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INTRODUCTION Every single day I have a conversation with a patient in which I say, 'Abortion would be a really safe and valid option for you and I'm so sorry [...]

Introduction In 2021 the Uniform Law Commission (ULC) gave final approval to the Uniform Cohabitants' Economic Remedies Act (UCERA). (1) Resting on both contractual and equitable principles, the Act provides [...]

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson’s disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

Selfish genetic elements contribute to hybrid incompatibility and bias or ‘drive’ their own transmission1,2. Chromosomal drive typically functions in asymmetric female meiosis, whereas gene drive is normally post-meiotic and typically found in males. Here, using single-molecule and single-pollen genome sequencing, we describe Teosinte Pollen Drive, an instance of gene drive in hybrids between maize (Zea maysssp. mays) and teosinte mexicana(Z. maysssp. mexicana) that depends on RNA interference (RNAi). 22-nucleotide small RNAs from a non-coding RNA hairpin in mexicanadepend on Dicer-like 2(Dcl2) and target Teosinte Drive Responder 1(Tdr1), which encodes a lipase required for pollen viability. Dcl2, Tdr1and the hairpin are in tight pseudolinkage on chromosome 5, but only when transmitted through the male. Introgression of mexicanainto early cultivated maize is thought to have been critical to its geographical dispersal throughout the Americas3, and a tightly linked inversion in mexicanaspans a major domestication sweep in modern maize4. A survey of maize traditional varieties and sympatric populations of teosinte mexicanareveals correlated patterns of admixture among unlinked genes required for RNAi on at least four chromosomes that are also subject to gene drive in pollen from synthetic hybrids. Teosinte Pollen Driveprobably had a major role in maize domestication and diversification, and offers an explanation for the widespread abundance of ‘self’ small RNAs in the germ lines of plants and animals.

Retrotransposons have invaded eukaryotic centromeres in cycles of repeat expansion and purging, but the function of centromeric retrotransposons has remained unclear. In Arabidopsis, centromeric ATHILAretrotransposons give rise to epigenetically activated short interfering RNAs in mutants in DECREASE IN DNA METHYLATION1(DDM1). Here we show that mutants that lose both DDM1 and RNA-dependent RNA polymerase have pleiotropic developmental defects and mis-segregate chromosome 5 during mitosis. Fertility and segregation defects are epigenetically inherited with centromere 5, and can be rescued by directing artificial small RNAs to ATHILA5retrotransposons that interrupt tandem satellite repeats. Epigenetically activated short interfering RNAs promote pericentromeric condensation, chromosome cohesion and chromosome segregation in mitosis. We propose that insertion of ATHILAsilences centromeric transcription, while simultaneously making centromere function dependent on retrotransposon small RNAs in the absence of DDM1. Parallels are made with the fission yeast Schizosaccharomycespombe, where chromosome cohesion depends on RNA interference, and with humans, where chromosome segregation depends on both RNA interference and HELLSDDM1.

IMPORTANCE: Inconsistent reporting of outcomes in clinical trials of rosacea is impeding and likely preventing accurate data pooling and meta-analyses. There is a need for standardization of outcomes assessed during intervention trials of rosacea. OBJECTIVE: To develop a rosacea core outcome set (COS) based on key domains that are globally relevant and applicable to all demographic groups to be used as a minimum list of outcomes for reporting by rosacea clinical trials, and when appropriate, in clinical practice. EVIDENCE REVIEW: A systematic literature review of rosacea clinical trials was conducted. Discrete outcomes were extracted and augmented through discussions and focus groups with key stakeholders. The initial list of 192 outcomes was refined to identify 50 unique outcomes that were rated through the Delphi process Round 1 by 88 panelists (63 physicians from 17 countries and 25 patients with rosacea in the US) on 9-point Likert scale. Based on feedback, an additional 11 outcomes were added in Round 2. Outcomes deemed to be critical for inclusion (rated 7-9 by ≥70% of both groups) were discussed in consensus meetings. The outcomes deemed to be most important for inclusion by at least 85% of the participants were incorporated into the final core domain set. FINDINGS: The Delphi process and consensus-building meetings identified a final core set of 8 domains for rosacea clinical trials: ocular signs and symptoms; skin signs of disease; skin symptoms; overall severity; patient satisfaction; quality of life; degree of improvement; and presence and severity of treatment-related adverse events. Recommendations were also made for application in the clinical setting. CONCLUSIONS AND RELEVANCE: This core domain set for rosacea research is now available; its adoption by researchers may improve the usefulness of future trials of rosacea therapies by enabling meta-analyses and other comparisons across studies. This core domain set may also be useful in clinical practice.

In two phase 3 trials for first-line therapy in adults with HIV-1, doravirine showed non-inferior efficacy, a favourable safety profile, and a superior lipid profile to darunavir and efavirenz through to 48 and 96 weeks. Here we report 192-week results from both studies.

AbstractWe evaluated the prevalence and treatment of asymptomatic bacteriuria (ASB) in 17 critical-access hospitals. Among 891 patients with urine cultures from September 2021 to June 2022, 170 (35%) had ASB. Also, 76% of patients with ASB received antibiotics for a median duration of 7 days, demonstrating opportunities for antimicrobial stewardship.

Environmental, social and governance (ESG) measures are taking over the world of investor activism, driving corporate change--and shareholder votes. While boards weigh policies to add ESG objectives to company strategy, [...]

In 2018, Germany's Federal Court of Justice considered whether the parents of a 15-year-old girl who had been killed by a train could access her Facebook account. Her parents wanted [...]

Cryogenic treatment of metal offers breakthrough reductions in wear and corrosion to users of marine components--lowering maintenance and capital replacement cost and increasing operational uptime. The technology has languished in the starting gate since WWII, however, and only recently emerged as a way to address wear and corrosion in post-heat-treated items., This article will explore the benefits of deep cryogenics, why the technology stalled and where it can be next used by the oil-and-gas (O&G) and marine communities. The Problem Increasing [...]

The Trace of An Implied Presence The Shed, New York August 3-December 11, 2022 Tiona Nekkia McClodden's The Trace of An Implied Presence features an ambitious multimedia installation that follows [...]

Severe insulin resistance syndromes result from primary insulin signaling defects, adipose tissue abnormalities or other complex syndromes. Mutations in TBC1D4lead to partial insulin signaling defects, characterized mainly by postprandial insulin resistance. We describe an individual with severe insulin-resistant diabetes unresponsive to multiple therapies, in whom exome and genome analyses identified a complex rearrangement in TBC1D4. The rearrangement was of the pattern DUP-TRP/INV-DUP, with mutational signatures suggestive of replicative repair and Alu-Alurecombination as the underlying mechanisms. TBC1D4encodes the TBC1D4/AS160 RabGTPase activating protein (RabGAP) involved in the translocation of glucose transporter 4 (GLUT4) from the cytosol to the cell membrane. Although the precise functional mechanism underlying insulin resistance in the proband is yet to be determined, this case provides further support for the link between TBC1D4and hereditary insulin-resistant diabetes.

ObjectivesVarious organic acids are used to create nicotine salt formulations, which may improve the appeal and sensory experience of vaping electronic cigarettes (e-cigarettes). This clinical experiment examined the effects of partially and highly protonated forms of two nicotine salt formulations (nicotine lactate and benzoate) versus free-base (no acid additive) on the appeal and sensory attributes of e-cigarettes.MethodsCurrent adult tobacco product users (n=116) participated in an online remote double-blind within-subject randomised experiment involving standardised self-administration of e-cigarette solutions varying in nicotine formulation (free-base, 50% nicotine lactate –1:2 lactic acid to nicotine molar ratio, 100% nicotine lactate – 1:1 ratio, 50% nicotine benzoate and 100% nicotine benzoate). Each formulation had equivalent nicotine concentrations (27.0–33.0 mg/mL) and was administered in four flavours in a pod-style device. After each administration, participants rated appeal (liking, disliking and willingness to use again) and sensory attributes (0–100 scale).ResultsCompared with free-base nicotine, 50% and 100% nicotine lactate and benzoate yielded higher appeal, smoothness and sweetness and lower harshness and bitterness. Dose–response analyses found 100% vs 50% nicotine salt improved appeal, smoothness, bitterness and harshness for nicotine lactate and sweetness, smoothness and harshness for nicotine benzoate. Solutions with higher pH were associated with worse appeal and sensory attributes across nicotine formulations. Nicotine formulation effects did not differ by tobacco use status and flavours.ConclusionRestricting benzoic acid or lactic acid additives or setting minimal pHs in e-cigarettes merits consideration in regulations designed to reduce vaping among populations deterred from using e-cigarettes with aversive sensory properties.Trial registration numberThis study was registered under ClinicalTrials.gov Identifier: NCT03742817under the title ‘Effects of e-Cigarettes on Perceptions and Behavior’.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5and DCC), synaptic structure and function genes (for example, PCLO, NCAM1and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

This scoping review identifies existing literature that investigates what factors contribute to success on the American Board of Surgery (ABS) Certifying Exam (CE) to provide practical, evidence-based recommendations.

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ABSTRACT: In an increasing number of states, divorce presumptively renders an ex-spouse ineligible to benefit from the testator's will. Divorce may also impact other revocable dispositions in favor of the [...]

the United States Supreme Court has held that criminal defense counsel is constitutionally obligated to advise noncitizen defendants about the immigration consequences of guilty pleas and to defend against these [...]

•Age of >60 years and remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS.•Use of myeloablative conditioning with total body irradiation was predictive for improved DFS and reduced risk of relapse.

Almost half of prostate cancer patients with pathogenic germline variants (PGVs) are missed by the National Comprehensive Cancer Network criteria, which were also less effective at predicting PGVs in patients from under-represented populations. Universal germline genetic testing should be considered for all prostate cancer patients.

Involvement of lower gastrointestinal tract (LGI) occurs in 60% of patients with graft-versus-host-disease (GVHD). Complement components C3 and C5 are involved in GVHD pathogenesis. In this phase 2a study, we evaluated the safety and efficacy of ALXN1007, a monoclonal antibody against C5a, in patients with newly diagnosed LGI acute GVHD receiving concomitant corticosteroid. Twenty-five patients were enrolled; one was excluded from the efficacy analysis based upon negative biopsy. Most patients (16/25, 64%) had acute leukemia; 52% (13/25) had an HLA-matched unrelated donor; and 68% (17/25) received myeloablative conditioning. Half the patients (12/24) had a high biomarker profile, Ann Arbor score 3; 42% (10/24) had high-risk GVHD per Minnesota classification. Day-28 overall response was 58% (13/24 complete response, 1/24 partial response), and 63% by Day-56 (all complete responses). Day-28 overall response was 50% (5/10) in Minnesota high-risk and 42% (5/12) in high-risk Ann Arbor patients, increasing to 58% (7/12) by Day-56. Non-relapse mortality at 6-months was 24% (95% CI 11–53). The most common treatment-related adverse event was infection (6/25, 24%). Neither baseline complement levels (except for C5), activity, nor inhibition of C5a with ALXN1007 correlated with GVHD severity or responses. Further studies are needed to evaluate the role of complement inhibition in GVHD treatment.

Is your plan already a member of a health care coalition, and are you wondering if the coalition is benefiting your plan and decreasing its costs? Or is your plan [...]

Although there is considerable uncertainty regarding the future of health care legislation and its effect on the health care industry, one thing remains highly likely: Providers can expect to see [...]

Although there is considerable uncertainty regarding the future of health care legislation and its effect on the health care industry, one thing remains highly likely: Providers can expect to see [...]

Although there is considerable uncertainty regarding the future of healthcare legislation and its effect on the healthcare industry, one thing remains highly likely: Providers can expect to see continuing proliferation [...]

Introduction The Harvard Committee Prior to 1968, death in the United States was defined as cessation of all vital functions including respiration and heartbeat. In 1968, the Dean of Harvard [...]

Newspapers are filled with stories about Martin Shkreli's $750 per pill Daraprim[R], Mylan's $600 per package EpiPen[R] treatments and projected double-digit prescription price increases for 2017. But if you think [...]

This newsletter examines problems and rights of Romani children in East Central Europe, focusing on such topics as: the displaced childhoods of Romani children; snapshots of living conditions in various European countries; Roma child rights; Romani and non-Romani schools in Bulgaria; Romani children's rights to education in Central and Eastern Europe and in France; institutionalizing Romani children in Italy; testimony from a Romani mother in Hungary who had her children removed from her; human rights education (the United Nations 2001 special session on children); advocacy (the United Nations Race Discrimination Committee's thematic discussion on the Roma); attacks against Kosovo's Romani minorities; testing to prove racial discrimination in Hungary; grants and donors supporting human rights work; one Central European family's experiences; Romani language publications; guidelines for European Roma Rights Center grants; grants awarded; a chronicle of efforts to campaign for Roma rights; and conferences and meetings. (SM)

If your plan is seeking ways to control soaring prescription coverage costs, you must position yourself to learn about--and respond to--at least six marketplace challenges that undoubtedly are driving up [...]

I. Introduction The 2010s have been a decade of greatly increased scrutiny regarding the level of control that franchisors exert over their franchisees. While much of that scrutiny has been [...]

Lessons in Censorship: How Schools and Courts Subvert Students' First Amendment Rights (Catherine J. Ross) I. Introduction Public school officials have considerable authority to regulate student expression within the school [...]

Introduction A half century ago, American family lives did not differ markedly by class or region; children were born to married parents, shotgun marriages helped keep the nonmarital birth rate [...]

Fifth Circuit Upholds the Enforcement of Two Abortion Provisions of a Texas Act--Whole Woman's Health v. Lakey (1)--On August 29, 2014, the District Court for the Western District of Texas [...]

AbstractNonspecific respiratory symptoms overlap with coronavirus disease 2019 (COVID-19). Prompt diagnosis of COVID-19 in hospital employees is crucial to prevent nosocomial transmission. Rapid molecular SARS-CoV-2 testing was performed for 115 symptomatic employees. The case positivity rate was 2.6%. Employees with negative tests returned to work after 80 (±28) minutes.

IMPORTANCE: Dapagliflozin reduces the risk of hospitalizations for heart failure and the progression of chronic kidney disease in patients with and without type 2 diabetes (T2D), whereas the effects on reducing atherosclerotic events appear less clear. OBJECTIVE: To explore whether N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) levels can identify a subset of patients with T2D at higher risk and who might benefit more from dapagliflozin with regard to atherosclerotic events. DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of the DECLARE-TIMI 58 trial, a randomized clinical trial of dapagliflozin in patients with T2D and either multiple risk factors for atherosclerotic cardiovascular disease (ASCVD; approximately 60%) or established ASCVD (approximately 40%). All patients with available blood samples at randomization were included in these analyses. Data were collected from May 2013 to September 2018, and data were analyzed from May 2019 to June 2022. INTERVENTIONS: Dapagliflozin vs placebo. MAIN OUTCOMES AND MEASURES: Major adverse cardiovascular events (MACE), the composite of myocardial infarction, ischemic stroke, or cardiovascular death, which was one of dual primary outcomes of the main trial. RESULTS: Of 14 565 included patients, 9143 (62.8%) were male, and the mean (SD) age was 63.9 (6.8) years. When tested individually in a multivariable model for MACE risk, NT-proBNP and hsTnT were each significantly associated with the risk of MACE (adjusted hazard ratio [aHR] per 1 SD in log-transformed biomarker: NT-proBNP, 1.62; 95% CI, 1.49-1.76; hsTnT: 1.59; 95% CI, 1.46-1.74). The magnitude of the association was similar in patients with ASCVD (NT-proBNP: aHR, 1.60; 95% CI, 1.45-1.77; hsTnT: aHR, 1.62; 95% CI, 1.45-1.81) and multiple risk factors for ASCVD (NT-proBNP: aHR, 1.62; 95% CI, 1.40-1.88; hsTnT: aHR, 1.51; 95% CI, 1.29-1.77). Moreover, both biomarkers remained independently associated with MACE when both were included in the multivariable model (NT-proBNP: aHR, 1.46; 95% CI, 1.34-1.60; hsTnT: aHR, 1.39; 95% CI, 1.26-1.53). Modeled as a continuous variable, baseline biomarker levels did not modify the relative treatment effect of dapagliflozin vs placebo with MACE. However, the relative risk reduction numerically grew with higher biomarker levels, as did the baseline risk. Thus, MACE event rates were nominally lower in dapagliflozin-treated vs placebo-treated patients with biomarker concentrations in the top quartile (NT-proBNP: HR, 0.83; 95% CI, 0.71-0.97; absolute risk reduction [ARR], 2.4%; hsTnT: HR, 0.85; 95% CI, 0.72-0.99; ARR, 2.7%), whereas there was no significant treatment effect in patients with biomarkers levels in quartiles 1 to 3 (NT-proBNP: HR, 1.02; 95% CI, 0.88-1.18; ARR, 0%; hsTnT: HR, 0.97; 95% CI, 0.84-1.13; ARR, 0.2%). CONCLUSIONS AND RELEVANCE: In this study, NT-proBNP and hsTnT levels were associated with the risk for future cardiovascular events in both primary and secondary prevention patients with T2D. Both cardiac biomarkers were helpful to identify patients at very high risk for atherosclerotic events that may derive reduction in risk of MACE with dapagliflozin. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01730534

In people with type 2 diabetes at high risk of cardiovascular or kidney disease, sodium-glucose co-transporter 2 (SGLT2) inhibitors consistently reduce the risk of hospitalisations for heart failure. Less is known about their effects on hospitalisation from any cause, especially in people with type 2 diabetes without atherosclerotic cardiovascular disease, which includes most of the global population of people with type 2 diabetes. We aimed to assess the effect of the SGLT2 inhibitor, dapagliflozin, on the risks of hospitalisations for any cause and for specific causes in people with type 2 diabetes with and without atherosclerotic cardiovascular disease.

The article focuses on the transformation of TimeBanks.org and their vision for the future of TimeBanking. It mentions the aim to connect communities, strengthen the TimeBanking movement, and provide support to TimeBanks through community programs and technological advancements. It highlight the organization seeks to build a global network of TimeBanks and foster a culture of collaboration and mutual respect.

People living with HIV have accounted for 38–50% of those affected in the 2022 multicountry mpox outbreak. Most reported cases were in people who had high CD4 cell counts and similar outcomes to those without HIV. Emerging data suggest worse clinical outcomes and higher mortality in people with more advanced HIV. We describe the clinical characteristics and outcomes of mpox in a cohort of people with HIV and low CD4 cell counts (CD4 <350 cells per mm3).

The world is a different place today than it was at the beginning of 2020 mainly because of the coronavirus, which has led to big changes in the economy, socializing, [...]

In 2013, U.S. Trust commissioned a survey of over 700 high net worth individuals. Although three-quarters had a will, almost the same number did not have a comprehensive estate plan, [...]