential risk factor for ICI-related pneumonitis. Materials and Methods Patients with non-small cell lung cancer, malignant melanoma, renal cell carcinoma, and gastric cancer, who was administered either nivolumab, pembrolizumab, or atezolizumab between September 2014 and January 2019 were retrospectively reviewed. Information on baseline characteristics, computed tomography findings before administration of ICIs, clinical outcomes, and irAEs were collected from their medical records. Pre-existing ILA was categorized based on previous studies. Results Two-hundred-nine patients with a median age of 68 years were included and 23 (11.0%) developed ICI-related pneumonitis. While smoking history and ICI agents were associated with ICI-related pneumonitis (P =.005 and.044, respectively), the categories of ILA were not associated with ICI-related pneumonitis (P =.428). None of the features of lung abnormalities were also associated with ICI-related pneumonitis. Multivariate logistic analysis indicated that smoking history was the only significant predictor of ICI-related pneumonitis (P =.028). Conclusion This retrospective study did not demonstrate statistically significant association between pre-existing ILA and ICI-related pneumonitis, nor an association between radiologic features of ILA and ICI-related pneumonitis. Smoking history was independently associated with ICI-related pneumonitis. Further research is warranted for further understanding of the risk factors of ICI-related pneumonitis. [ABSTRACT FROM AUTHOR]

BACKGROUND Emerging evidence from clinical and epidemiological studies suggests that dietary polyphenols play an important role in the prevention of chronic diseases, including cancer, cardiovascular disease, diabetes and neurodegenerative disorders. Although these beneficial health claims are supported by experimental data for many subpopulation groups, some studies purport that excessive polyphenol consumption may have negative health effects in other subpopulations. The ever-growing interest and public awareness surrounding the potential benefits of natural health products and polyphenols, in addition to their widespread availability and accessibility through nutritional supplements and fortified foods, has led to increased consumption throughout gestation. Therefore, understanding the implications of polyphenol intake on obstetrical health outcomes is of utmost importance with respect to safe consumption during pregnancy. METHODS Using relevant keywords, a literature search was performed to gather information regarding polyphenol pharmacology and the molecular mechanisms by which polyphenols exert their biological effects. The primary focus of this paper is to understand the relevance of these findings in the context of reproductive physiology and medicine. RESULTS Evidence from both in vitro experiments and in vivo studies using animals and humans demonstrates that polyphenols regulate key targets related to oxidative stress, inflammation and advanced glycation end products. Although the majority of these studies have been conducted in the context of chronic diseases, such as cancer and diabetes, several of the key targets influenced by polyphenols are also related to a variety of obstetrical complications, including pre-eclampsia, intrauterine growth restriction and preterm birth. Polyphenols have also been shown to influence fertility and sexual development, fetal health and the bioavailability of nutrients. CONCLUSIONS Further research leading to a thorough understanding of the physiological roles and potential clinical value that polyphenol consumption may play in pregnancy is urgently needed to help inform patient safety. [ABSTRACT FROM PUBLISHER]

Introduction Management of hepatitis C virus (HCV) is rapidly changing as a result of new direct-acting antivirals (DAA). Sources of data Several peer-reviewed papers featuring new DAAs are now available. Additionally, as new data are emerging so quickly, we also reviewed recent presentations at international congresses, published in abstract form. Areas of agreement New DAAs are efficacious and superior to prior treatment regimens, with minimal side effects. Shorter interferon-free regimens will soon be the mainstay of HCV treatment. Areas of controversy Access to new DAAs is variable across global regions. One approach to treating HCV may be to assess early viral kinetics of treatment to identify who may be cured with standard peg-interferon/ribavirin therapy as opposed to using a DAA in all patients. Growing points Newer studies with combination of DAAs are being conducted. The ideal interferon-free regimen has yet to be determined. Areas timely for developing research HCV genotype 3 is the new difficult-to-treat genotype. More efficacious regimens for treating HCV genotype 3 are needed. Subgroups of patients who only require even shorter regimens of 6–8 weeks need to be identified. There is still very little data on interferon-free regimens in patients with decompensated cirrhosis and certain other subgroups. [ABSTRACT FROM AUTHOR]

Objectives. This paper aims to examine the current state of knowledge about adverse events associated with interventional pain techniques. Methods. This paper reviews the available databases on risk from sources such as closed claim analysis, peer review, and published literature; and also examines risk stratification for pain practitioners, the current state of malpractice insurance, and the procedures that are considered to have elevated risk. Conclusions. Substantial neurological sequelae can occur from interventional pain techniques. Considering the growing number of physicians who perform these procedures the actual occurrence of these problems appears to be low. The incidences of complications are difficult to correctly identify based on limitations of reporting and data analysis. The author recommends a national data bank be created to allow better monitoring and self assessment of the specialty of pain medicine. This information could be used to improve outcomes, reduce risk, and change clinical practice. [ABSTRACT FROM AUTHOR]

Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare conditions (affecting 1‐2 people per million per year) usually caused by a severe immune reaction to certain medications and, in some cases, the cause may be linked to particular infections. Those affected are likely to have a loss of skin and mucous membranes. People who get these conditions become very ill quickly and experience severe pain. SJS and TEN can have long‐term physical effects such as skin, eye, breathing and stomach problems. Little is known about the psychological effects on patients' lives. This research was inspired by a man diagnosed with TEN. Because he appeared anxious and fearful, the authors questioned how SJS/TEN affected patients' lives. The authors systematically searched for research papers regarding SJS and TEN, to help understand the psychological impact of these conditions on patients' lives, and they found six relevant studies. The findings highlight that some healthcare practitioners lacked information about the conditions, leading to fear and anxiety in patients. Some patients had symptoms of post‐traumatic stress disorder (PTSD), anxiety and depression. The findings conclude that SJS/TEN impacts psychologically on patients' lives. The authors suggest that, if healthcare practitioners are educated about SJS/TEN, this should assist them to provide patients with the information and support which they need in order to be less anxious. In addition, on discharge, patients should have a follow up appointment with a relevant healthcare practitioner to reduce the possibility of PTSD occurring. Linked Article: O'Reilly et al. Br J Dermatol 2020; 183:452–461. Linked Article: O'Reilly et al. Br J Dermatol 2020; 183:452–461. [ABSTRACT FROM AUTHOR]

The aim of this paper was to analyse the results of published studies looking at the use of topically applied medications (meaning they are applied to the skin) to treat warts on the external genitalia, to see if there was enough evidence to favour one or more treatments on the basis of good results and safety. The investigators selected 41 studies, which together involved 6371 patients. The main treatments analysed where topical podophyllotoxin (a cytotoxic agent ‐ meaning it kills cells ‐ applied to the surface of warts) in different strengths, sinecatechin (a product, again, used topically and derived from green tea extract), cidofovir gel and idoxuridine cream (both antiviral medications applied directly to warts), imiquimod (a topically applied medication used to increase immunity). Of the two most commonly used treatments, podophyllotoxin in a 0·5% solution was more effective than imiquimod 5% cream although it also caused more side effects such a stinging and irritation. By contrast sinecatchin was not as effective as imiquimod. The antiviral medications, idoxuridine and cidofovir, produced very similar results to those seen with imiquimod and podophyllotoxin. Generally, the rates of recurrence after therapy were similar whichever treatment was applied. The investigators concluded that there was little difference to be found between the different treatments and that selection of the most suitable in each individual case should also take into account factors such as the likelihood of irritation at the site to be treated or the length of time required to achieve cure, as some, such as imiquimod, take longer to produce results than others. Linked Article: Jung et al. Br J Dermatol 2020; 183:24–36. [ABSTRACT FROM AUTHOR]

We study the macroeconomic effects of unconventional monetary policy in the euro area using structural vector autoregressions, identified with external instruments. The instruments are based on the common unexpected variation in euro area sovereign yields for different maturities on policy announcement days. We first show that expansionary monetary surprises are effective at lowering public and private interest rates and increasing economic activity, consumer prices, and inflation expectations. We then document that the shocks lead to a rise in primary public expenditures and a widening of internal trade balances. [ABSTRACT FROM AUTHOR]

The article reports on a general handout that details requirements linked with the use of investigational oral chemotherapy medication. Topics mentioned include a paper released by the Hematology/Oncology Pharmacy Association in 2014 that calls for best practice standards within an investigational drug service, oral chemotherapy education sheets with information to patients with cancer and caregivers, and the increased needs and risks associated with the use of oral investigational medications.

There is growing evidence that chronic kidney disease (CKD) is an independent risk factor for cognitive impairment, especially due to vascular damage, blood–brain barrier disruption and uremic toxins. Given the presence of multiple comorbidities, the medication regimen of CKD patients often becomes very complex. Several medications such as psychotropic agents, drugs with anticholinergic properties, GABAergic drugs, opioids, corticosteroids, antibiotics and others have been linked to negative effects on cognition. These drugs are frequently included in the treatment regimen of CKD patients. The first review of this series described how CKD could represent a risk factor for adverse drug reactions affecting the central nervous system. This second review will describe some of the most common medications associated with cognitive impairment (in the general population and in CKD) and describe their effects. [ABSTRACT FROM AUTHOR]

Background Upacicalcet is a novel small-molecule calcimimetic agent developed for intravenous injection. Here, we evaluated the long-term efficacy and safety of upacicalcet treatment via intraindividual dose adjustment in haemodialysis patients with secondary hyperparathyroidism (SHPT). Methods A phase 2, multicentre, open-label, single-arm study was conducted. Upacicalcet was administered for 52 weeks; the starting dose was 50 μg thrice a week, and then adjusted to 25, 50, 100, 150, 200, 250, or 300 μg, according to the dose-adjustment method set in the protocol. The primary endpoint was the percentage of patients with serum intact parathyroid hormone (iPTH) level achieving a target range of 60–240 pg/mL (target achievement rate) at week 18. Results A total of 58 patients were administered upacicalcet. The target achievement rate of serum iPTH level at week 18 was 57.9%, which increased to 80.8% at week 52. The serum-corrected calcium (cCa) level decreased immediately after upacicalcet administration, but no further decrease was observed. Adverse events were observed in 94.8% of patients, and adverse drug reactions (ADRs) occurred in 20.7% of patients. The most common ADR was decreased adjusted calcium in eight patients; dizziness occurred as a serious ADR in one patient. The serum cCa level of patients who interrupted upacicalcet treatment at a serum cCa level of <7.5 mg/dL recovered to ≥7.5 mg/dL immediately after the interruption. Conclusions In haemodialysis patients with SHPT, upacicalcet doses of 25–300 μg for 52 weeks were found to be highly effective and well-tolerated, with minor safety concerns. [ABSTRACT FROM AUTHOR]

Objective To investigate the knowledge of medical students and their perception on adverse drug reaction ( ADR) reporting and pharmacovigilance. Methods Cross-sectional study was carried out on clinical or preclinical year medical students using paper-based questionnaires during their coursework. Key findings There were differences between the two groups in responses relating to ADR reporting (preclinical 3.3 versus clinical 3.7; P < 0.01) and reasons for not reporting a suspected ADR (preclinical 3.4 versus clinical 3.8; P = 0.001). Conclusions Medical students from clinical years had higher knowledge of ADR reporting. The perception on ADR reporting by clinical year students was significantly higher. [ABSTRACT FROM AUTHOR]

Mammalian target of rapamycin inhibitor (mTOR-I)/proliferation signal inhibitors (PSI) including sirolimus and everolimus represent a new class of drugs increasingly used in solid-organ transplantation as alternatives to calcineurin inhibitors for patients with renal dysfunction, transplant coronary arterial vasculopathy or malignancy. The most frequently occurring mTOR-I/PSI-related adverse events are similar to those associated with other immunosuppressive therapies, but some side effects are more characteristic of proliferation signal inhibitors (e.g. lymphocele, arthralgia, oedema and hyperlipidaemia). The present paper review incidence, clinical presentation and mechanism of oedema within the clinical experience of mTOR-I/PSI in solid organ transplantation. [ABSTRACT FROM PUBLISHER]

Omission of relevant covariates can lead to bias when estimating treatment or exposure effects from survival data in both randomized controlled trials and observational studies. This paper presents a general approach to assessing bias when covariates are omitted from the Cox model. The proposed method is applicable to both randomized and non-randomized studies. We distinguish between the effects of three possible sources of bias: omission of a balanced covariate, data censoring and unmeasured confounding. Asymptotic formulae for determining the bias are derived from the large sample properties of the maximum likelihood estimator. A simulation study is used to demonstrate the validity of the bias formulae and to characterize the influence of the different sources of bias. It is shown that the bias converges to fixed limits as the effect of the omitted covariate increases, irrespective of the degree of confounding. The bias formulae are used as the basis for developing a new method of sensitivity analysis to assess the impact of omitted covariates on estimates of treatment or exposure effects. In simulation studies, the proposed method gave unbiased treatment estimates and confidence intervals with good coverage when the true sensitivity parameters were known. We describe application of the method to a randomized controlled trial and a non-randomized study. [ABSTRACT FROM AUTHOR]

Background. In this paper, we explore nephrogenic hypophosphatemic osteomalacia associated with low-dose adefovir dipivoxil (ADV) therapy. Methods. Five patients who were treated with ADV for >2 years were included in this study. The metabolic index of phosphate and calcium, renal tubular function, renal function and pathological changes of the patients were investigated. Results. Two male and three female patients were studied. All of the patients presented with a reduced serum phosphate level (0.38-0.60 mmol/L) accompanied with hyperphosphaturia at 10.9-23.8 mmol/24 h. The serum potassium level was also reduced or at lower range (2.56-3.54 mmol/L), but the 24-h urinary potassium was relatively increased. Urinalysis also demonstrated increased excretion of glucose in four patients. Urine protein electrophoresis showed low-to-moderate molecular weight protein. Three patients manifested urine acidification function impairment. Four patients had accompanying renal insufficiency. Three patients had difficulty walking and presented with a reduction in height (2.5-14 cm). Renal biopsy revealed that most of the glomeruli were normal accompanied by mild interstitial fibrosis with inflammatory cell infiltration. ADV treatment was subsequently ceased. Patients were treated with regular phosphate supplementation, citrate acid potassium and calcium bicarbonate. After 6-month treatment, the bone pain was significantly alleviated. Serum creatinine of one patient returned to normal levels and two patients who had difficulty walking were able to walk independently. Conclusions. The current study showed long-term and low-dose ADV treatment in a Chinese population may lead to proximal tubular impairment, metabolic acidosis, hypophosphatemia, hypokalemia, metabolic bone disease, renal osteopathia and renal functional damage. [ABSTRACT FROM AUTHOR]

Current antidepressants are ineffective in many depressed patients. Thus there is an urgent need to develop treatment strategies which have significantly faster response, can be sustained and have minimal side-effects. This paper reviews clinical data, potential biomarkers, mechanisms of action and future research directions for two proven strategies that produce marked improvement in severe depressive symptoms within 48 h, ketamine and sleep deprivation therapy (SDT). These treatments provide unequivocal evidence that the depressive process can be rapidly reversed in a subgroup of patients. Seventeen ketamine studies in over 150 patients showed a rapid response. Low-dose intravenous ketamine produced mild psychotomimetic effects but response has not been effectively sustained. SDT has been investigated in over 60 studies with a 40-60% response rate within 48 h. Although SDT is often used in Europe to initiate a rapid response, it is less utilized within the USA, in part, because it has a short duration when administered alone. We review data concerning chronotherapeutic strategies of bright-light therapy (BLT) and sleep-phase advance (SPA) which successfully sustain the antidepressant efficacy of SDT. Evidence is further discussed that a significant group of mood disorders have abnormal circadian rhythms which are known to be controlled by clock genes. It is hypothesized that chronotherapeutic manipulations can reset clock genes and thus, abnormalities in circadian rhythms. Further findings are reviewed that ketamine, in addition to its role as an NMDA antagonist, can also alter circadian rhythms. Thus, ketamine may share a critical mechanism with SDT. [ABSTRACT FROM AUTHOR]

The Supreme Court ruled in Matrixx that statistical significance is not necessary to show that a drug caused an adverse reaction. Five circuit court decisions holding otherwise preceded this decision. This paper examines the extent to which the Supreme Court’s reasoning differed from those of the circuit courts. [ABSTRACT FROM AUTHOR]