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

Using high-resolution contact networks to evaluate SARS-CoV-2 transmission and control in large-scale multi-day events

The emergence of highly transmissible SARS-CoV-2 variants has created a need to reassess the risk posed by increasing social contacts as countries resume pre-pandemic activities, particularly in the context of resuming large-scale events over multiple days. To examine how social contacts formed in different activity settings influences interventions required to control Delta variant outbreaks, we collected high-resolution data on contacts among passengers and crew on cruise ships and combined the data with network transmission models. We found passengers had a median of 20 (IQR 10–36) unique close contacts per day, and over 60% of their contact episodes were made in dining or sports areas where mask wearing is typically limited. In simulated outbreaks, we found that vaccination coverage and rapid antigen tests had a larger effect than mask mandates alone, indicating the importance of combined interventions against Delta to reduce event risk in the vaccine era

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Variability in Findings From Adult Protective Services Investigations of Elder Abuse in California.

Adult Protective Services (APS) workers in California investigate complaints of elder abuse and must determine the validity of a complaint with minimal guidelines. It is unclear whether APS workers reach similar conclusions given cases with similar circumstances. To assess variation in case findings and reasons for them, we used data from monthly reports of completed investigations, and investigation outcomes from all 58 California counties from September 2004 to August 2005, telephone interviews with 54 of 58 counties, and site visits to 17 counties. We also compared the data from 2004-2005 with more recent data from 2013. Large variability was found from county to county in the proportions of cases found to be conclusive, inconclusive, and unfounded. The combined analyses revealed significant differences in how individual APS workers interpret definitions of different types of case outcomes, varying skill and experience of the APS workers, individual and county agency factors, and other reasons that influence variability in case findings. Widespread inconsistencies in the outcomes of elder abuse investigations raise issues to be addressed on multiple levels, including the use of APS data for developing policy, standardizing training of APS workers, and seeking just outcomes for the victims of elder abuse

Variability in Findings From Adult Protective Services Investigations of Elder Abuse in California.

Adult Protective Services (APS) workers in California investigate complaints of elder abuse and must determine the validity of a complaint with minimal guidelines. It is unclear whether APS workers reach similar conclusions given cases with similar circumstances. To assess variation in case findings and reasons for them, we used data from monthly reports of completed investigations, and investigation outcomes from all 58 California counties from September 2004 to August 2005, telephone interviews with 54 of 58 counties, and site visits to 17 counties. We also compared the data from 2004-2005 with more recent data from 2013. Large variability was found from county to county in the proportions of cases found to be conclusive, inconclusive, and unfounded. The combined analyses revealed significant differences in how individual APS workers interpret definitions of different types of case outcomes, varying skill and experience of the APS workers, individual and county agency factors, and other reasons that influence variability in case findings. Widespread inconsistencies in the outcomes of elder abuse investigations raise issues to be addressed on multiple levels, including the use of APS data for developing policy, standardizing training of APS workers, and seeking just outcomes for the victims of elder abuse

The mental health and substance use treatment experiences of racially and ethnically minoritised women who have experienced sexual violence

The mental health and substance use treatment experiences of racially and ethnically minoritised women who have experienced sexual violence is not well understood. To address this we conducted a systematic review and meta-synthesis of qualitative studies. Our search strategy included electronic searches of 18 databases and grey literature, citation tracking and reference list screening. Studies were eligible if they presented qualitative data from racially and/or ethnically minoritised women or girls, who had experienced sexual violence at any age and described their experiences of receiving treatment from statutory mental health and/or substance use services. Studies were analysed using meta-ethnography. Fourteen papers based on 12 individual studies were included. Analysis developed three main themes: (1) understanding minoritised women holistically, (2) processing the trauma and beginning the healing and (3) the need for social connectedness and empowering relationships. For minoritised women to benefit from treatment, mental health and substance use services need to challenge the dynamics of the multiple traumas minoritised women experience. Knowledge and understanding of the racial trauma minoritised women experience is limited and many are subjected to further harm from racist practices occurring in some treatment services. Offering culturally safe, trauma-informed care which promotes anti- racist practices may help improve mental health and substance use service responses to minoritised women who have experienced sexual violence

High-Mobility Group Box 1 Disrupts Metabolic Function with Cigarette Smoke Exposure in a Ceramide-Dependent Manner

We have previously found that cigarette smoke disrupts metabolic function, in part, by increasing muscle ceramide accrual. To further our understanding of this, we sought to determine the role of the cytokine high-mobility group box 1 (HMGB1), which is increased with smoke exposure, in smoke-induced muscle metabolic perturbations. To test this theory, we determined HMGB1 from lungs of human smokers, as well as from lung cells from mice exposed to cigarette smoke. We also treated cells and mice directly with HMGB1, in the presence or absence of myriocin, an inhibitor of serine palmitoyltransferase, the rate-limiting enzyme in ceramide biosynthesis. Outcomes included assessments of insulin resistance and muscle mitochondrial function. HMGB1 was significantly increased in both human lungs and rodent alveolar macrophages. Further testing revealed that HMGB1 treatment elicited a widespread increase in ceramide species and reduction in myotube mitochondrial respiration, an increase in reactive oxygen species, and reduced insulin-stimulated Akt phosphorylation. Inhibition of ceramide biosynthesis with myriocin was protective. In mice, by comparing treatments of HMGB1 injections with or without myriocin, we found that HMGB1 injections resulted in increased muscle ceramides, especially C16 and C24, which were necessary for reduced muscle mitochondrial respiration and compromised insulin and glucose tolerance. In conclusion, HMGB1 may be a necessary intermediate in the ceramide-dependent metabolic consequences of cigarette smoke exposure