WHO and endemic countries target elimination of transmission of Onchocerca volvulus, the parasite causing onchocerciasis. Population genetic analysis of O. volvulus may provide data to improve the evidence base for decisions on when, where, and for how long to deploy which interventions and post-intervention surveillance to achieve elimination. Development of necessary methods and tools requires parasites suitable for genetic analysis. Based on our experience with microfilariae obtained from different collaborators, we developed a microfilariae transfer procedure for large-scale studies in the Democratic Republic of Congo (DRC) comparing safety and efficacy of ivermectin, the mainstay of current onchocerciasis elimination strategies, and moxidectin, a new drug. This procedure is designed to increase the percentage of microfilariae in skin snips suitable for genetic analysis, improve assignment to metadata, and minimize time and materials needed by the researchers collecting the microfilariae. Among 664 microfilariae from South Sudan, 35.7% and 39.5% failed the mitochondrial and nuclear qPCR assay. Among the 576 microfilariae from DRC, 16.0% and 16.7% failed these assays, respectively. This difference may not only be related to the microfilariae transfer procedure but also to other factors, notably the ethanol concentration in the tubes in which microfilariae were stored (64% vs. ≥75%).

Atrial fibrillation (AF) inducibility, sustainability and response to pharmacological treatment of individual patients are expected to be determined by their ionic current properties, especially in structurally-healthy atria. Mechanisms underlying AF and optimal cardioversion are however still unclear. In this study, in-silico drug trials were conducted using a population of human structurally-healthy atria models to 1) identify key ionic current properties determining AF inducibility, maintenance and pharmacological cardioversion, and 2) compare the prognostic value for predicting individual AF cardioversion of ionic current properties and electrocardiogram (ECG) metrics. In the population of structurally-healthy atria, 477 AF episodes were induced in ionic current profiles with both steep action potential duration (APD) restitution (eliciting APD alternans), and high excitability (enabling propagation at fast rates that transformed alternans into discordant). High excitability also favored 211 sustained AF episodes, so its decrease, through prolonged refractoriness, explained pharmacological cardioversion. In-silico trials over 200 AF episodes, 100 ionic profiles and 10 antiarrhythmic compounds were consistent with previous clinical trials, and identified optimal treatments for individual electrophysiological properties of the atria. Algorithms trained on 211 simulated AF episodes exhibited >70% accuracy in predictions of cardioversion for individual treatments using either ionic current profiles or ECG metrics. In structurally-healthy atria, AF inducibility and sustainability are enabled by discordant alternans, under high excitability and steep restitution conditions. Successful pharmacological cardioversion is predicted with 70% accuracy from either ionic or ECG properties, and it is optimal for treatments maximizing refractoriness (thus reducing excitability) for the given ionic current profile of the atria.

OBJECTIVE: Children have generally been excluded from early-stage clinical trials owing to safety concerns based in social expectations and not data. However, the repositioning of adult therapeutics for pediatric use and the increase in the development of therapies for pediatric only conditions require the participation of children in phase 1-2 trials. Therefore, the aim of this article is to systematically review the history and current state of early phase pediatric clinical pharmacology trials in order to understand safety concerns, trends, and challenges in pediatric trials.
METHODS: This review analyzed the nature of early phase pediatric clinical trials conducted for nononcology conditions through a systematic search that was performed for pediatric non-oncologic phase 1 or phase 1-2 drug and vaccine studies in MEDLINE.
RESULTS: The data show that the number of early phase pediatric clinical trials is still small relative to adults but has been on the rise in the past decade with relatively few serious adverse effects observed.
CONCLUSIONS: The widespread concerns about children\'s safety when they participate in early phase clinical trials seem disproportionate, based on our findings. The data confirm that these studies can be conducted safely, and that their results can contribute significantly to pediatric pharmacotherapy.

Psychedelics are hallucinogenic drugs that alter the state of consciousness substantially. They bring about psychological, auditory, and visual changes. The psychedelics act on the brain, implying that they have a powerful psychological impact. One of the main factors contributing to disability worldwide is pain. The majority of people deal with pain on a daily basis. Living with chronic pain affects daily life and has social implications. Chronic pain can be associated with any disease that may be genetic, idiopathic, or traumatic. The standard management of pain is done with pharmacological intervention and physical therapy. However, with time, patients may become resistant to a particular class of drugs. As these drugs do not help in treating the cause of pain, they act by blocking receptors and suppressing nervous systems, as this pharmacological intervention is not a permanent solution for pain management. Long-term use of the pharmacological intervention, which acts by suppressing the nervous system, may develop other side effects on the body. These standard therapies are not as effective in managing pain. The opioid class of drugs has good pain-relieving properties but causes addiction; it needs therapeutic drug monitoring to monitor that it is not abused. Since the first synthetic psychedelic was developed, until today, we have had a fair chance to understand its effects and side effects.​These drugs are very potent and effective. They have shown promising developments in the field of clinical psychology. There is upcoming research on psychedelics\' use in treating pain disorders. In this article, let us understand the effect of psychedelic drugs on the brain and body and how they modulate pain. Even today, the precise mechanism of chronic pain is still not understood completely. Psychedelics\' application and uses in future medicine and pain management are being studied. Understanding psychedelics\' effects on the brain and how they function allows us to link how they might be used to treat chronic pain.

UNASSIGNED: Hypertrophic cardiomyopathy (HCM) is a complex cardiac disease with highly variable phenotypic expression and clinical course most often caused by sarcomeric gene mutations resulting in left ventricular hypertrophy, fibrosis, hypercontractility, and diastolic dysfunction. For almost 60 years, HCM has remained an orphan disease and still lacks a disease-specific treatment.
UNASSIGNED: This review summarizes recent preclinical and clinical trials with repurposed drugs and new emerging pharmacological and gene-based therapies for the treatment of HCM.
UNASSIGNED: The off-label drugs routinely used alleviate symptoms but do not target the core pathophysiology of HCM or prevent or revert the phenotype. Recent advances in the genetics and pathophysiology of HCM led to the development of cardiac myosin adenosine triphosphatase inhibitors specifically directed to counteract the hypercontractility associated with HCM-causing mutations. Mavacamten, the first drug specifically developed for HCM successfully tested in a phase 3 trial, represents the major advance for the treatment of HCM. This opens new horizons for the development of novel drugs targeting HCM molecular substrates which hopefully modify the natural history of the disease. The role of current drugs in development and genetic-based approaches for the treatment of HCM are also discussed.

To review dasiglucagon, a novel glucagon analogue approved by the Food and Drug Administration (FDA) for treatment of severe hypoglycemia in 2021.
A literature search using the PubMed database (current to March 2022) and ClinicalTrials.gov was conducted using the search term dasiglucagon.
Relevant clinical data from English-language clinical trials were included.
Dasiglucagon was studied in 3 clinical trials: 1 in patients aged 6 to 17 years and 2 in adults. In all 3 trials, dasiglucagon was found to provide clinically significant benefit in minutes to plasma glucose recovery compared with placebo (10 vs 40, P < 0.001; 10 vs 30, P < 0.001; 10 vs 35, P < 0.0001). Dasiglucagon was also comparable with reconstituted glucagon in plasma glucose recovery time measured from time of administration. The most common adverse events with dasiglucagon were nausea, vomiting, and headache; no serious safety events were observed.
Dasiglucagon is a novel glucagon analogue that is safe and effective for the treatment of severe hypoglycemia, and it is the first to be stable in aqueous solution. This makes dasiglucagon one of only 3 currently available glucagon treatment options that does not require reconstitution prior to administration.
Dasiglucagon offers safe and effective treatment for severe hypoglycemia in patients aged 6 years and older. The stability of dasiglucagon in aqueous solution provides an additional option for emergency glucagon treatment that does not require reconstitution prior to administration.

To review the pharmacokinetics, efficacy, and safety of a newly approved topical Janus kinase 1 (JAK) inhibitor, ruxolitinib (RUX), in patients with atopic dermatitis (AD).
A literature search was completed May 1, 2022. The term RUX and AD was queried in MEDLINE (PubMed) and EMBASE databases.
Peer-reviewed articles written in English and published prior to May 1, 2022 were included.
In the phase II clinical trial, more patients treated with 1.5% topical RUX twice a day had a mean percentage improvement in Eczema Area and Severity Index (EASI) scores from baseline to 4 weeks, when compared to vehicle (71.6% vs 15.5%; P < 0.001). In phase III clinical trials, greater percentage of patients who received 0.75% topical RUX (TRuE-AD1 50.0% and TRuE-AD2 39.0%) or 1.5% topical RUX (TRuE-AD1 53.8% and TRuE-AD2 51.3%) achieved an Investigator\'s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) and had a ≥2-grade improvement from baseline to 8 weeks, when compared to vehicle (TRuE-AD1 15.1% and TRuE-AD2 7.6%; P < 0.001).
Atopic dermatitis is a highly prevalent long-term inflammatory skin condition. Pruritus is the main contributor of decreased quality of life in patients with AD. Topical RUX inhibits JAK1 and JAK2 producing antiinflammatory and antipruritic effects. Patients experienced a reduction in pruritus within 2 days. This decreased pruritus translated to increased quality of life and less sleep disturbances.
Data from phase II and III clinical trials in adult patients suggest RUX is an effective and safe therapy for AD.

BACKGROUND: COVID-19 triggered an unprecedented crisis affecting society at every level. Research in pediatric and congenital cardiology is currently in full development and may have been disrupted. The aim of the study was to determine the impact of COVID-19 on pediatric and congenital cardiology clinical research and to analyze decision-making and adaptation processes, from a panel of ongoing academic and industry-sponsored research at the time of the pandemic.
METHODS: This observational study was carried out in April 2020, from a CHD clinical research network involving five tertiary care pediatric and congenital cardiology centers. Investigators and clinical research assistants from each participating research center completed an online survey questionnaire, and each principal investigator underwent a 1-h web-based videoconference interview.
RESULTS: A total of 34 study questionnaires were collected, reporting that 18 studies were totally suspended. Upon the investigator\'s decision, after discussion on ethical issues and with facilitating support from health authorities, 16 studies were resumed. The rate of study suspension in interventional research (53%) was similar to that in non-interventional research (56%). Logistical problems were predominantly reported in both continued and suspended trials. Research protocols were adapted, largely thanks to telemedicine, which in some cases even improved the course of the study.
CONCLUSIONS: The impact of the COVID-19 pandemic on clinical research in pediatric and congenital cardiology has been limited by a rapid adaptation of all research structures and an extensive use of telemedicine at all stages of the studies.

Based on reported trends in relapse incidence among patients with relapsing-remitting multiple sclerosis, an original model for the response to disease modifying therapies is proposed. With a population approach and separate states for patients accounting for their risk of relapses, a system of nonlinear equations is formulated, similarly to established epidemiological models. Different parameters describe the effect of drugs and treatment switch in reducing the frequency of relapses. The model allows for a good fit to previously published data for experiments where different drugs are used. It also shows that different treatments maintain a high degree of similarity, with analogous dynamical features: a pre-treatment increment in relapse frequency leading to a distinct peak, a rapid drop after treatment switch and a plateau corresponding to a new base relapse activity, which seems dependant on the treatment chosen. A sensitivity analysis shows that the uncertainty in the initial proportions of different populations and the frequency of relapses can modify the overall dynamics of the response to treatment. Drugs are observed to induce effects that depend on patient sample\'s intrinsic characteristics, producing two clearly distinct and independent dynamics of relapse response. This confirms the clinical observation that certain drugs may be overall more successful in lowering the rate of relapses more significantly than others, notwithstanding the fact that patients behave differently across experiments.

To assess the impact of trials with potential financial conflict of interests (FCOIs) on evidence synthesis in meta-analyses (MAs).
A total of 96 MAs from the Cochrane Library about drug trials were investigated. The primary outcomes examined the proportion of conclusions that would change with the exclusion of trials with potential FCOIs. If the proportion of changed conclusions was below the non-inferiority margin of 10%, we considered that it was not inferior to include the trials with potential FCOIs in the MAs.
Only 54.17% of MAs reported the funding sources of each included trial, and in 21.88% of MAs, the author-industry-related financial ties of each included trial were reported. When trials with FCOIs were excluded, the changed conclusions of effectiveness and major adverse events were 13.16% and 11.11%, respectively, and the I2 decreased by 13.56% and 10.09%, respectively. For serious adverse events, the exclusion of FCOIs trials did not lead to any change in conclusions; however, the I2 decreased by 24.24%. The impact of trials without reported FCOIs was also examined on evidence synthesis, and the results showed that the changed conclusions of effectiveness and major adverse events were 5.26% and 6.25%, respectively, indicating non-inferiority. However, the I2 increased by 13.60% and 12.37%, respectively.
In this meta-epidemiological study, we demonstrated that trials with FCOIs may not only influence the final outcome of MAs but may also increase the heterogeneity of results. It is suggested that all MAs fully report the FCOIs involved in evidence-based research and explore the impact of its FCOIs to better provide a more valuable reference for patients, clinicians, and policy-makers.