Discovery and Optimization of N-Heteroaryl Indazole LRRK2 Inhibitors.

Inhibition of leucine-rich repeat kinase 2 is a genetically supported mechanism for the treatment of Parkinson's disease. We previously disclosed the discovery of an indazole series lead that demonstrated both safety and translational risks. The safety risks were hypothesized to be of unknown origin, so structural diversity in subsequent chemical matter was prioritized.

Policy responses to COVID-19: lessons for the global trade and investment regime.

Background: During the past two years, the COVID-19 pandemic has cost millions of lives around the globe, caused major morbidity and provoked widespread economic and social disruption. In response, governments have enacted policies to mitigate the impacts of the pandemic. This research focuses in on policies aimed at increasing access to essential health products and services by comparing them to the global rules governing trade, investment and intellectual property.

Contracting retail pharmacies as a source of essential medicines for public sector clients in low- and middle-income countries: a scoping review of key considerations, challenges, and opportunities.

Background: Insurances in high-income countries (HIC) often contract with private community pharmacies to dispense medicines to outpatients. In contrast, dispensing of medicines in low- and middle-income countries (LMICs) often lacks such contractual arrangements. Furthermore, many LMICs lack sufficient investment in supply chains and financial and human resources to guarantee stock levels and services at public medicine-dispensing institutions.

Taiwan's National Health Insurance at the Emergency Department following the COVID-19 outbreak.

Taiwan's National Health Insurance (NHI) is a widely acclaimed universal healthcare system. In the past few years, particularly following the COVID-19 outbreak, challenges related to maintaining the NHI system have surfaced. Since 2020, NHI has faced a series of challenges, including excessive patient visits to the hospital emergency department, a lack of an effective primary care and referral system, and a high turnover rate of healthcare workers.

Heritable defects in telomere and mitotic function selectively predispose to sarcomas.

Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls.

Community Genetics screening in a pandemic: solutions for pre-test education, informed consent, and specimen collection.

A Community Genetics carrier screening program for the Jewish community has operated on-site in high schools in Sydney (Australia) for 25 years. During 2020, in response to the COVID-19 pandemic, government-mandated social-distancing, 'lock-down' public health orders, and laboratory supply-chain shortages prevented the usual operation and delivery of the annual testing program. We describe development of three responses to overcome these challenges: (1) pivoting to online education sufficient to ensure informed consent for both genetic and genomic testing; (2) development of contactless telehealth with remote training and supervision for collecting genetic samples using buccal swabs; and (3) a novel patient and specimen identification 'GeneTrustee' protocol enabling fully identified clinical-grade specimens to be collected and DNA extracted by a research laboratory while maintaining full participant confidentiality and privacy.

Assessment and referral of patients with short stature by primary care physicians in the Arabian gulf region: Current perspectives from a regional survey.

Children with short stature are frequently referred late to pediatric endocrinologists in the Arabian Gulf region. This is likely a contributing factor to late initiation of treatment despite current evidence suggesting that children with short stature have better outcomes with earlier treatment. This delay in referral could be due to a lack of identification or proper assessment of short stature by front-line physicians.

Patent "Evergreening" of Medicine-Device Combination Products: A Global Perspective.

Background: Patenting medicine-delivery devices (inhalers and pens) is controversial when it extends market protections beyond that of the underlying therapeutic agent. We evaluated how common device patenting is, internationally.

Method: Using a product sample (n = 88) and an international patent database, we assessed the issue's scope.

Out-of-pocket expenditure on medicines in Bangladesh: An analysis of the national household income and expenditure survey 2016-17.

Background And Objectives: High out-of-pocket expenditures (OOPE) increases the probability that households will become impoverished or will forgo needed care. The aim of this paper is to study household medicines expenditure and its associated determining factors to develop policies to protect households from financial hardship.

Methods: The present cross-sectional and population-level study used the Bangladesh 2016-17 National Household Income and Expenditure Survey (HIES).

The Solubility Limit of Carbon in Alumina at 1,600°C.

The solubility limit of carbon in -AlO (alumina) equilibrated at 1,600°C under He in a graphite furnace was measured by wavelength-dispersive spectroscopy. Undoped alumina and alumina containing carbon at a concentration resulting in the precipitation of a second phase were prepared and equilibrated at 1,600°C. The undoped alumina was used to quantify the amount of carbon deposited on the surface of samples because of hydrocarbon contamination in the electron microscope, and this background level was removed from the signal measured from carbon-doped samples.

Randomized trial of prophylactic antibiotics vs. placebo after midshaft-to-distal hypospadias repair: the PROPHY Study.

Background: Use of prophylactic antibiotics after stented hypospadias repair is very common, but most research has not identified any clinical benefits of this practice. Only one study has found that postoperative prophylaxis reduces symptomatic urinary tract infections (UTIs). Data from the same trial suggested that prophylaxis may also reduce urethroplasty complications.

Diabetes and Ramadan: Practical guidelines 2021.

Fasting during Ramadan is one of the five pillars of Islam and is obligatory for all healthy Muslims from the age of puberty. Though individuals with some illness and serious medical conditions, including some people with diabetes, can be exempted from fasting, many will fast anyway. It is of paramount importance that people with diabetes that fast are given the appropriate guidance and receive proper care.

Id Proteins Promote a Cancer Stem Cell Phenotype in Mouse Models of Triple Negative Breast Cancer via Negative Regulation of Robo1.

Breast cancers display phenotypic and functional heterogeneity and several lines of evidence support the existence of cancer stem cells (CSCs) in certain breast cancers, a minor population of cells capable of tumor initiation and metastatic dissemination. Identifying factors that regulate the CSC phenotype is therefore important for developing strategies to treat metastatic disease. The Inhibitor of Differentiation Protein 1 (Id1) and its closely related family member Inhibitor of Differentiation 3 (Id3) (collectively termed Id) are expressed by a diversity of stem cells and are required for metastatic dissemination in experimental models of breast cancer.

Equitable Expanded Carrier Screening Needs Indigenous Clinical and Population Genomic Data.

Expanded carrier screening (ECS) for recessive monogenic diseases requires prior knowledge of genomic variation, including DNA variants that cause disease. The composition of pathogenic variants differs greatly among human populations, but historically, research about monogenic diseases has focused mainly on people with European ancestry. By comparison, less is known about pathogenic DNA variants in people from other parts of the world.

Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer.

Background: Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies.

The Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly.

Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes.

ELF5 modulates the estrogen receptor cistrome in breast cancer.

Acquired resistance to endocrine therapy is responsible for half of the therapeutic failures in the treatment of breast cancer. Recent findings have implicated increased expression of the ETS transcription factor ELF5 as a potential modulator of estrogen action and driver of endocrine resistance, and here we provide the first insight into the mechanisms by which ELF5 modulates estrogen sensitivity. Using chromatin immunoprecipitation sequencing we found that ELF5 binding overlapped with FOXA1 and ER at super enhancers, enhancers and promoters, and when elevated, caused FOXA1 and ER to bind to new regions of the genome, in a pattern that replicated the alterations to the ER/FOXA1 cistrome caused by the acquisition of resistance to endocrine therapy.

Impacts of intellectual property provisions in trade treaties on access to medicine in low and middle income countries: a systematic review.

Background: We present a systematic review describing ex-ante and ex-post evaluations of the impacts of intellectual property provisions in trade treaties on access to medicine in low and middle income countries. These evaluations focused on multilateral and bilateral trade agreements. We ascertained which IP provisions impacting access to medicines were the focus of these evaluations.

The implementation of the bioequivalence certification policy in Chile: An analysis of market authorization data.

Background: Affordability is a key barrier to access to medicines. Generic medicines policies can address this barrier and promote access. Successful uptake of generic medicines depends, in part, on ensuring that these products are interchangeable with reference products.

Evaluation of the effects of a generic substitution policy implemented in Chile.

Introduction: Chile implemented a generic substitution policy in 2014 to improve access to medicines. This study aims to measure if the generic substitution policy had an effect on the sales volume and prices of referent and the branded generic products with demonstrated bioequivalence (BEQ) in the private pharmaceutical market.

Methods: The volume and total private sales of medicines sold at private sector retail outlets between November 2011 and October 2016 were considered in the analysis.

A perspective on global access to insulin: a descriptive study of the market, trade flows and prices.

Aim: To describe the global insulin market.

Methods: Market intelligence data, United Nations Commodity Trade Statistics for insulin trade, the International Medical Products Price Guide for prices of human insulin and additional web searches were used as data sources. These sources were combined to gain further insight into possible links among market, trade flows and prices.

Modular Total Synthesis and Cell-Based Anticancer Activity Evaluation of Ouabagenin and Other Cardiotonic Steroids with Varying Degrees of Oxygenation.

A Cu(II)-catalyzed diastereoselective Michael/aldol cascade approach is used to accomplish concise total syntheses of cardiotonic steroids with varying degrees of oxygenation including cardenolides ouabagenin, sarmentologenin, 19-hydroxysarmentogenin, and 5- epi-panogenin. These syntheses enabled the subsequent structure activity relationship (SAR) studies on 37 synthetic and natural steroids to elucidate the effect of oxygenation, stereochemistry, C3-glycosylation, and C17-heterocyclic ring. Based on this parallel evaluation of synthetic and natural steroids and their derivatives, glycosylated steroids cannogenol-l-α-rhamnoside (79a), strophanthidol-l-α-rhamnoside (92), and digitoxigenin-l-α-rhamnoside (97) were identified as the most potent steroids demonstrating broad anticancer activity at 10-100 nM concentrations and selectivity (nontoxic at 3 μM against NIH-3T3, MEF, and developing fish embryos).