Mask mandates for children during the COVID-19 pandemic: an international human rights perspective.

Epidemiological and physical safety issues form the core of the debate on whether children should be mandated to wear face masks during the COVID-19 pandemic. Largely absent from this debate are the crucial implications of international human rights law. Although the World Health Organization and the United Nations Children's Fund have different mask-wearing recommendations for children aged 0-5 years, 6-11 years, and 12+ years, the UN Convention on the Rights of the Child applies to children of all ages. Children's human rights under the UN Convention on the Rights of the Child and other treaties require decision makers to tread particularly carefully when deciding whether to mandate mask-wearing for children. Special consideration must be given to the potential for any detrimental impact of mask-wearing on children's physical, psychological and psychosocial health and wellbeing. Other non-pharmaceutical interventions for children, such as physical distancing, good hand hygiene and improved indoor ventilation do not engage the legal complexities of mask-wearing and are a safer policy option for reducing SARS-CoV-2 transmission.

International comparisons of COVID-19 case and mortality data and the effectiveness of non-pharmaceutical interventions: a plea for reconsideration.

International comparisons of the effectiveness of coronavirus disease 2019 (COVID-19) non-pharmaceutical interventions (NPIs) based on national case and mortality data are fraught with underestimated complexity. This article calls for stronger attention to just how extensive is the multifactorial nature of national case and mortality data, and argues that, unless a globally consistent benchmark of measurement can be devised, such comparisons are facile, if not misleading. This can lead to policy decisions and public support for the adoption of potentially harmful NPIs that are ineffective in combating the COVID-19 pandemic and damaging to mental health, social cohesion, human rights and economic development. The unscientific use of international comparisons of case and mortality data in public discourse, media reporting and policymaking on NPI effectiveness should be subject to greater scrutiny.

A knowledge-based, structural-aided discovery of a novel class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors.

Through an internal virtual screen at GlaxoSmithKline a distinct class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors were discovered. Careful evaluation of crystal structures and SAR led to a novel, potent, and orally active imidazopyridine inhibitor of H-PGDS, 20b. Herein, describes the identification of 2 classes of inhibitors, their syntheses, and their challenges.

The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure.

GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.

The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.

With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50 = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50 = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50 = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.

Administrative law as a determinant of public health.

Administrative law comprises the rules, values, and processes by which government and regulatory decision-making is subject to administrative monitoring, review, and accountability. It impacts public health in two ways: through the design, powers, and processes of institutions that enforce administrative law; and through the substantive rules of administrative law. Yet despite its fundamental regulation of the way in which public health decisions are made, insufficient research has been conducted on administrative law as a determinant of public health. Administrative law and public health operate as siloed academic disciplines with very little cross-disciplinary collaboration, engagement, or understanding. This results in major, untapped research opportunities exploring how administrative law could contribute to an optimized model of planetary health in both higher income and lower-middle income countries. Put simply, a holistic, global view of the determinants of public health must take due account of the accountability rules and controls that regulate how public health, and other, decisions are made. This commentary is a call to action to better understand how administrative law mechanisms, such as judicial review, administrative tribunals, ombudsmen, information commissioners, public auditors, and human rights monitors, can be designed or redesigned to better promote sustainable public health outcomes.

RéSUMé: Le droit administratif comprend les règles, les valeurs et les processus qui assujettissent la prise de décisions gouvernementales et réglementaires à la responsabilité, aux examens et aux suivis administratifs. Il influence la santé publique de deux façons : par la conception, les pouvoirs et les processus des institutions qui appliquent le droit administratif, et par les règles de fond du droit administratif. Pourtant, bien qu'il régisse fondamentalement la façon dont les décisions de santé publique se prennent, il n'y a pas suffisamment d'études sur le droit administratif en tant que déterminant de la santé publique. Le droit administratif et la santé publique sont exercés en tant que disciplines universitaires cloisonnées, avec très peu de collaboration, de participation ou de compréhension entre elles. Il y a donc d'immenses possibilités de recherche inexplorées pour savoir comment le droit administratif pourrait contribuer à un modèle de santé planétaire optimisé, dans les pays à revenu élevé comme dans les pays à revenu intermédiaire ou faible. En clair, une perspective holistique et mondiale des déterminants de la santé publique doit tenir compte des règles et des contrôles de responsabilité qui régissent la prise des décisions de santé publique, entre autres. Notre commentaire est un appel à mieux comprendre comment les mécanismes du droit administratif, comme le contrôle judiciaire, les tribunaux administratifs, les protecteurs du citoyen, les commissaires à l'information, les auditeurs du secteur public et les observateurs ayant pour fonction de veiller au respect des droits de la personne, peuvent être conçus ou redéfinis pour favoriser des effets durables sur le plan de la santé publique.

A Rare Multi-vessel Spontaneous Coronary Artery Dissection Case Requiring Balloon Intervention.

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome. This case involves a multivessel SCAD requiring intervention. The patient is a 39-year-old woman suffering from a non-ST elevation myocardial infarction caused by SCAD. The first coronary angiography revealed changes suggestive of acute distal left anterior descending (LAD) spontaneous dissection with partial occlusion and changes suggestive of old distal left anterior circumflex artery and obtuse marginal spontaneous dissections. A repeated angiogram revealed total occlusion of the distal LAD. Balloon angioplasty was done to the distal LAD, achieving a good flow. This case highlights the importance of diagnosis and treatment of SCAD. This case enhances our knowledge of atypical SCAD presentation (multi-vessel and required intervention) and emphasizes the need for individualized management strategies for optimal outcomes in each case.

The relationship between type 2 diabetes mellitus and failure to proton pump inhibitor treatment in gastroesophageal reflux disease.

BACKGROUND: There is limited information regarding the contribution of diabetes mellitus (DM) to proton pump inhibitor (PPI) failure in gastroesophageal reflux disease (GERD) patients. AIM: To determine whether type 2 DM is a risk factor for PPI failure and the potential predictive factors for PPI failure among type 2 DM patients with GERD. DESIGN: A case-control study was performed using hospital medical records of GERD patients treated with a PPI. The prevalence of type 2 DM and other risk factors (established >1 y before study enrollment) was determined in the PPI failure (treatment with more than once daily PPI) as compared with PPI responders. RESULTS: A total of 732 GERD patients receiving PPI therapy, including 285 who failed PPI treatment, were included. The overall prevalence of PPI failure was significantly higher in diabetic versus nondiabetic patients. The relationship between PPI failure and type 2 DM depended on body mass index. Only in obese patients the odds ratio of PPI failure was significantly higher in type 2 DM as compared with non-DM patients. In the subgroup of GERD patients with type 2 DM (n=349), PPI failure was significantly associated with female sex, the presence of general comorbidities, and adequate DM control. Duration of DM, type of antidiabetic medication prescribed, and DM-associated complications were not associated with PPI failure. CONCLUSIONS: PPI failure was significantly associated with type 2 DM in obese patients. Among GERD patients with type 2 DM, failure of PPI treatment was significantly associated with female sex and the presence of general comorbidities.

Impairment of skeletal muscle oxygen extraction and cardiac output are matched in precapillary pulmonary hypertension.

In precapillary pulmonary hypertension, exercising muscles extract oxygen to a similar level seen in healthy individuals. Exercise limitation is a result of impaired oxygen delivery, which is matched to any impairment in skeletal muscle oxygen extraction. https://bit.ly/3hQUY8m.

The Department of Veterans Affairs Gulf War Veterans' Illnesses Biorepository: Supporting Research on Gulf War Veterans' Illnesses.

AIMS: To introduce a resource supporting research on Gulf War illness (GWI) and related disorders, the Gulf War Veterans' Illnesses Biorepository (GWVIB). METHODS: Gulf War era veterans (GWVs) are recruited nationally and enrolled via telephone and email/postal mail. Enrolled veterans receive annual telephone and mail follow-up to collect health data until their passing. A postmortem neuropathological examination is performed, and fixed and frozen brain and spinal cord samples are banked to support research. Investigators studying GWI and related disorders may request tissue and data from the GWVIB. RESULTS: As of September 2021, 127 GWVs from 39 states were enrolled; 60 met the criteria for GWI, and 14 met the criteria for chronic multisymptom illness (CMI). Enrollees have been followed up to six years. Postmortem tissue recoveries were performed on 14 GWVs. The most commonly found neuropathologies included amyotrophic lateral sclerosis, chronic traumatic encephalopathy, and Lewy body disease. Tissue was of good quality with an average RNA integrity number of 5.8 (SD = 1.0) and ≥4.8 in all of the cases. DISCUSSION: The availability of health data and high-quality CNS tissue from this well-characterized GWV cohort will support research on GWI and related disorders affecting GWVs. Enrollment is ongoing.

N-{3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl}benzamide analogs as potent Kv1.3 inhibitors. Part 1.

We report the synthesis and in vitro activity of a series of novel N-{3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl}benzamide analogs. These analogs showed potent inhibitory activity against Kv1.3. Several compounds, including compound 8b, showed similar potency to the known Kv1.3 inhibitor PAP-1 when tested under the IonWorks patch clamp assay conditions.

Substituted N-{3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl}benzamide analogs as potent Kv1.3 ion channel blockers. Part 2.

We report the synthesis and in vitro activity of a series of novel substituted N-{3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl}benzamide analogs. These analogs showed potent inhibitory activity against Kv1.3. Several demonstrated similar potency to the known Kv1.3 inhibitor PAP-1 when tested under the IonWorks patch clamp assay conditions. Two compounds 13i and 13rr were advanced further as potential tool compounds for in vivo validation studies.

COVID-19 emergency measures and the impending authoritarian pandemic.

COVID-19 has brought the world grinding to a halt. As of early August 2020, the greatest public health emergency of the century thus far has registered almost 20 million infected people and claimed over 730,000 lives across all inhabited continents, bringing public health systems to their knees, and causing shutdowns of borders and lockdowns of cities, regions, and even nations unprecedented in the modern era. Yet, as this Article demonstrates-with diverse examples drawn from across the world-there are unmistakable regressions into authoritarianism in governmental efforts to contain the virus. Despite the unprecedented nature of this challenge, there is no sound justification for systemic erosion of rights-protective democratic ideals and institutions beyond that which is strictly demanded by the exigencies of the pandemic. A Wuhan-inspired all-or-nothing approach to viral containment sets a dangerous precedent for future pandemics and disasters, with the global copycat response indicating an impending 'pandemic' of a different sort, that of authoritarianization. With a gratuitous toll being inflicted on democracy, civil liberties, fundamental freedoms, healthcare ethics, and human dignity, this has the potential to unleash humanitarian crises no less devastating than COVID-19 in the long run.

Anthranilimide-based glycogen phosphorylase inhibitors for the treatment of Type 2 diabetes: 2. Optimization of serine and threonine ether amino acid residues.

Optimization of the amino acid residue of a series of anthranilimide-based glycogen phosphorylase inhibitors is described leading to the identification of serine and threonine ether analogs. t-Butylthreonine analog 20 displayed potent in vitro inhibition of GPa, low potential for P450 inhibition, and excellent pharmacokinetic properties.

Anthranilimide based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. Part 3: X-ray crystallographic characterization, core and urea optimization and in vivo efficacy.

Key binding interactions of the anthranilimide based glycogen phosphorylase a (GPa) inhibitor 2 from X-ray crystallography studies are described. This series of compounds bind to the AMP site of GP. Using the binding information the core and the phenyl urea moieties were optimized. This work culminated in the identification of compounds with single nanomolar potency as well as in vivo efficacy in a diabetic model.

Anthranilimide-based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes: 1. Identification of 1-amino-1-cycloalkyl carboxylic acid headgroups.

Optimization of the amino acid residue within a series of anthranilimide-based glycogen phosphorylase inhibitors is described. These studies culminated in the identification of anthranilimides 16 and 22 which displayed potent in vitro inhibition of GPa in addition to reduced inhibition of CYP2C9 and excellent pharmacokinetic properties.

Amino acid anthranilamide derivatives as a new class of glycogen phosphorylase inhibitors.

A series of amino acid anthranilamide derivatives identified from a high-throughput screening campaign as novel, potent, and glucose-sensitive inhibitors of human liver glycogen phosphorylase a are described. A solid-phase synthesis using Wang resin was also developed which provided efficient access to a variety of analogues, and resulted in the identification of key structure-activity relationships, and the discovery of a potent exemplar (IC(50)=80 nM). The SAR scope, synthetic strategy, and in vitro results for this series are presented herein.

Short-Term Hemodynamic Effects of Apelin in Patients With Pulmonary Arterial Hypertension.

Apelin agonism causes systemic vasodilatation and increased cardiac contractility in humans, and improves pulmonary arterial hypertension (PAH) in animal models. Here, the authors examined the short-term pulmonary hemodynamic effects of systemic apelin infusion in patients with PAH. In a double-blind randomized crossover study, 19 patients with PAH received intravenous (Pyr1)apelin-13 and matched saline placebo during invasive right heart catheterization. (Pyr1)apelin-13 infusion caused a reduction in pulmonary vascular resistance and increased cardiac output. This effect was accentuated in the subgroup of patients receiving concomitant phosphodiesterase type 5 inhibition. Apelin agonism is a novel potential therapeutic target for PAH. (Effects of Apelin on the Lung Circulation in Pulmonary Hypertension; NCT01457170).