Inhibitory Effects of Novel Immucillin Analogues on \u3ci\u3eBorrelia burgdorferi\u3c/i\u3e Bgp Nucleosidase

The pathogenic spirochaete Borrelia burgdorferi causes Lyme disease and is transmitted by deer ticks when they feed. Lyme disease is multisystemic—it adversely affects the heart, joints, and skin. Recent studies demonstrate that B. burgdorferi possesses three methylthioadenosine/Sadenosylhomocysteine (MTA/SAH) nucleosidases essential for the catabolic breakdown of both MTA and SAH. Both MTA and SAH are by-products of major pathways involving Sadenosylmethionine (SAM) and are kept at low micromolar concentrations due to their inhibitory activity. This project examined the effect of transition state inhibitors on the surface binding Borrelia glycosaminoglycanbinding protein (Bgp) nucleosidase using recombinant Bgp and whole-cell B. burgdorferi activity assays. The transition state analogues are potent inhibitors of Bgp activity with Ki values ranging from 6pM-6nM. Bgp on the surface of live B. burgdorferi was also inhibited by treatment with low nanomolar concentrations of transition state analogues

Pair Formation in Structured Populations

This issue was undated. The date given is an estimate.26 pages, 1 article*Pair Formation in Structured Populations* (Castillo-Chavez, Carlos; Busenberg, Stavros; Gerow, Ken) 26 page

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Fisher Consistency - the Evolution of a Concept: It's Hard to Get It Right the First Time

23 pages, 1 article*Fisher Consistency - the Evolution of a Concept: It's Hard to Get It Right the First Time* (Gerow, Ken) 23 page

Post COVID-19 Water and Waste Water Management to Protect Public Health and Geoenvironment

The coronavirus disease 2019 pandemic has posed severe threats to humans and the geoenvironment. The findings of severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) traces in waste water and the practice of disinfecting outdoor spaces in several cities in the world, which can result into the entry of disinfectants and their by-products into storm drainage systems and their subsequent discharge into rivers and coastal waters, raise the issue of environmental, ecological and public health effects. The aims of the current paper are to investigate the potential of water and waste water to operate as transmission routes for Sars-CoV-2 and the risks of this to public health and the geoenvironment. Additionally, several developing countries are characterised by low water-related disaster resilience and low household water security, with measures for protection of water resources and technologies for clean water and sanitation being substandard or not in place. To mitigate the impact of the pandemic in such cases, practical recommendations are provided herein. The paper calls for the enhancement of research into the migration mechanisms of viruses in various media, as well as in the formation of trihalomethanes and other disinfectant by-products in the geoenvironment, in order to develop robust solutions to combat the effects of the current and future pandemics

Model-Unbiased, Unbiased-in-General Estimation of the Average of a Regression Function

16 pages, 1 article*Model-Unbiased, Unbiased-in-General Estimation of the Average of a Regression Function* (Gerow, Ken; McCulloch, Charles E.) 16 page