Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876-A Less Toxic and More Potent Analogue of Bedaquiline.

Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia.

Enhancing diastolic function by strain-dependent detachment of cardiac myosin crossbridges.

The force response of cardiac muscle undergoing a quick stretch is conventionally interpreted to represent stretching of attached myosin crossbridges (phase 1) and detachment of these stretched crossbridges at an exponential rate (phase 2), followed by crossbridges reattaching in increased numbers due to an enhanced activation of the thin filament (phases 3 and 4). We propose that, at least in mammalian cardiac muscle, phase 2 instead represents an enhanced detachment rate of myosin crossbridges due to stretch, phase 3 represents the reattachment of those same crossbridges, and phase 4 is a passive-like viscoelastic response with power-law relaxation. To test this idea, we developed a two-state model of crossbridge attachment and detachment.

Informing diversion strategy: A comparison of parent and general practitioner-referred paediatric patients presenting to a metropolitan hospital.

Objective: To determine whether the characteristics and outcomes of parent-referred children differ substantially from general practitioner (GP)-referred children attending a metropolitan ED.

Methods: Prospective cross-sectional observational study of consecutive patients aged less than 16 years of age attending a mixed adult and paediatric metropolitan teaching hospital ED in Melbourne. Data collected included patient characteristics (age, sex, arrival mode and triage category) and outcomes (admission, specialty consultation, treatment time >1 h, intravenous or nasogastric therapy, procedural sedation, procedures, imaging studies and pathology collection).

Let Them Eat Healthy: Can Emerging Potassium Binders Help Overcome Dietary Potassium Restrictions in Chronic Kidney Disease?

Potassium-rich foods might provide many health benefits even to people who have declining renal function. The barrier to obtaining these health benefits has long been the concern over hyperkalemia. There are new and novel treatment options available which may enable patients with chronic kidney disease to obtain the health benefits of eating a diet that contains foods such as fruits and vegetables which are high in potassium while reducing the risk of hyperkalemia.

Relationships between hamstring morphological characteristics and postural balance in elderly men.

Objectives: The link between hamstring morphology and postural balance performance in older adults is not well understood. This study aimed to examine the relationships between hamstring morphological characteristics of muscle size (cross-sectional area [CSA]) and quality (echo intensity [EI]) and postural balance with the eyes open and closed in elderly men.

Methods: Nineteen healthy elderly men (age= 73±4 years) participated in this study.

Can gut microbiota of men who have sex with men influence HIV transmission?

Gaining a complete understanding of transmission risk factors will assist in efforts to reduce new HIV infections, especially within the disproportionally affected population of men who have sex with men (MSM). We recently reported that the fecal microbiota of MSM elevates immune activation in gnotobiotic mice and enhances HIV infection over that of fecal microbiota from men who have sex with women. We also demonstrated elevation of the gut homing marker CD103 (integrin αE) on CD4 T cells by MSM-microbiota.

Mirtazapine's effect on the QT interval in medically hospitalized patients.

Introduction: Mirtazapine is generally well tolerated in medically ill patients with and without formal psychiatric comorbidity to target sleep, appetite, nausea, and pain. However, there is little data regarding mirtazapine's potential to prolong the corrected QT interval (QTc) in this population.

Methods: From a retrospective cohort of patients hospitalized on a variety of medical units for whom a psychiatric consult recommended mirtazapine, electrocardiogram (ECG) data were extracted for ECGs obtained up to 3 days before and 6 days after the initial consult.

A highly reflective biogenic photonic material from core-shell birefringent nanoparticles.

Spectacular natural optical phenomena are produced by highly reflective assemblies of organic crystals. Here we show how the tapetum reflector in a shrimp eye is constructed from arrays of spherical isoxanthopterin nanoparticles and relate the particle properties to their optical function. The nanoparticles are composed of single-crystal isoxanthopterin nanoplates arranged in concentric lamellae around a hollow core.

Routine Repeat Head CT Does Not Change Management in Trauma Patients on Novel Anticoagulants.

Introduction: Guidelines for imaging anticoagulated patients following a traumatic injury are unclear. Interval CT head (CTH) is often routinely performed after initial negative CTH to assess for delayed intracranial hemorrhage (ICH-d). The rate of ICH-d for patients taking novel oral anticoagulants (NOACs) is unknown.

Qualitative study of loneliness in a senior housing community: the importance of wisdom and other coping strategies.

Objective: Older adults are at a high risk for loneliness, which impacts their health, well-being, and longevity. While related to social isolation, loneliness is a distinct, internally experienced, distressing feeling. The present qualitative study sought to identify characteristics of loneliness in older adults living independently within a senior housing community, which is typically designed to reduce social isolation.

Potassium Homeostasis, Chronic Kidney Disease, and the Plant-Enriched Diets.

There are data demonstrating that ingestion of potassium-rich foods reduces the incidence of stroke, hypertension, nephrolithiasis, and osteoporosis. Dietary-consumption data indicate Westernized diets are high in processed foods, high in sodium content, and low in potassium. In fact, there are data suggesting individuals are not consuming enough potassium in their diet.

Aging and Trauma: Post Traumatic Stress Disorder Among Korean War Veterans.

Having experienced posttraumatic stress disorder 30 years prior to its recognition as a formal disorder, Korean War veterans are now an aging population that requires unique clinical management.

B Cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis.

Activated B cells modulate infection by differentiating into pathogen-specific antibody-producing effector plasmablasts/plasma cells, memory cells, and immune regulatory B cells. In this context, the B cell phenotypes that infiltrate the central nervous system during human immunodeficiency virus (HIV) and cryptococcal meningitis coinfection are ill defined. We characterized clinical parameters, mortality, and B cell phenotypes in blood and cerebrospinal fluid (CSF) by flow cytometry in HIV-infected adults with cryptococcal ( = 31) and noncryptococcal ( = 12) meningitis and in heathy control subjects with neither infection ( = 10).

The role of estrogens in the adipose tissue milieu.

One of the leading causes for the development of adverse metabolic effects, including type 2 diabetes, dyslipidemia, and cardiovascular diseases, is the accumulation of excess body weight, often measured by body mass index (BMI). Although BMI, calculated using weight and height, is the standard measure used to determine body adiposity in clinical and public health guidelines, an inherent limitation is that BMI does not distinguish where in the body adiposity is deposited. Central obesity, characterized by greater accumulation of adiposity in the abdominal region, has been associated with a higher risk of mortality, independent of BMI.

Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology.

Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.

Guanine and 7,8-Dihydroxanthopterin Reflecting Crystals in the Zander Fish Eye: Crystal Locations, Compositions, and Structures.

The eyes of many fish contain a reflecting layer of organic crystals partially surrounding the photoreceptors of the retina, which are commonly believed to be composed of guanine. Here we study an unusual fish eye from that contains two layers of organic crystals. The crystals in the outer layer are thin plates, whereas the crystals in the inner tapetum layer are block-shaped.

Fluid overload as a therapeutic target for the preservative management of chronic kidney disease.

Purpose Of Review: There is growing clinical evidence of adverse effects of fluid overload on kidney outcomes in patients with cardiovascular disease who are not yet receiving kidney replacement therapy. In this review, we discuss the patient populations most at risk for fluid overload, the pathophysiology associated with fluid overload, and finally treatment options.

Recent Findings: The severity of fluid overload is an independent risk factor for both an increased risk of rapidly declining kidney function and increased risk for the need of kidney replacement therapy.

Potassium binding for conservative and preservative management of chronic kidney disease.

Purpose Of Review: Hyperkalemia is a life-threatening complication of chronic kidney disease (CKD). Risk factors include advanced kidney impairment, diabetes, hypertension, heart failure, and consumption of a K-enriched diet. High-K diets provide health benefits to include reductions in blood pressure, stroke risk, and osteoporosis.

Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Potassium disorders are common in patients with kidney disease, particularly in patients with tubular disorders and low glomerular filtration rate. A multidisciplinary group of researchers and clinicians met in October 2018 to identify evidence and address controversies in potassium management. The issues discussed encompassed our latest understanding of the regulation of tubular potassium excretion in health and disease; the relationship of potassium intake to cardiovascular and kidney outcomes, with increasing evidence showing beneficial associations with plant-based diet and data to suggest a paradigm shift from the idea of dietary restriction toward fostering patterns of eating that are associated with better outcomes; the paucity of data on the effect of dietary modification in restoring abnormal serum potassium to the normal range; a novel diagnostic algorithm for hypokalemia that takes into account the ascendency of the clinical context in determining cause, aligning the educational strategy with a practical approach to diagnosis; and therapeutic approaches in managing hyperkalemia when chronic and in the emergency or hospital ward.

Potassium Binders for Hyperkalemia in Chronic Kidney Disease-Diet, Renin-Angiotensin-Aldosterone System Inhibitor Therapy, and Hemodialysis.

Hyperkalemia is a potentially life-threatening complication of chronic kidney disease (CKD). The management of CKD requires balancing the benefits of specific treatments, which may exacerbate the potential for hyperkalemia, with the risks of hyperkalemia itself. Renin-angiotensin-aldosterone system (RAAS) inhibitors, which slow CKD progression and improve cardiovascular outcomes, are often discontinued if hyperkalemia develops.

Mediators of a Physical Activity Intervention on Cognition in Breast Cancer Survivors: Evidence From a Randomized Controlled Trial.

Background: Emerging research suggests that increasing physical activity can help improve cognition among breast cancer survivors. However, little is known about the mechanism through which physical activity impacts cancer survivors' cognition.

Objective: The objective of this secondary analysis examined physical and psychological function potentially linking physical activity with changes in cognition among breast cancer survivors in a randomized controlled trial where the exercise arm had greater improvements in cognition than the control arm.

Reply to comment on Couzi . (2018): a phenomenological model for structural phase transitions in incommensurate alkane/urea inclusion compounds.

In a recent paper (Couzi 2018 , 180058. (doi:10.1098/rsos.