Fewer COVID-19 neurological complications with dexamethasone and remdesivir

OBJECTIVE: To assess the impact of treatment with dexamethasone, remdesivir or both on neurological complications in acute COVID-19. METHODS: We used observational data from the International Severe Acute and emerging Respiratory Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK). Hospital inpatients aged ≥18 years with laboratory-confirmed SARS-CoV-2 infection admitted between 31 January 2020 and 29 June 2021 were included. Treatment allocation was non-blinded and performed by reporting clinicians. A propensity scoring methodology was used to minimize confounding. Treatment with remdesivir, dexamethasone or both was assessed against standard of care. The primary outcome was a neurological complication occurring at the point of death, discharge, or resolution of the COVID-19 clinical episode. RESULTS: Out of 89,297 hospital inpatients, 64,088 had severe COVID-19 and 25,209 had non-hypoxic COVID-19. Neurological complications developed in 4.8% and 4.5% respectively. In both groups, neurological complications associated with increased mortality, ICU admission, worse self-care on discharge and time to recovery. In severe COVID-19, treatment with dexamethasone (n=21,129), remdesivir (n=1,428) and both combined (n=10,846) associated with a lower frequency of neurological complications: OR=0.76 (95% CI=0.69-0.83), OR 0.69 (95% CI=0.51-0.90) and OR=0.54, (95% CI=0.47-0.61) respectively. In non-hypoxic COVID-19, dexamethasone (n=2,580) associated with less neurological complications (OR=0.78, 95% CI 0.62-0.97), while the dexamethasone/remdesivir combination (n=460) showed a similar trend (OR=0.63, 95% CI=0.31-1.15). INTERPRETATION: Treatment with dexamethasone, remdesivir or both in patients hospitalised with COVID-19 associated with a lower frequency of neurological complications in an additive manner, such that the greatest benefit was observed in patients who received both drugs together. This article is protected by copyright. All rights reserved

Chromatographic and spectral studies of jetsam and archived ambergris

<p>We describe determination of the dichloromethane-soluble components of 12 samples of the natural product, ambergris, using capillary gas chromatography–mass spectrometry (GC–MS). Ambergris is produced <i>in vivo</i> in about 1% of Sperm whales and is used in perfumery and for odour fixation. Whilst descriptions of ambergris chemistry appeared until about 40 years ago, few accounts of analyses of whole extracts of multiple samples of ambergris by GC–MS have been published before. As expected, our analyses revealed that the major component (up to 97% of the dichloromethane-soluble material) was ambrein, with co-occurring, variable proportions of steroids. Moreover, we report apparently for the first time, mass spectra and retention indices of derivatised ambrein. These data should now allow reliable, rapid confirmation of even small amounts of jetsam, archived museum and customs samples of ambergris and an assessment of ambergris ‘quality’.</p

Changes in in-hospital mortality in the first wave of COVID-19: a multicentre prospective observational cohort study using the WHO Clinical Characterisation Protocol UK

BACKGROUND: Mortality rates in hospitalised patients with COVID-19 in the UK appeared to decline during the first wave of the pandemic. We aimed to quantify potential drivers of this change and identify groups of patients who remain at high risk of dying in hospital. METHODS: In this multicentre prospective observational cohort study, the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK recruited a prospective cohort of patients with COVID-19 admitted to 247 acute hospitals in England, Scotland, and Wales during the first wave of the pandemic (between March 9 and Aug 2, 2020). We included all patients aged 18 years and older with clinical signs and symptoms of COVID-19 or confirmed COVID-19 (by RT-PCR test) from assumed community-acquired infection. We did a three-way decomposition mediation analysis using natural effects models to explore associations between week of admission and in-hospital mortality, adjusting for confounders (demographics, comorbidities, and severity of illness) and quantifying potential mediators (level of respiratory support and steroid treatment). The primary outcome was weekly in-hospital mortality at 28 days, defined as the proportion of patients who had died within 28 days of admission of all patients admitted in the observed week, and it was assessed in all patients with an outcome. This study is registered with the ISRCTN Registry, ISRCTN66726260. FINDINGS: Between March 9, and Aug 2, 2020, we recruited 80 713 patients, of whom 63 972 were eligible and included in the study. Unadjusted weekly in-hospital mortality declined from 32·3% (95% CI 31·8-32·7) in March 9 to April 26, 2020, to 16·4% (15·0-17·8) in June 15 to Aug 2, 2020. Reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. After adjustment, there was a 32% reduction in the risk of mortality per 7-week period (odds ratio [OR] 0·68 [95% CI 0·65-0·71]). The higher proportions of patients with severe disease and comorbidities earlier in the first wave (March and April) than in June and July accounted for 10·2% of this reduction. The use of respiratory support changed during the first wave, with gradually increased use of non-invasive ventilation over the first wave. Changes in respiratory support and use of steroids accounted for 22·2%, OR 0·95 (0·94-0·95) of the reduction in in-hospital mortality. INTERPRETATION: The reduction in in-hospital mortality in patients with COVID-19 during the first wave in the UK was partly accounted for by changes in the case-mix and illness severity. A significant reduction in in-hospital mortality was associated with differences in respiratory support and critical care use, which could partly reflect accrual of clinical knowledge. The remaining improvement in in-hospital mortality is not explained by these factors, and could be associated with changes in community behaviour, inoculum dose, and hospital capacity strain. FUNDING: National Institute for Health Research and the Medical Research Council

Two-marker protein profile predicts poor prognosis in patients with early rectal cancer

The aim of this study was to establish an immunohistochemical protein profile to complement preoperative staging and identify rectal cancer patients at high-risk of adverse outcome. Immunohistochemistry was performed on a tissue microarray including 482 rectal cancers for APAF-1, EphB2, MST1, Ki67, p53, RHAMM, RKIP and CD8+ tumour infiltrating lymphocytes (TILs). After resampling of the data and multivariable analysis, the most reproducible markers were combined and prognosis evaluated as stratified by pT and pN status. In multivariable analysis, only positive RHAMM (P<0.001; HR=1.94 (1.44–2.61)) and loss of CD8+ TILs (P=0.006; HR=0.63 (0.45–0.88)) were independent prognostic factors. The 5-year cancer-specific survival rate for RHAMM+/TIL− patients was 30% (95% CI 21–40%) compared to 76% (95% CI: 66–84%) for RHAMM−/TIL+ patients (P<0.001). The 5-year cancer-specific survival of T1/T2/RHAMM+/TIL− patients was 48% (20–72%) and significantly worse compared to T3/T4/RHAMM−/TIL+ patients (71% 95% CI 56–82%); P=0.039). Stratifying by nodal status, only N+/RHAMM+/TIL− patients demonstrated a significantly worse prognosis than N0/RHAMM+/TIL− patients (P=0.005). Loss of CD8+ TILs was predictive of local recurrence in RHAMM+ tumours (P=0.009) only. RHAMM and CD8+ TILs may assist in identifying early stage rectal cancer patients facing a particularly poor prognosis and who may derive a benefit from preoperative therapy

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Protective effect of leptin against ischemia-reperfusion injury in the rat small intestine

BACKGROUND: The small intestine is extremely sensitive to ischemia-reperfusion (I/R) injury and a range of microcirculatory disturbances which contribute to tissue damage. Previous studies have shown that leptin plays an important physiological role in the microvasculature. The aim of this study was to evaluate the protective effects of leptin in I/R – induced mucosal injury in the small intestine. METHODS: Forty rats were divided into 5 groups (n = 8). Group I was subjected to a sham operation. Following mesenteric ischemia in group II (control); physiologic saline 1 cm(3), in group III; leptin 100 μg/kg, and physiologic saline 1 cm(3), in group IV; N(G)-L-arginine methyl ester (L-NAME) 20 mg/kg, and physiologic saline 1 cm(3), in group V; leptin 100 μg/kg, L-NAME 20 mg/kg, and physiologic saline 1 cm(3 )were given intra-peritoneally. In these groups, an I/R procedure was performed by occlusion of the superior mesenteric artery for 45 min followed by 120 min reperfusion. After reperfusion, the small intestines were resected for malondialdehyde (MDA) and nitric oxide (NO) concentration and histopathologic properties. Mucosal lesions were scored between 0 and 5. Tissue MDA and NO concentration and histopathologic grades were compared statistically. RESULTS: Tissue MDA level significantly increased (P < 0.05), tissue NO level significantly decreased in group V animals, compared to group III animals respectively (P < 0.001). Histopathologically, intestinal injury significantly decreased in the leptin treated ischemic group. CONCLUSION: Leptin can be used safely in mesenteric occlusive diseases, since it induces NO formation and release in mesenteric vessels

Adaptive design methods in clinical trials – a review

In recent years, the use of adaptive design methods in clinical research and development based on accrued data has become very popular due to its flexibility and efficiency. Based on adaptations applied, adaptive designs can be classified into three categories: prospective, concurrent (ad hoc), and retrospective adaptive designs. An adaptive design allows modifications made to trial and/or statistical procedures of ongoing clinical trials. However, it is a concern that the actual patient population after the adaptations could deviate from the originally target patient population and consequently the overall type I error (to erroneously claim efficacy for an infective drug) rate may not be controlled. In addition, major adaptations of trial and/or statistical procedures of on-going trials may result in a totally different trial that is unable to address the scientific/medical questions the trial intends to answer. In this article, several commonly considered adaptive designs in clinical trials are reviewed. Impacts of ad hoc adaptations (protocol amendments), challenges in by design (prospective) adaptations, and obstacles of retrospective adaptations are described. Strategies for the use of adaptive design in clinical development of rare diseases are discussed. Some examples concerning the development of Velcade intended for multiple myeloma and non-Hodgkin's lymphoma are given. Practical issues that are commonly encountered when implementing adaptive design methods in clinical trials are also discussed

Psychosocial Needs of Children in Foster Care and the Impact of Sexual Abuse

Children in family foster care, especially those who have experienced sexual abuse, require a safe and nurturing environment in which their psychosocial needs are met. However, there is limited knowledge on how youth prioritize various needs and what impact previous experiences have on these needs. In this study, we asked youth (formerly) in family foster care to indicate their psychosocial needs, and analyzed if youth with a history of sexual abuse have different needs. A Q methodological study was conducted with 44 youth (age 16–28). Fifteen of them reported sexual abuse during their childhood. Using by-person factor analyses, respondents who share similar subjective views were grouped together. Qualitative interpretations of the factors show differences and similarities between and within the two groups, related to help from others, being independent, processing the past, and working toward the future. Although the needs of youth with and without experiences of sexual abuse seem mostly similar, one group of sexually abused youth specifically indicated not wanting an emotional connection to foster parents, but instead a strictly instrumental, professional relationship. This study captured the diverse perspectives of youth themselves, revealing that children in foster care differ with regard to what they consider as (most) important safety, belonging, self-esteem and self-actualization needs

Integration of Global Signaling Pathways, cAMP-PKA, MAPK and TOR in the Regulation of FLO11

The budding yeast, Saccharomyces cerevisiae, responds to various environmental cues by invoking specific adaptive mechanisms for their survival. Under nitrogen limitation, S. cerevisiae undergoes a dimorphic filamentous transition called pseudohyphae, which helps the cell to forage for nutrients and reach an environment conducive for growth. This transition is governed by a complex network of signaling pathways, namely cAMP-PKA, MAPK and TOR, which controls the transcriptional activation of FLO11, a flocculin gene that encodes a cell wall protein. However, little is known about how these pathways co-ordinate to govern the conversion of nutritional availability into gene expression. Here, we have analyzed an integrative network comprised of cAMP-PKA, MAPK and TOR pathways with respect to the availability of nitrogen source using experimental and steady state modeling approach. Our experiments demonstrate that the steady state expression of FLO11 was bistable over a range of inducing ammonium sulphate concentration based on the preculturing condition. We also show that yeast switched from FLO11 expression to accumulation of trehalose, a STRE response controlled by a transcriptional activator Msn2/4, with decrease in the inducing concentration to complete starvation. Steady state analysis of the integrative network revealed the relationship between the environment, signaling cascades and the expression of FLO11. We demonstrate that the double negative feedback loop in TOR pathway can elicit a bistable response, to differentiate between vegetative growth, filamentous growth and STRE response. Negative feedback on TOR pathway function to restrict the expression of FLO11 under nitrogen starved condition and also with re-addition of nitrogen to starved cells. In general, we show that these global signaling pathways respond with specific sensitivity to regulate the expression of FLO11 under nitrogen limitation. The holistic steady state modeling approach of the integrative network revealed how the global signaling pathways could differentiate between multiple phenotypes

Roles for the Conserved Spc105p/Kre28p Complex in Kinetochore-Microtubule Binding and the Spindle Assembly Checkpoint

Kinetochores attach sister chromatids to microtubules of the mitotic spindle and orchestrate chromosome disjunction at anaphase. Although S. cerevisiae has the simplest known kinetochores, they nonetheless contain approximately 70 subunits that assemble on centromeric DNA in a hierarchical manner. Developing an accurate picture of the DNA-binding, linker and microtubule-binding layers of kinetochores, including the functions of individual proteins in these layers, is a key challenge in the field of yeast chromosome segregation. Moreover, comparison of orthologous proteins in yeast and humans promises to extend insight obtained from the study of simple fungal kinetochores to complex animal cell kinetochores.We show that S. cerevisiae Spc105p forms a heterotrimeric complex with Kre28p, the likely orthologue of the metazoan kinetochore protein Zwint-1. Through systematic analysis of interdependencies among kinetochore complexes, focused on Spc105p/Kre28p, we develop a comprehensive picture of the assembly hierarchy of budding yeast kinetochores. We find Spc105p/Kre28p to comprise the third linker complex that, along with the Ndc80 and MIND linker complexes, is responsible for bridging between centromeric heterochromatin and kinetochore MAPs and motors. Like the Ndc80 complex, Spc105p/Kre28p is also essential for kinetochore binding by components of the spindle assembly checkpoint. Moreover, these functions are conserved in human cells.Spc105p/Kre28p is the last of the core linker complexes to be analyzed in yeast and we show it to be required for kinetochore binding by a discrete subset of kMAPs (Bim1p, Bik1p, Slk19p) and motors (Cin8p, Kar3p), all of which are nonessential. Strikingly, dissociation of these proteins from kinetochores prevents bipolar attachment, even though the Ndc80 and DASH complexes, the two best-studied kMAPs, are still present. The failure of Spc105 deficient kinetochores to bind correctly to spindle microtubules and to recruit checkpoint proteins in yeast and human cells explains the observed severity of missegregation phenotypes