Sex differences in post-acute neurological sequelae of SARS-CoV-2 and symptom resolution in adults after COVID-19 hospitalization: An international multicenter prospective observational study

Although it is known that COVID-19 can present with a range of neurological manifestations and in-hospital complications, sparse data exist if these initial neurological symptoms of COVID-19 are closely associated with post-acute neurological sequelae of SARS-CoV-2 (PANSC) and if female versus male sex impacts the symptom resolution. In this international, multicentre, prospective observational study across 407 sites from 15 countries (January/30th/2020-April/30th/2022), we report the prevalence and risk factors of PANSC among hospitalized adults and investigate the differences between males and females on neurological symptom resolution over time. PANSC included altered consciousness/confusion, fatigue/malaise, anosmia, dysgeusia, and muscle aches/joint pain, which were collected at the index hospitalization and during the follow-up assessments. The analysis considered time to resolution of individual and all neurological symptoms. Resulting times were modeled by Weibull regression, assuming mixed-case interval censoring, with sex and age included as covariates. Model results were summarized as cumulative probability functions and age- and sex-adjusted median times to resolution. We included 6,862 hospitalized adults with COVID-19, who had follow-up assessments. The median age of participants was 57 years (39.2% females). Males and females had similar baseline characteristics except that more males (vs. females) were admitted to Intensive Care Unit (30.5% vs. 20.3%) and received mechanical ventilation (17.2% vs. 11.8%). Approximately 70% of patients had multiple neurological symptoms at the first follow-up (median=102 days). Fatigue (49.9%) and myalgia/arthralgia (45.2%) were the most prevalent symptoms of PANSC at the initial follow-up. Reported prevalence in females was generally higher (vs. males) for all symptoms. At 12 months, anosmia and dysgeusia were resolved in most patients, though fatigue, altered consciousness, and myalgia remained unresolved in >10% of the cohort. Females had a longer time to resolution (5.2 vs. 3.4 months) of neurological symptoms at follow-up for those with more than one neurological symptom. In multivariable analysis, males were associated with a shorter time to resolution of symptoms (Hazard Ratio=1.53; 95% Confidence Interval =1.39–1.69). Intensive Care Unit admission was associated with a longer time to the resolution of symptoms (Hazard Ratio =0.68; 95% Confidence Interval=0.60–0.77). Post-discharge stroke was uncommon (0.3% in females; 0.5% in males). Despite the methodological challenges of survey data, this international multicentre prospective cohort study demonstrates that PANSC following index hospitalization is high. Symptom prevalence was higher and took longer to resolve in females than in males. This supports that whilst males were sicker during acute illness, females were disproportionately affected by PANSC

Effects of transfusing older red blood cells and platelets on obstetric patient outcomes: A retrospective cohort study

Objective: To investigate associations between transfusion of blood products close to the end of shelf-life and clinical outcomes in obstetric inpatients. Methods: Mortality and morbidity were compared in patients transfused exclusively with red blood cells (RBC) stored for less than 21 days (fresh) versus RBC stored for 35 days or longer (old), and platelets (PLT) stored for 3 days or fewer (fresh) versus 4 days or longer (old) in Queensland, Australia from 2007 to 2013. Multivariable models were used to examine associations between these groups of blood products and clinical end points. Results: There were 3371 patients who received RBC and 280 patients who received PLT of the eligible storage durations. Patients transfused with old RBC received fewer transfusions (2.7 ± 1.8 vs. 2.3 ± 1.0 units; P < 0.001). However, a higher rate of single-unit transfusions was also seen in those patients who exclusively received old RBC (252 [9.3%] vs. 92 [13.7%]; P = 0.003). Comparison of fresh vs. old blood products revealed no differences in the quantities of transfused RBC (9.5 ± 5.9 vs. 9.1 ± 5.2 units; P = 0.680) or PLT (1.5 ± 0.8 vs. 1.4 ± 1.1 units; P = 0.301) as well as the length of hospital stay for RBC (3 [2–5] vs. 3 [2–5] days; P = 0.124) or PLT (5 [4–8] vs. 6 [4–9] days; P = 0.120). Conclusion: Transfusing exclusively older RBC or PLT was not associated with increased morbidity or mortality.</p

Pre-clinical study protocol:Blood transfusion in endotoxaemic shock

The Surviving Sepsis Campaign (SCC) and the American College of Critical Care Medicine (ACCM) guidelines recommend blood transfusion in sepsis when the haemoglobin concentration drops below 7.0 g/dL and 10.0 g/dL respectively, while the World Health Organisation (WHO) guideline recommends transfusion in septic shock ‘if intravenous (IV) fluids do not maintain adequate circulation’, as a supportive measure of last resort. Volume expansion using crystalloid and colloid fluid boluses for haemodynamic resuscitation in severe illness/sepsis, has been associated with adverse outcomes in recent literature. However, the volume expansion effect(s) following blood transfusion for haemodynamic circulatory support, in severe illness remain unclear with most previous studies having focused on evaluating effects of either different RBC storage durations (short versus long duration) or haemoglobin thresholds (low versus high threshold) pre-transfusion. • We describe the protocol for a pre-clinical randomised controlled trial designed to examine haemodynamic effect(s) of early volume expansion using packed RBCs (PRBCs) transfusion (before any crystalloids or colloids) in a validated ovine-model of hyperdynamic endotoxaemic shock. • Additional exploration of mechanisms underlying any physiological, haemodynamic, haematological, immunologic and tissue specific-effects of blood transfusion will be undertaken including comparison of effects of short (≤5 days) versus long (≥30 days) storage duration of PRBCs prior to transfusion

Widespread establishment of adventive populations of Leptopilina japonica (Hymenoptera, Figitidae) in North America and development of a multiplex PCR assay to identify key parasitoids of Drosophila suzukii (Diptera, Drosophilidae)

In recent years, there has been an increase in the adventive establishment and spread of parasitoid wasps outside of their native range. However, lack of taxonomic tools can hinder the efficient screening of field-collected samples to document the establishment and range expansion of parasitoids on continent-wide geographic scales. Here we report that Leptopilina japonica (Hymenoptera, Figitidae), a parasitoid of the globally invasive fruit pest Drosophila suzukii (Diptera, Drosophilidae), is now widespread in much of North America despite not having been intentionally introduced. Surveys in 2022 using a variety of methods detected L. japonica in 10 of 11 surveyed USA States and one Canadian Province where it was not previously known to occur. In most surveys, L. japonica was the most common species of D. suzukii parasitoid found. The surveys also resulted in the detection of Ganaspis cf. brasiliensis (Hymenoptera, Figitidae), the recently-released biological control agent of D. suzukii, in six USA States where it had not previously been found. These new detections are likely a result of intentional biological control introductions rather than spread of adventive populations. A species-specific multiplex PCR assay was developed as a rapid, accurate and cost-effective method to distinguish L. japonica, G. cf. brasiliensis, the closely-related cosmopolitan parasitoid Leptopilina heterotoma (Hymenoptera, Figitidae) and other native parasitoid species. This dataset and the associated molecular tools will facilitate future studies of the spread and ecological impacts of these introduced parasitoids on multiple continents

Widespread establishment of adventive populations of Leptopilina japonica (Hymenoptera, Figitidae) in North America and development of a multiplex PCR assay to identify key parasitoids of Drosophila suzukii (Diptera, Drosophilidae)

In recent years, there has been an increase in the adventive establishment and spread of parasitoid wasps outside of their native range. However, lack of taxonomic tools can hinder the efficient screening of field-collected samples to document the establishment and range expansion of parasitoids on continent-wide geographic scales. Here we report that Leptopilina japonica (Hymenoptera, Figitidae), a parasitoid of the globally invasive fruit pest Drosophila suzukii (Diptera, Drosophilidae), is now widespread in much of North America despite not having been intentionally introduced. Surveys in 2022 using a variety of methods detected L. japonica in 10 of 11 surveyed USA States and one Canadian Province where it was not previously known to occur. In most surveys, L. japonica was the most common species of D. suzukii parasitoid found. The surveys also resulted in the detection of Ganaspis cf. brasiliensis (Hymenoptera, Figitidae), the recently-released biological control agent of D. suzukii, in six USA States where it had not previously been found. These new detections are likely a result of intentional biological control introductions rather than spread of adventive populations. A species-specific multiplex PCR assay was developed as a rapid, accurate and cost-effective method to distinguish L. japonica, G. cf. brasiliensis, the closely-related cosmopolitan parasitoid Leptopilina heterotoma (Hymenoptera, Figitidae) and other native parasitoid species. This dataset and the associated molecular tools will facilitate future studies of the spread and ecological impacts of these introduced parasitoids on multiple continents

Thrombotic and hemorrhagic complications of COVID-19 in adults hospitalized in high-income countries compared with those in adults hospitalized in low- and middle-income countries in an international registry

Background: COVID-19 has been associated with a broad range of thromboembolic, ischemic, and hemorrhagic complications (coagulopathy complications). Most studies have focused on patients with severe disease from high-income countries (HICs). Objectives: The main aims were to compare the frequency of coagulopathy complications in developing countries (low- and middle-income countries [LMICs]) with those in HICs, delineate the frequency across a range of treatment levels, and determine associations with in-hospital mortality. Methods: Adult patients enrolled in an observational, multinational registry, the International Severe Acute Respiratory and Emerging Infections COVID-19 study, between January 1, 2020, and September 15, 2021, met inclusion criteria, including admission to a hospital for laboratory-confirmed, acute COVID-19 and data on complications and survival. The advanced-treatment cohort received care, such as admission to the intensive care unit, mechanical ventilation, or inotropes or vasopressors; the basic-treatment cohort did not receive any of these interventions. Results: The study population included 495,682 patients from 52 countries, with 63% from LMICs and 85% in the basic treatment cohort. The frequency of coagulopathy complications was higher in HICs (0.76%-3.4%) than in LMICs (0.09%-1.22%). Complications were more frequent in the advanced-treatment cohort than in the basic-treatment cohort. Coagulopathy complications were associated with increased in-hospital mortality (odds ratio, 1.58; 95% CI, 1.52-1.64). The increased mortality associated with these complications was higher in LMICs (58.5%) than in HICs (35.4%). After controlling for coagulopathy complications, treatment intensity, and multiple other factors, the mortality was higher among patients in LMICs than among patients in HICs (odds ratio, 1.45; 95% CI, 1.39-1.51). Conclusion: In a large, international registry of patients hospitalized for COVID-19, coagulopathy complications were more frequent in HICs than in LMICs (developing countries). Increased mortality associated with coagulopathy complications was of a greater magnitude among patients in LMICs. Additional research is needed regarding timely diagnosis of and intervention for coagulation derangements associated with COVID-19, particularly for limited-resource settings.</p

Neurological manifestations of COVID-19 in adults and children

Different neurological manifestations of coronavirus disease 2019 (COVID-19) in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicentre observational study using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort across 1507 sites worldwide from 30 January 2020 to 25 May 2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161 239 patients (158 267 adults; 2972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%) and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%) and CNS infection (0.2%). Each occurred more frequently in intensive care unit (ICU) than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU versus non-ICU (7.1% versus 2.3%, P < 0.001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age.</p

Thrombotic and hemorrhagic complications of COVID-19 in adults hospitalized in high-income countries compared with those in adults hospitalized in low- and middle-income countries in an international registry

Background: COVID-19 has been associated with a broad range of thromboembolic, ischemic, and hemorrhagic complications (coagulopathy complications). Most studies have focused on patients with severe disease from high-income countries (HICs). Objectives: The main aims were to compare the frequency of coagulopathy complications in developing countries (low- and middle-income countries [LMICs]) with those in HICs, delineate the frequency across a range of treatment levels, and determine associations with in-hospital mortality. Methods: Adult patients enrolled in an observational, multinational registry, the International Severe Acute Respiratory and Emerging Infections COVID-19 study, between January 1, 2020, and September 15, 2021, met inclusion criteria, including admission to a hospital for laboratory-confirmed, acute COVID-19 and data on complications and survival. The advanced-treatment cohort received care, such as admission to the intensive care unit, mechanical ventilation, or inotropes or vasopressors; the basic-treatment cohort did not receive any of these interventions. Results: The study population included 495,682 patients from 52 countries, with 63% from LMICs and 85% in the basic treatment cohort. The frequency of coagulopathy complications was higher in HICs (0.76%-3.4%) than in LMICs (0.09%-1.22%). Complications were more frequent in the advanced-treatment cohort than in the basic-treatment cohort. Coagulopathy complications were associated with increased in-hospital mortality (odds ratio, 1.58; 95% CI, 1.52-1.64). The increased mortality associated with these complications was higher in LMICs (58.5%) than in HICs (35.4%). After controlling for coagulopathy complications, treatment intensity, and multiple other factors, the mortality was higher among patients in LMICs than among patients in HICs (odds ratio, 1.45; 95% CI, 1.39-1.51). Conclusion: In a large, international registry of patients hospitalized for COVID-19, coagulopathy complications were more frequent in HICs than in LMICs (developing countries). Increased mortality associated with coagulopathy complications was of a greater magnitude among patients in LMICs. Additional research is needed regarding timely diagnosis of and intervention for coagulation derangements associated with COVID-19, particularly for limited-resource settings

\u3ci\u3eDrosophila\u3c/i\u3e Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu