Aetiology of community-acquired neonatal sepsis in low and middle income countries

99% of the approximate 1 million annual neonatal deaths from life-threatening invasive bacterial infections occur in developing countries, at least 50% of which are from home births or community settings. Data concerning aetiology of sepsis in these settings are necessary to inform targeted therapy and devise management guidelines. This review describes and analyses the bacterial aetiology of community-acquired neonatal sepsis in developing countries

Inpatient Physician and Nurse Experience During the COVID-19 Crisis at a Public Safety Net Hospital

**Background:** The COVID-19 pandemic has been associated with front line health care provider burnout, depression, and post-traumatic stress disorder. We sought to better understand how nurses and physicians of differing genders may have been affected differently by the COVID-19 crisis. **Methods:** Between July 17, 2020, and October 31, 2020, we surveyed nurses and physicians caring for COVID-19 patients at a large, academic, public safety net hospital in the southern United States. Survey questions were adapted from validated questionnaires used to determine quality of life, assess levels of anxiety, and determine how COVID-19 may have affected our nurses' and physicians' work, home and social lives. **Results:** Overall, 120 (41.7%) providers responded, including 39 (50%) physicians and 81 (38.6%) nurses. 69.3% reported disruption to their home/family, 76.3% to their social lives, and 29.8% worried about financial strain. More nurses than physicians worried about being excluded from social gatherings (59.7% v 35.1%, p=0.01). Similarly, 70.1% of nurses and 46.0% of physicians expressed concern of exposing others to COVID-19 (p=0.01). Nurses also expressed greater concern about being treated differently by others when compared to physicians (64.5% v 37.8%, p= 0.01). Female physicians reported greater difficulty separating their personal lives from their professional lives than male physicians and either male or female nurses (84.6%% vs 35% vs 33.3% vs 35.9%, p \<0.05). Most physicians (89.7%) and nurses (93.8%) reported some level of anxiety, with 31.5% of respondents experiencing moderate or severe anxiety. **Conclusion:** Healthcare workers on the frontline of COVID-19 pandemic, regardless of profession, reported increased anxiety that extended beyond the hospital into their homes and social lives. Physicians and nurses, as well as men and women, reported different sources and degrees of stress and disruption to their work, home and social lives

Debiased ambient vibrations optical coherence elastography to profile cell, organoid and tissue mechanical properties

The role of the mechanical environment in defining tissue function, development and growth has been shown to be fundamental. Assessment of the changes in stiffness of tissue matrices at multiple scales has relied mostly on invasive and often specialist equipment such as AFM or mechanical testing devices poorly suited to the cell culture workflow.In this paper, we have developed a unbiased passive optical coherence elastography method, exploiting ambient vibrations in the sample that enables real-time noninvasive quantitative profiling of cells and tissues. We demonstrate a robust method that decouples optical scattering and mechanical properties by actively compensating for scattering associated noise bias and reducing variance. The efficiency for the method to retrieve ground truth is validated in silico and in vitro, and exemplified for key applications such as time course mechanical profiling of bone and cartilage spheroids, tissue engineering cancer models, tissue repair models and single cell. Our method is readily implementable with any commercial optical coherence tomography system without any hardware modifications, and thus offers a breakthrough in on-line tissue mechanical assessment of spatial mechanical properties for organoids, soft tissues and tissue engineering

Self-harm in people experiencing homelessness: an investigation of incidence, characteristics and outcomes using data from the Multicentre Study of Self-harm in England

BackgroundPeople who experience homelessness are thought to be at high risk of suicide, but little is known about self-harm in this population.AimsTo examine characteristics and outcomes in people experiencing homelessness who presented to hospital following self-harm.MethodData were collected via specialist assessments and/or hospital patient records from emergency departments in Manchester, Oxford and Derby, UK. Data were collected from 1 January 2000 to 31 December 2016, with mortality follow-up via data linkage with NHS Digital to 31 December 2019. Trend tests estimated change in self-harm over time; descriptive statistics described characteristics associated with self-harm. Twelve-month repetition and long-term mortality were analysed using Cox proportional hazards models and controlled for age and gender.ResultsThere were 4841 self-harm presentations by 3270 people identified as homeless during the study period. Presentations increased after 2010 (IRR = 1.09, 95% CI 1.04–1.14, P < 0.001). People who experienced homelessness were more often men, White, aged under 54 years, with a history of previous self-harm and contact with psychiatric services. Risk of repetition was higher than in domiciled people (HR = 2.05, 95% CI 1.94–2.17, P < 0.001), as were all-cause mortality (HR = 1.45, 95% CI 1.32–1.59. P < 0.001) and mortality due to accidental causes (HR = 2.93, 95% CI 2.41–3.57, P < 0.001).ConclusionsPeople who self-harm and experience homelessness have more complex needs and worse outcomes than those who are domiciled. Emergency department contact presents an opportunity to engage people experiencing homelessness with mental health, drug and alcohol, medical and housing services, as well as other sources of support

Molecular analysis of post-harvest withering in grape by AFLP transcriptional profiling

Post-harvest withering of grape berries is used in the production of dessert and fortified wines to alter must quality characteristics and increase the concentration of simple sugars. The molecular processes that occur during withering are poorly understood, so a detailed transcriptomic analysis of post-harvest grape berries was carried out by AFLP-transcriptional profiling analysis. This will help to elucidate the molecular mechanisms of berry withering and will provide an opportunity to select markers that can be used to follow the drying process and evaluate different drying techniques. AFLP-TP identified 699 withering-specific genes, 167 and 86 of which were unique to off-plant and on-plant withering, respectively. Although similar molecular events were revealed in both withering processes, it was apparent that off-plant withering induced a stronger dehydration stress response resulting in the high level expression of genes involved in stress protection mechanisms, such as dehydrin and osmolite accumulation. Genes involved in hexose metabolism and transport, cell wall composition, and secondary metabolism (particularly the phenolic and terpene compound pathways) were similarly regulated in both processes. This work provides the first comprehensive analysis of the molecular events underpinning post-harvest withering and could help to define markers for different withering processes

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities