Gallbladder microbiota in healthy dogs and dogs with mucocele formation

To date studies have not investigated the culture-independent microbiome of bile from dogs, a species where aseptic collection of bile under ultrasound guidance is somewhat routine. Despite frequent collection of bile for culture-based diagnosis of bacterial cholecystitis, it is unknown whether bile from healthy dogs harbors uncultivable bacteria or a core microbiota. The answer to this question is critical to understanding the pathogenesis of biliary infection and as a baseline to exploration of other biliary diseases in dogs where uncultivable bacteria could play a pathogenic role. A pressing example of such a disease would be gallbladder mucocele formation in dogs. This prevalent and deadly condition is characterized by excessive secretion of abnormal mucus by the gallbladder epithelium that can eventually lead to rupture of the gallbladder or obstruction of bile flow. The cause of mucocele formation is unknown as is whether uncultivable, and therefore unrecognized, bacteria play any systematic role in pathogenesis. In this study we applied next-generation 16S rRNA gene sequencing to identify the culture-negative bacterial community of gallbladder bile from healthy dogs and gallbladder mucus from dogs with mucocele formation. Integral to our study was the use of 2 separate DNA isolations on each sample using different extraction methods and sequencing of negative control samples enabling recognition and curation of contaminating sequences. Microbiota findings were validated by simultaneous culture-based identification, cytological examination of bile, and fluorescence in-situ hybridization (FISH) performed on gallbladder mucosa. Using culture-dependent, cytological, FISH, and 16S rRNA sequencing approaches, results of our study do not support existence of a core microbiome in the bile of healthy dogs or gallbladder mucus from dogs with mucocele formation. Our findings further document how contaminating sequences can significantly contribute to the results of sequencing analysis when performed on samples with low bacterial biomass

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Uranium distribution as a proxy for basin-scale fluid flow in distributive fluvial systems

We infer system-scale fluid flow in the Late Jurassic Salt Wash fluvial succession (SW USA) by plotting uranium deposit distribution against sedimentological data, using uranium distribution as a proxy for subsurface fluid flow. More than 90% of uranium deposits in the Salt Wash occur where sandstone forms 40–55% and sand-rich channel-belts form 20–50% of the succession, which coincides with changes in channel-belt connectivity and gross-scale architecture. The paucity of uranium below these cut-off values suggests that fluid flow is related directly to predictable downstream fining and facies variations in distributive fluvial systems

Analysis of practice of the social support of families with disabled children and children with limited opportunities of health in the municipality Pervouralsk

Social development of disabled children and children with limited opportunities of health isone of the most important problem in modern society.These children have a broken relationship with the world, rather low mobility, they are limited in contacts with peers and adults. Disabled persons and persons with limited opportunities of healthare characterized by alienation, isolation from society, dissatisfaction with their situation, which is associated primarily with loneliness, the presence of the problem of adaptation to their situation and the need to overcome psychological discomfort. The relevance of a problem also increases in connection with increase in number of such children. This article analyzes statistical data on the number of disabled children and children with limited opportunities of health in the city of Pervouralsk, and forms of their social support are considered. Presents the results of a survey of parents of children with various types of violations of vital functions with the aim of identifying the level of need in the introduction of new forms of social support. Now most of parents aren't satisfied with measures of the social support provided by the state. As a new form of social support it is proposed to introduce the technology of support apartment accommodation for children with disabilities and children with limited opportunities of health. For this purpose, special apartments are organized in which children with disabilities and children with limited opportunities of health live under the constant supervision of social workers. This innovative form contributes to the acquisition of self-service skills, self-control and communication, household management. Children are integrated into a single educational and social rehabilitation process. The created conditions of stay contribute to the formation of skills of independent life, social competence.В современном обществе одной из наиболее актуальных проблем является социальное развитие детей-инвалидов и детей с ограниченными возможностями здоровья. У таких детей нарушена взаимосвязь с миром, достаточно низкая мобильность, они ограничены в контактах со сверстниками и взрослыми. Для инвалидов и лиц с ограниченными возможностями характерны отчужденность, отгороженность от жизни общества, неудовлетворенность своим положением, которая связана, прежде всего, с одиночеством, наличием проблемы приспособления к своему положению и необходимостью преодоления психологического дискомфорта. Актуальность проблемы также возрастает в связи с увеличением числа таких детей. В статье проанализированы статистические данные о численности детей-инвалидов и детей с ограниченными возможностями здоровья в городе Первоуральске, а также рассмотрены формы и их социального сопровождения. Представлены результаты опроса родителей детей с различными типами нарушений жизнедеятельности с целью выявления уровня потребности во внедрении новых форм социального сопровождения. В настоящее время большинство родителей не удовлетворены мерами социальной поддержки, предоставленной государством. В качестве новой формы социального сопровождения предлагается внедрение технологии сопровождения квартирного проживания детей-инвалидов и детей с ограниченными возможностями здоровья. Для этого организуются специальные квартиры, в которых под постоянным присмотром социальных работников проживают дети-инвалиды и дети с ограниченными возможностями. Данная инновационная форма способствует приобретению навыков самообслуживания, самоконтроля и общения, ведению домашнего хозяйства. Дети интегрируются в единый воспитательный и социально-реабилитационный процесс. Создаваемые условия пребывания способствуют формированию навыков самостоятельной жизни, социальной компетентности