Liability

Using an electrochemical C(sp3 )-H fluorination reaction, a series of α-fluorinated tropane compounds were synthesized and their druglikeness parameters were assessed to compare with the parent compounds. Improvements were observed in membrane permeability, P-gp liability, and inhibitory effects on hERG and Nav 1.5 channels, accompanied with a trend of decreased aqueous solubility and microsomal stability. It was also revealed that α-fluorination reduced the basicity of tropane nitrogen atom for about 1000-fold...

New therapies to treat or prevent viral infections are essential, as recently observed during the COVID-19 pandemic. Here, we propose a therapeutic strategy based on monoclonal antibodies that block the specific interaction between the host receptor Siglec-1/CD169 and gangliosides embedded in the viral envelope. Antibodies are an excellent option for treating infectious diseases based on their high specificity, strong targeting affinity, and relatively low toxicity. Through a process of humanization, we optimized monoclonal antibodies to eliminate sequence liabilities and performed biophysical characterization...

BACKGROUND: The increased pervasiveness of digital health technology is producing large amounts of person-generated health data (PGHD). These data can empower people to monitor their health to promote prevention and management of disease. Women make up one of the largest groups of consumers of digital self-tracking technology. OBJECTIVE: In this scoping review, we aimed to (1) identify the different areas of women's health monitored using PGHD from connected health devices, (2) explore personal metrics collected through these technologies, and (3) synthesize facilitators of and barriers to women's adoption and use of connected health devices...

BACKGROUND: Clinical signs of dysphagia, pancreatic achalasia, and esophagitis have been reported in patients with COVID-19. However, the causal relationship between COVID-19 and esophageal diseases is not clear. Therefore, we utilized Mendelian randomization to explore the potential association between COVID-19 and esophageal diseases. METHODS: The summary statistics for a Genome-wide association study (GWAS) were obtained from The COVID-19 Host Genetics Initiative, encompassing four types of COVID-19 as exposure: severe COVID-19, hospitalized COVID-19 versus ambulatory COVID-19, hospitalized COVID-19 versus uninfected, and confirmed COVID-19...

INTRODUCTION: Rare copy number variants (CNVs) and polygenic risk for intelligence (PRS-IQ) both confer susceptibility for autism spectrum disorder (ASD) but have opposing effects on cognitive ability. The field has struggled to disentangle the effects of these two classes of genomic variants on cognitive ability from their effects on ASD susceptibility, in part because previous studies did not include controls with cognitive measures. We aim to investigate the impact of these genomic variants on ASD risk while adjusting for their known effects on cognitive ability...

In a genome-wide association study (GWAS) meta-analysis of 685,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries and across diverse and admixed ancestries, we identify 697 independent associations at 636 loci, 293 of which are novel. Using fine-mapping and functional genomic tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. Leveraging new single-cell gene expression data, we conducted a causal neural cell type enrichment analysis that implicates dysregulation of excitatory and inhibitory midbrain and forebrain neurons, peptidergic neurons, and medium spiny neurons in MD...

S1P (sphingosine 1-phosphate) receptor modulator (SRM) drugs interfere with lymphocyte trafficking by downregulating lymphocyte S1P receptors. While the immunosuppressive activity of SRM drugs has proved useful in treating autoimmune diseases such as multiple sclerosis, that drug class is beset by on-target liabilities such as initial dose bradycardia. The S1P that binds to cell surface lymphocyte S1P receptors is provided by S1P transporters. Mice born deficient in one of these, spinster homolog 2 (Spns2), are lymphocytopenic and have low lymph S1P concentrations...

OBJECTIVE: Treatment-resistant depression (TRD) occurs in roughly one-third of all individuals with major depressive disorder (MDD). Although research has suggested a significant common variant genetic component of liability to TRD, with heritability estimated at 8% when compared with non-treatment-resistant MDD, no replicated genetic loci have been identified, and the genetic architecture of TRD remains unclear. A key barrier to this work has been the paucity of adequately powered cohorts for investigation, largely because of the challenge in prospectively investigating this phenotype...

PURPOSE OF REVIEW: This review outlines novel, emerging legal risks for in-vitro fertilization (IVF) providers and patients. RECENT FINDINGS: This article reviews recent antiabortion legal developments that create novel legal risks to IVF. This article examines new potential liability for the handling or managing of embryos, and threats to safe, efficient, standard-of-care practice of IVF. It reviews established US and international judicial and regulatory frameworks based on scientifically grounded recognition of IVF embryos as deserving of 'special respect', and finds this approach to be an alternative for law and policy makers...

Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule L-2-hdroxyglutarate (L-2HG) is elevated in the most common histology of renal cancer. Similar to other oncometabolites, L-2HG has the potential to profoundly impact gene expression. Here, we demonstrate that L-2HG remodels amino acid metabolism in renal cancer cells through the combined effects on histone methylation and RNA N6-methyladenosine (m6A)...

Perceptual learning is commonly understood as conferring some benefit to the learner, such as allowing for the extraction of more information from the environment. However, perceptual learning can be biased in several different ways, some of which do not appear to provide such a benefit. Here we outline a systematic framework for thinking about bias in perceptual learning and discuss how several cases fit into this framework. We argue these biases are compatible with an understanding in which perceptual learning is beneficial, but that its benefits are tied to both a person's narrow interests and the training environment or domain, and so if there are changes to either of these, then benefits can turn into liabilities, though these are often temporary...

Introduction Polygenic Score (PGS) is a valuable method for assessing the estimated genetic liability to a given outcome or genetic variability contributing to a quantitative trait. While PRSs are widely used for complex traits, their application in uncovering shared genetic predisposition between phenotypes, i.e. when genetic variants influence more than one phenotype, remains limited. Methods We developed an R package, comorbidPGS, which facilitates a systematic evaluation of shared genetic effects among (cor)related phenotypes using PGSs...

High rates of suicide continue to plague the modern world, with clinicians, researchers, and policymakers working urgently to ameliorate what has been recognized as a worldwide public health crisis. Under American Law, individuals- including health care providers, could generally not be held liable for causing the suicide of another person. This article presents a review of suicide law in the United States in the context of a recent civil case in which a physician with expertise in mental health was sued for the death of an ex-partner who committed suicide in his home...

Benzodiazepines are commonly prescribed drugs for numerous indications such as epilepsy, anti-anxiety, sleep aids, sedatives, and hypnotics. Although the well-tolerated effects of benzodiazepine are seen in many clinical instances, the severity of side effects reduces its quantifiable use. Benzodiazepines, which are medically useful but theoretically unsafe, are frequently recommended by medical practitioners for psychotic patients but have misuse and dependence liabilities. It is impelled as a debateable topic globally about which no one talks...

In contemporary healthcare systems, the pursuit of justice intertwines with fault attribution and liability determination. The exploration of no-fault liability as a potential alternative within India's healthcare landscape delves into its feasibility and implications. Drawing from international experiences, regulatory frameworks, and societal readiness, the complexities and potential benefits of adopting a no-fault liability system are elucidated. Perspectives from patients, healthcare providers, and broader societal stakeholders are considered, highlighting both the advantages and challenges associated with such a transition...

The relationship between a doctor and a patient is a contract, retaining the essential elements of the tort. Modern medical practice has evolved alongside the court of law to regulate the conduct of doctors and hospitals to reduce litigations of medical negligence. Lately, Indian patients have become more aware of their rights and the Consumer Protection Act. This awareness encourages patients to litigate and seek the help of redressal forums to mitigate their loss/injury in cases of medical negligence. Though there is a rise in complaints of medical negligence filed against doctors and hospitals, these allegations are often frivolous...

PURPOSE OF REVIEW: The pace of psychedelic treatments continues to increase. Regulation and coherent clinical guidance have not been established. A philosophical divide limits effective resolution of a practice delivery quandary: is this primarily a pharmacological or psychotherapeutic intervention? RECENT FINDINGS: Lykos (formerly MAPS) has submitted its new drug application (NDA) request to the FDA for 3-4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for PTSD and is expecting a response by the summer of 2024...

OBJECTIVES: Increased rates of mental health disorders and substance use among youth and young adults have increased globally, furthering the strain on an already burdened mental health system. Digital solutions have been proposed as a potential option for the provision of timely mental health services for youth, with little research exploring mental health professional views about using such innovative tools. In Alberta, Canada, we are evaluating the implementation and integration of a digital mental health (dMH) platform into existing service pathways...

UNLABELLED: Policy Points Opioid treatment agreements (OTAs) are controversial because of the lack of evidence that their use reduces opioid-related harms and the potential risks they pose of stigmatizing patients and undermining the clinician-patient relationship. Even so, their use is now required in most jurisdictions, and their use is influencing the outcomes of civil and criminal lawsuits. More research is needed to evaluate how OTAs are implemented given existing requirements. If additional research does not resolve the current level of uncertainty regarding OTA benefits, then policymakers in jurisdictions where they are required should consider eliminating OTA mandates or providing flexibility in the legal requirements to make room for clinicians and health care institutions to implement best practices...

BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism ( n = 3681; ages 11-36)...