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Background and Objective Atorvastatin is dosed in its active acid form although it exists in equilibrium with its inactive lactone form in vivo. Although in vitro atorvastatin acid displays pH-dependent conversion to the lactone metabolite, pharmacokinetic (PK) data on the effect of elevated gastric pH on atorvastatin and major atorvastatin-related species are not currently available. In this dedicated study, we investigated the effect of food and acid-reducing agents on the PK of atorvastatin and its three major metabolites in humans. Methods This was an open label, randomized, crossover study conducted in 17 healthy volunteers. Part 1 examined the PK of a 10-mg dose of atorvastatin co-administered with or without a 600-mg dose of sodium bicarbonate in fasted and fed states. Part 2 was a single assessment to examine the PK of a 10-mg dose of atorvastatin in the fasted state following a 5-day treatment course of 40-mg daily esomeprazole. Gastric pH was monitored during treatments using Heidelberg capsules. A linear mixed effects model was used to derive ratios for PK parameters of atorvastatin and metabolites between treatments. Results Similar to previous food effect studies, food significantly decreased the maximum concentration ( C max ) and increased the time to C max ( t max ) of atorvastatin, with minimal effect on total exposure of atorvastatin or metabolites. Neither sodium bicarbonate, in the fed or fasted state, nor treatment with esomeprazole had a clinically meaningful effect on the exposure of atorvastatin or its metabolites. Conclusions According to these results, atorvastatin PK does not appear to be sensitive to changes in gastric pH.

Atorvastatin is dosed in its active acid form although it exists in equilibrium with its inactive lactone form in vivo. Although in vitro atorvastatin acid displays pH-dependent conversion to the lactone metabolite, pharmacokinetic (PK) data on the effect of elevated gastric pH on atorvastatin and major atorvastatin-related species are not currently available. In this dedicated study, we investigated the effect of food and acid-reducing agents on the PK of atorvastatin and its three major metabolites in humans. This was an open label, randomized, crossover study conducted in 17 healthy volunteers. Part 1 examined the PK of a 10-mg dose of atorvastatin co-administered with or without a 600-mg dose of sodium bicarbonate in fasted and fed states. Part 2 was a single assessment to examine the PK of a 10-mg dose of atorvastatin in the fasted state following a 5-day treatment course of 40-mg daily esomeprazole. Gastric pH was monitored during treatments using Heidelberg capsules. A linear mixed effects model was used to derive ratios for PK parameters of atorvastatin and metabolites between treatments. Similar to previous food effect studies, food significantly decreased the maximum concentration (C ) and increased the time to C (t ) of atorvastatin, with minimal effect on total exposure of atorvastatin or metabolites. Neither sodium bicarbonate, in the fed or fasted state, nor treatment with esomeprazole had a clinically meaningful effect on the exposure of atorvastatin or its metabolites. According to these results, atorvastatin PK does not appear to be sensitive to changes in gastric pH.

Once again there has been a tragedy involving a child and a firearm [\"Tragedy's Aftermath,\" March 2]. The firearm in question was stolen and taken to a crack house where the 6-year-old shooter lived. His mom and dad were nowhere to be found. No safety lock, no instant check, no waiting period, no law, would have prevented this shooting. President Bill Clinton is leading the way for further restrictions on law-abiding citizens. There are already 20,000 laws on the books in the United States regarding firearms. Would one more have helped here? No. Nassau's fiscal woes were a long time in the making and the result of many factors, not the least of which was total denial. I was encouraged that a number of key Republican elected officials have finally begun to acknowledge the enormity of the county's fiscal situation, reflected in recent comments from County Executive Thomas Gulotta and Minority Leader Peter Schmitt. Sen. Dean Skelos (R- Rockville Centre) has now at least opened the door to some kind of helpful oversight board for Nassau County [\"As Nassau Fiddles, Control From Albany Looms,\" Viewpoints, Feb. 28]. But his article contained one glaring omission. He wrote, \"While the county executive has the ultimate responsibility to balance Nassau's budget, the new Democratic majority in the county legislature has to step up and be accountable as well.\" But where are the state senators who \"helped\" us last year with the transfer tax, and what is the role of the Republican minority, whose stellar \"leadership\" helped create this fiscal quagmire?

The RNA-binding protein (RBP) TAF15 is implicated in amyotrophic lateral sclerosis (ALS). To compare TAF15 function to that of two ALS-associated RBPs, FUS and TDP-43, we integrate CLIP-seq and RNA Bind-N-Seq technologies, and show that TAF15 binds to ∼4,900 RNAs enriched for GGUA motifs in adult mouse brains. TAF15 and FUS exhibit similar binding patterns in introns, are enriched in 3′ untranslated regions and alter genes distinct from TDP-43. However, unlike FUS and TDP-43, TAF15 has a minimal role in alternative splicing. In human neural progenitors, TAF15 and FUS affect turnover of their RNA targets. In human stem cell-derived motor neurons, the RNA profile associated with concomitant loss of both TAF15 and FUS resembles that observed in the presence of the ALS-associated mutation FUS R521G, but contrasts with late-stage sporadic ALS patients. Taken together, our findings reveal convergent and divergent roles for FUS, TAF15 and TDP-43 in RNA metabolism. Abnormal functions of RNA-binding proteins TAF15, FUS and TDP43 are associated with amyotrophic lateral sclerosis. Here, Kapeli et al . characterize the RNA targets of TAF15 and identify points of convergence and divergence between the targets of TAF15, FUS and TDP43 in several neuronal systems.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year. Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described. De novo mutations in developmental disorders Matthew Hurles, Jeremy McRae and colleagues from the Deciphering Developmental Disorders Study report exome sequencing of 4,293 families containing individuals with severe, undiagnosed developmental disorders. They find enrichment of damaging de novo mutations in 94 genes, implicating them in developmental disorders. They estimate that 42% of the cohort carry pathogenic de novo mutations in coding sequences resulting in disrupted or altered protein function.

Cardiovascular, respiratory, and related disorders (CVRDs) are the leading causes of adult death worldwide, and substantial inequalities in care of patients with CVRDs exist between countries of high income and countries of low and middle income. Based on current trends, the UN Sustainable Development Goal to reduce premature mortality due to CVRDs by a third by 2030 will be challenging for many countries of low and middle income. We did systematic literature reviews of effectiveness and cost-effectiveness to identify priority interventions. We summarise the key findings and present a costed essential package of interventions to reduce risk of and manage CVRDs. On a population level, we recommend tobacco taxation, bans on trans fats, and compulsory reduction of salt in manufactured food products. We suggest primary health services be strengthened through the establishment of locally endorsed guidelines and ensured availability of essential medications. The policy interventions and health service delivery package we suggest could serve as the cornerstone for the management of CVRDs, and afford substantial financial risk protection for vulnerable households. We estimate that full implementation of the essential package would cost an additional US$21 per person in the average low-income country and $24 in the average lower-middle-income country. The essential package we describe could be a starting place for low-income and middle-income countries developing universal health coverage packages. Interventions could be rolled out as disease burden demands and budgets allow. Our outlined interventions provide a pathway for countries attempting to convert the UN Sustainable Development Goal commitments into tangible action.

Background SARS-CoV-2 is a recently emerged pandemic coronavirus (CoV) capable of causing severe respiratory illness. However, a significant number of infected people present as asymptomatic or pauci-symptomatic. In this prospective assessment of at-risk healthcare workers (HCWs) we seek to determine whether pre-existing antibody or T cell responses to previous seasonal human coronavirus (HCoV) infections affect immunological or clinical responses to SARS-CoV-2 infection or vaccination. Methods A cohort of 300 healthcare workers, confirmed negative for SARS-CoV-2 exposure upon study entry, will be followed for up to 1 year with monthly serology analysis of IgM and IgG antibodies against the spike proteins of SARS-CoV-2 and the four major seasonal human coronavirus - HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63. Participants will complete monthly questionnaires that ask about Coronavirus Disease 2019 (COVID-19) exposure risks, and a standardized, validated symptom questionnaire (scoring viral respiratory disease symptoms, intensity and severity) at least twice monthly and any day when any symptoms manifest. SARS-CoV-2 PCR testing will be performed any time participants develop symptoms consistent with COVID-19. For those individuals that seroconvert and/or test positive by SARS-CoV-2 PCR, or receive the SARS-CoV-2 vaccine, additional studies of T cell activation and cytokine production in response to SARS-CoV-2 peptide pools and analysis of Natural Killer cell numbers and function will be conducted on that participant’s cryopreserved baseline peripheral blood mononuclear cells (PBMCs). Following the first year of this study we will further analyze those participants having tested positive for COVID-19, and/or having received an authorized/licensed SARS-CoV-2 vaccine, quarterly (year 2) and semi-annually (years 3 and 4) to investigate immune response longevity. Discussion This study will determine the frequency of asymptomatic and pauci-symptomatic SARS-CoV-2 infection in a cohort of at-risk healthcare workers. Baseline and longitudinal assays will determine the frequency and magnitude of anti-spike glycoprotein antibodies to the seasonal HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63, and may inform whether pre-existing antibodies to these human coronaviruses are associated with altered COVID-19 disease course. Finally, this study will evaluate whether pre-existing immune responses to seasonal HCoVs affect the magnitude and duration of antibody and T cell responses to SARS-CoV-2 vaccination, adjusting for demographic covariates.

The 27,540-ha (68,000-acre) Sacramento–San Joaquin River Delta of northern California is the largest freshwater estuary on the western coast of the United States. The Delta provides irrigation water for over$30 billion in crops in the Delta and Central Valley and drinking water for 27 million people, supports $ 300 million in recreational boating, and includes the ports of West Sacramento and Stockton. The Delta’s sloughs, wetlands and riparian habitats host 56 threatened or endangered species. Invasions by nonnative aquatic weeds constitute a major environmental challenge. The USDA–ARS Areawide Pest Management Program focuses on integrated, adaptive control of invasive pests, by supporting implementation of new, science-based control solutions. The Delta Region Areawide Aquatic Weed Project (DRAAWP) was funded from 2014 to 2018 to improve control of floating water hyacinth [Eichhornia crassipes (Mart.) Solms], submersed Brazilian waterweed (Egeria densa Planch.), and riparian arundo (Arundo donax L.) in the Delta. Outputs from the DRAAWP are now informing control of nine aquatic weeds and arundo using adaptive, integrated chemical, mechanical, and biological approaches. Project outputs include improved knowledge of aquatic weed growth and dispersal, models of watershed nutrients, weed control prioritization protocols based on remote sensing and economic cost modeling, and new tools. Outcomes include the implementation of use of new herbicides and biological control agents, improved control efficacy, lowered stakeholder costs, and the leveraging of expertise and funding focused on aquatic weed control for habitat restoration. Benefits include reduced floating aquatic weed coverage, conservation of water and wildlife natural resources, and protection of boating and other economic activities.

ObjectiveThe objective of the study was to assess the effectiveness of training low-to-middle-income countries' local healthcare providers using the Train-the-trainers model in basic colposcopy for cervical cancer prevention.MethodThis project was designed based on a philosophy known as Train-the-trainers which train proficient colposcopists and a cadre of local trainers who can continue to train and maintain their expertise in a self-sustaining system. The Train-the-trainers workshop is a 1-day program that focuses on three domains; knowledge, communication, and practical skills. Trainer candidates were given pre-course reading assignments and presentation decks. The expert trainers provided feedback on their presentations and tips on communication skills. The practical aspects of the training are supported by proficiency at the Loop Electro-excision procedure simulator and their responses to frequently asked questions.ResultsSixteen physicians from Vietnam attended the Colposcopy Workshop in 2018 and are used as controls. Eleven attended a workshop conducted by trainer candidates who went through the training program outlined above in 2019. A Wilcoxon Signed-ranks test indicated that differences between pre- and post-quizzes' scores were statistically significant in both the 2018 (Z=4.21, P=0.003, r=1.26) and 2019 cohorts (Z=3.558, P<0.001, r=0.89) while Mann–Whitney U test did not detect the difference between the 2018 and 2019 cohorts, U=70.0, P=0.359, r=0.176. The subjective feedback scores from Year 2019 were similar to scores to Year 2018.ConclusionOur preliminary data did not highlight any differences between lectures delivered by expert trainers and lectures delivered by trainer candidates trained in the program. Train-the- trainers might be a more sustainable model for organically raising expertise to effectively provide cervical cancer screening and prevention in low-to-middle-income countries.