Early trajectories of virological and immunological biomarkers and clinical outcomes in patients admitted to hospital for COVID-19: an international, prospective cohort study.

BACKGROUND: Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes. METHODS: In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery. FINDINGS: The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors. INTERPRETATION: Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment. FUNDING: US National Institutes of Health.

Household-level lifestyle interventions for the prevention of cognitive decline; A Systematic review.

BACKGROUND: Lifestyle interventions targeting households may be an effective means of promoting healthier cognitive function in later life, with extended benefit to other household members. In this systematic review and meta-analysis, we sought to assess the effect of targeting lifestyle behaviours of households on cognitive outcomes METHODS: An electronic search strategy was designed to identify randomised controlled trials (RCTs) where households were randomised to receive a lifestyle intervention for the prevention of cognitive decline, from database inception until April 2020. Our initial search identified no eligible studies, so we revised our search strategy to include trials enroling dyads. We reported the cognitive outcomes, functional outcomes, caregiver outcomes and long-term care (LTC) admissions for eligible studies. FINDINGS: We identified no RCTs which randomised households to receive a lifestyle intervention for preventing cognitive decline. We identified five RCTs (n = 1721, with mean follow-up of 9.6 months) which randomised dyads, which evaluated diet (two trials) and physical activity (three trials). CONCLUSION: Trials evaluating dietary and exercise interventions in dyads were identified. No trial demonstrated a significant association of interventions with change in cognitive testing, functional outcomes or long-term care admissions, although trials were small with short-term follow-up. Future studies should consider targeting lifestyle behaviours of households for prevention of dementia.

A case of thrombocytopenia and multiple thromboses after vaccination with ChAdOx1 nCoV-19 against SARS-CoV-2.

Recently, reports of severe thromboses, thrombocytopenia, and hemorrhage in persons vaccinated with the chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19, AZD1222, Vaxzevria; Oxford/AstraZeneca) against severe acute respiratory syndrome coronavirus 2 have emerged. We describe an otherwise healthy 30-year-old woman who developed thrombocytopenia, ecchymosis, portal vein thrombosis, and cerebral venous sinus thrombosis the second week after she received the ChAdOx1 nCoV-19 vaccine. Extensive diagnostic workup for thrombosis predispositions showed heterozygosity for the prothrombin mutation, but no evidence of myeloproliferative neoplasia or infectious or autoimmune diseases. Her only temporary risk factor was long-term use of oral contraceptive pills (OCPs). Although both the prothrombin mutation and use of OCPs predispose to portal and cerebral vein thrombosis, the occurrence of multiple thromboses within a short time and the associated pattern of thrombocytopenia and consumption coagulopathy are highly unusual. A maximum 4T heparin-induced thrombocytopenia (HIT) score and a positive immunoassay for anti-platelet factor 4/heparin antibodies identified autoimmune HIT as a potential pathogenic mechanism. Although causality has not been established, our case emphasizes the importance of clinical awareness. Further studies of this potentially new clinical entity have suggested that it should be regarded as a vaccine-induced immune thrombotic thrombocytopenia.

Female Genital Schistosomiasis and HIV: Research Urgently Needed to Improve Understanding of the Health Impacts of This Important Coinfection.

Evidence suggests that there are important interactions between HIV and female genital schistosomiasis (FGS) that may have significant effects on individual and population health. However, the exact way they interact and the health impacts of the interactions are not well understood. In this article, we discuss what is known about the interactions between FGS and HIV, and the potential impact of the interactions. This includes the likelihood that FGS is an important health problem for HIV-positive women in Schistosoma-endemic areas potentially associated with an increased risk of mortality, cancer, and infertility. In addition, it may be significantly impacting the HIV epidemic in sub-Saharan Africa by making young women more susceptible to HIV. We call for immediate action and argue that research is urgently required to address these knowledge gaps and propose a research agenda to achieve this.

T cell costimulation blockade blunts pressure overload-induced heart failure.

Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant functions of individual cytokines. Searching for better cardiac inflammation targets, here we link T cells with HF development in a mouse model of pathological cardiac hypertrophy and in human HF patients. T cell costimulation blockade, through FDA-approved rheumatoid arthritis drug abatacept, leads to highly significant delay in progression and decreased severity of cardiac dysfunction in the mouse HF model. The therapeutic effect occurs via inhibition of activation and cardiac infiltration of T cells and macrophages, leading to reduced cardiomyocyte death. Abatacept treatment also induces production of anti-inflammatory cytokine interleukin-10 (IL-10). IL-10-deficient mice are refractive to treatment, while protection could be rescued by transfer of IL-10-sufficient B cells. These results suggest that T cell costimulation blockade might be therapeutically exploited to treat HF.

Elucidating causes of Diporeia decline in the Great Lakes via metabolomics: physiological responses after exposure to different stressors.

The benthic macroinvertebrate Diporeia spp. have been extirpated from many areas of the Laurentian Great Lakes, but the mechanisms underlying such declines are not fully understood. Diporeia declines coinciding with the invasion of exotic dreissenid mussels (zebra and quagga) have led to the hypothesis that Diporeia declines are a result of decreased food availability from increasing competition with dreissenids for diatoms. There is additional evidence that Diporeia are negatively affected when in close proximity to dreissenids, probably because of exposure to toxins present in the mussels' pseudofeces. Diporeia are also known to be sensitive to anthropogenic contaminants (such as polychlorinated biphenyls [PCBs]) present in Great Lakes sediments. To better understand the physiological responses of Diporeia to diverse stressors, we conducted three 28-d experiments evaluating changes in the metabolomes of Diporeia (1) fed diatoms (Cyclotella meneghiniana) versus starved, (2) exposed (from Lake Michigan and Cayuga Lake) to quagga mussels (Dreissena bugensis), and (3) exposed to sediments contaminated with PCBs. The metabolomes of samples were examined using both two-dimensional gas and liquid chromatography coupled with mass spectrometry. Each stressor elicited a unique metabolome response characterized by enhanced citric acid cycle, fatty acid biosynthesis, and protein metabolism in diatom-fed Diporeia; impaired glycolysis, protein catabolism, and folate metabolism in Diporeia from Lake Michigan irrespective of quagga mussel exposure, suggesting lake-specific adaptation mechanisms; and altered cysteine and phospholipid metabolism during PCB exposure. Subsequent comparisons of these stressor-specific metabolic responses with metabolomes of a feral Diporeia population would help identify stressors affecting Diporeia populations throughout the Great Lakes.

[How to identify adverse events in emergency services? A guide agreed for the screening]. / ¿Cómo identificar los efectos adversos en urgencias? Una guía consensuada para el cribado.

OBJECTIVE: Since a third of adverse events (AE) occur outside hospital, the Emergency Services are a suitable place to look at their incidence. We considered designing a screening guide, adapted to the conditions of the emergency services, to identify AE. MATERIAL AND METHODS: A qualitative technique was applied (nominal group) in which 14 professionals participated. They analysed which factors of intrinsic risk, extrinsic risk, and alert conditions, were suitable for a screening guide of AE in emergency services. The session was chaired by a specialist in these types of techniques. RESULTS: Consensus was high in that the most frequent AE in emergencies were those related to medicines, diagnostic tests and with the correct identification of the reason for emergency. With respect to screening guide, the group proposed adding alcohol abuse, patient social problems, cognitive deterioration, basal autonomy and disability. In relation to extrinsic risk factors, they pointed to the need of including defibrillation, spinal tap or drainage implantation. With respect to the alert conditions form, the professionals agreed in that all the criteria seemed correct and suitable, except for that related to damage relation childbirth or amniocentesis. CONCLUSIONS: By using this technique we have managed to validate materials already recognized, and widely used in our country. The screening guide was considered useful, with slight modifications in some risk factors and alert conditions. The professionals agreed that the MRF2 modular questionnaire is appropriate for the characterisation of AE in emergencies.

[Revision of obstructive sleep apnea syndrome in the child]. / Revision del síndrome de apnea obstructiva del sueño en el niño.

The obstructive sleep apnea syndrome (OSAS) is frequent in infancy and childhood. It is caused by a prolonged upper respiratory airway obstructioon during sleep, and adenotonsillar hypertrophy is the most important cause. OSAS may have an impact on physical and cognitive development, but syntoms in children are subtle and may pass unrecognised. Polysomnography is the gold standard technique for OSAS diagnosis and surgical approach with adenotonsillectomy is the most frequently treatment indicated. Early diagnosis and treatment and adequate follow up are important to prevent physical disturbances secondary to chronic hypoxemia and to avoid cognitive deficits associated with disrupted sleep architecture.

Oral and constitutional manifestations of HIV-infected hospital patients in Northern Vietnam.

This study reports clinical features, with emphasis on oral lesions and constitutional signs, of 170 patients in a regional hospital in northern Vietnam, of whom 56 were HIV positive. The purpose of the study was to investigate the relationship of oral hairy leukoplakia (OHL) and oropharyngeal candidiasis (OPC) with HIV infection and late stage HIV disease. Late stage HIV disease was defined as WHO stage III or IV and/or a total lymphocyte count below 1200 cells/mm3. The 56 HIV positive patients included all patients with a positive HIV test between July 7th and September 9th 2002. A total of 114 HIV negative controls were included as well. All patients had a detailed medical history and examination as well as a thorough oral examination, which were all done without prior knowledge of the patient's HIV serostatus. HIV positive patients were then grouped according to WHO clinical stage and total lymphocyte count. Thirty-six patients (64.3%) out of 56 HIV positives were in WHO stage III+IV and 28 patients (50.0%) had a total lymphocyte count below 1200 cells/mm3. The presence of OPC, weight loss of more than 10% of body weight and/or chronic fever of more than one month's duration showed a significant association and high positive prediction with HIV infection, especially late stage HIV disease [all with odds ratio (OR) and 95% confidence interval (CI > 1)]. The presence of OHL only showed a significant association with positive HIV serostatus and WHO stage III+IV. It can be concluded that in North Vietnam, HIV positive patients and patients suspected of having HIV infection would benefit from initial and repeat oral examinations. OPC, together with other signs of progressive infection (constitutional signs, such as weight loss and chronic fever) may serve as indicators for institution of prophylactic drugs against opportunistic infections and even antiretroviral (ARV) therapy, when available. However, further research is needed to demonstrate the role of OHL in HIV patients in North Vietnam.

Two homozygous mutations in the 11 beta-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess.

The human microsomal 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) metabolizes active cortisol into cortisone and protects the mineralocorticoid receptor from glucocorticoid occupancy. In a congenital deficiency of 11 beta-HSD2, the protective mechanism fails and cortisol gains inappropriate access to mineralocorticoid receptor, resulting in low-renin hypertension and hypokalemia. In the present study, we describe the clinical and molecular genetic characterization of a patient with a new mutation in the HSD11B2 gene. This is a 4-yr-old male with arterial hypertension. The plasma renin activity and serum aldosterone were undetectable in the presence of a high cortisol to cortisone ratio. PCR amplification and sequence analysis of HSD11B2 gene showed the homozygous mutation in exon 4 Asp223Asn (GAC-->AAC) and a single nucleotide substitution C-->T in intron 3. Using site-directed mutagenesis, we generated a mutant 11 beta HSD2 cDNA containing the Asp223Asn mutation. Wild-type and mutant cDNA was transfected into Chinese hamster ovary cells and enzymatic activities were measured using radiolabeled cortisol and thin-layer chromatography. The mRNA and 11 beta HSD2 protein were detected by RT-PCR and Western blot, respectively. Wild-type and mutant 11 beta HSD2 protein was expressed in Chinese hamster ovary cells, but the mutant enzyme had only 6% of wild-type activity. In silico 3D modeling showed that Asp223Asn changed the enzyme's surface electrostatic potential affecting the cofactor and substrate enzyme-binding capacity. The single substitution C-->T in intron 3 (IVS3 + 14 C-->T) have been previously reported that alters the normal splicing of pre-mRNA, given a nonfunctional protein. These findings may determine the full inactivation of this enzyme, explaining the biochemical profile and the early onset of hypertension seen in this patient.

Sindrome de Reye: criterios diagnosticos, secuelas neurologicas / Reye's Syndrome: diagnosis criteria, neurological sequels

El sindrome de Reye, se considera enfermedad poco comun entre adultos. Presentamos el cuarto caso informado en el pais y el primero que se recupera. Se trata de una mujer de 18 anos, quien con un diagnostico de "Hepatitis Viral", ingresa en estado de estupor, presenta vomito pertinaz y evoluciona al coma superficial, se le observa ademas hematosis, convulsiones focales y posteriormente se recupera. El reconocimiento precoz del sindrome se hace mediante la aplicacion de los criterios diagnosticos, la ayuda del laboratorio y hallazgos asociados que estan bien documentados en esta enfermedad.