Aggressive vs. conservative phototherapy for infants with extremely low birth weight.

BACKGROUND: It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less). METHODS: We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments. RESULTS: Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 micromol per liter], P\u3c0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g. CONCLUSIONS: Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials.gov number, NCT00114543.

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

DYX1C1 is required for axonemal dynein assembly and ciliary motility

DYX1C1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deleting exons 2–4 of Dyx1c1 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease, laterality defects and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1 c.T2A start-codon mutation recovered from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also caused laterality and ciliary motility defects. In humans, we identified recessive loss-of-function DYX1C1 mutations in 12 individuals with PCD. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans showed disruptions of outer and inner dynein arms (ODAs and IDAs, respectively). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA and IDA assembly factor DNAAF2 (KTU). Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4)

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

Mental health and psychological wellbeing in the early stages of doctoral study: A systematic review

As concerns about poor mental health and psychological wellbeing (wellbeing) in doctoral students grow, the early stage of doctoral study has been identified as a prime opportunity for early intervention and prevention strategies. To inform the development of such strategies, it is important and timely to understand what is known about doctoral student mental health and wellbeing in the early stages. The aim of this systematic mixed studies review was to synthesise published research on mental health and wellbeing in early-stage doctoral students (ESDS). After conducting electronic searches on 10 databases and manual searches, 26 studies matching the eligibility criteria were identified. Thematic synthesis revealed there is limited evidence regarding the prevalence of mental health and wellbeing concerns. and the effects of the transition to doctoral study on mental health and wellbeing. More promisingly, the synthesis generated understanding of factors related to mental health and wellbeing in ESDS. Finally, a single mental health and/or wellbeing intervention in ESDS was identified. The review underscores the need for more high-quality research to allow more robust conclusions to be drawn about mental health and wellbeing in ESDS

Mental health and psychological wellbeing in the early stages of doctoral study: What do we currently know?

Doctoral students appear to be at high risk of experiencing poor mental health and psychological wellbeing. The early stage of doctoral study has been identified as a potential opportunity to implement early intervention and prevention strategies to tackle these issues. Therefore, it is important and timely to understand what is known about mental health and psychological wellbeing in the early stages of the doctoral journey. The aim of this study was to systematically review, synthesise, and appraise research that has examined mental health and psychological wellbeing in early-stage doctoral students. After conducting electronic searches on 10 databases and manual searches, data from 24 studies were included in the review and analysed through thematic synthesis. The review identified stress as a prominent concern for early-stage doctoral students. Although there was limited evidence regarding the effects of the transition to doctoral study on mental health and psychological wellbeing, the existing evidence appeared to suggest that the demands of early-stage doctoral study can be detrimental. The synthesis generated novel understanding of factors related to mental health and wellbeing in early-stage doctoral students. No mental health and/or psychological wellbeing intervention in early-stage doctoral students was identified. The review underscores the need for more high-quality research to advance understanding of early-stage doctoral student mental health and psychological wellbeing. Based on the factors related to mental health and psychological wellbeing in the review, this paper discusses the potential utility of an ecological systems perspective to understand mental health and psychological wellbeing in early-stage doctoral students

A deeper meaning for shallow-level phylogenomic studies: nested anchored hybrid enrichment offers great promise for resolving the tiger moth tree of life (Lepidoptera: Erebidae: Arctiinae)

Anchored hybrid enrichment (AHE) has emerged as a powerful tool for uncovering the evolutionary relationships within many taxonomic groups. AHE probe sets have been developed for a variety of insect groups, though none have yet been shown to be capable of simultaneously resolving deep and very shallow (e.g., intraspecific) divergences. In this study, we present NOC1, a new AHE probe set (730 loci) for Lepidoptera specialized for tiger moths and assess its ability to deliver phylogenetic utility at all taxonomic levels. We test the NOC1 probe set with 142 individuals from 116 species sampled from all the major lineages of Arctiinae (Erebidae), one of the most diverse groups of noctuoids (\u3e11 000 species) for which no well-resolved, strongly supported phylogenetic hypothesis exists. Compared to previous methods, we generally recover much higher branch support (BS), resulting in the most well-supported, well-resolved phylogeny of Arctiinae to date. At the most shallow-levels, NOC1 confidently resolves species-level and intraspecific relationships and potentially uncovers cryptic species diversity within the genus Hypoprepia. We also implement a “sensitivity analysis” to explore different loci combinations and site sampling strategies to determine whether a reduced probe set can yield results similar to those of the full probe set. At both deep and shallow levels, only 50–175 of the 730 loci included in the complete NOC1 probe set were necessary to resolve most relationships with high confidence, though only when the more rapidly evolving sites within each locus are included. This demonstrates that AHE probe sets can be tailored to target fewer loci without a significant reduction in BS, allowing future studies to incorporate more taxa at a lower per-sample sequencing cost. NOC1 shows great promise for resolving long-standing taxonomic issues and evolutionary questions within arctiine lineages, one of the most speciose clades within Lepidoptera