RESUMO
Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
Assuntos
Internacionalidade , Programas Nacionais de Saúde , Doenças Raras/diagnóstico , Doenças Raras/genética , Sequenciamento Completo do Genoma , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Bases de Dados Factuais , Eritrócitos/metabolismo , Fator de Transcrição GATA1/genética , Humanos , Fenótipo , Locos de Características Quantitativas , Receptores de Trombopoetina/genética , Medicina Estatal , Reino UnidoRESUMO
BACKGROUND: Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain. METHODS: In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion. RESULTS: Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized. CONCLUSIONS: In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).
Assuntos
COVID-19 , Imunização Passiva , Adulto , Assistência Ambulatorial , COVID-19/terapia , Progressão da Doença , Método Duplo-Cego , Hospitalização , Humanos , Imunização Passiva/efeitos adversos , Imunização Passiva/métodos , Resultado do Tratamento , Estados Unidos , Soroterapia para COVID-19RESUMO
Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m2, including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m2. Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies.
Assuntos
Amiloidose , Apolipoproteínas A , Nefrite Intersticial , Insuficiência Renal Crônica , Humanos , Pessoa de Meia-Idade , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/genética , Nefrite Intersticial/complicações , Mutação , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/complicaçõesRESUMO
BACKGROUND: Outpatient monoclonal antibodies are no longer effective and antiviral treatments for coronavirus disease 2019 (COVID-19) disease remain largely unavailable in many countries worldwide. Although treatment with COVID-19 convalescent plasma (CCP) is promising, clinical trials among outpatients have shown mixed results. METHODS: We conducted an individual participant data meta-analysis from outpatient trials to assess the overall risk reduction for all-cause hospitalizations by day 28 in transfused participants. Relevant trials were identified by searching Medline, Embase, medRxiv, World Health Organization COVID-19 Research Database, Cochrane Library, and Web of Science from January 2020 to September 2022. RESULTS: Five included studies from 4 countries enrolled and transfused 2620 adult patients. Comorbidities were present in 1795 (69%). The virus neutralizing antibody dilutional titer levels ranged from 8 to 14 580 in diverse assays. One hundred sixty of 1315 (12.2%) control patients were hospitalized, versus 111 of 1305 (8.5%) CCP-treated patients, yielding a 3.7% (95% confidence interval [CI], 1.3%-6.0%; P = .001) absolute risk reduction and 30.1% relative risk reduction for all-cause hospitalization. The hospitalization reduction was greatest in those with both early transfusion and high titer with a 7.6% absolute risk reduction (95% CI, 4.0%-11.1%; P = .0001) accompanied by at 51.4% relative risk reduction. No significant reduction in hospitalization was seen with treatment >5 days after symptom onset or in those receiving CCP with antibody titers below the median titer. CONCLUSIONS: Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization and may be most effective when given within 5 days of symptom onset and when antibody titer is higher.
Assuntos
COVID-19 , Adulto , Humanos , COVID-19/terapia , Pacientes Ambulatoriais , SARS-CoV-2 , Soroterapia para COVID-19 , Ensaios Clínicos Controlados Aleatórios como Assunto , HospitalizaçãoRESUMO
BACKGROUND: The efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection. METHODS: This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection. RESULTS: In total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups. CONCLUSIONS: Administration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection. CLINICAL TRIALS REGISTRATION: NCT04323800.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Adolescente , Adulto , COVID-19/prevenção & controle , Profilaxia Pós-Exposição , Soroterapia para COVID-19 , Método Duplo-Cego , Imunização PassivaRESUMO
BACKGROUND: COVID-19 convalescent plasma (CCP) is an important therapeutic option for outpatients at high risk of hospitalization from SARS-CoV-2 infection. We assessed the safety of outpatient CCP transfusions administered during clinical trials. STUDY DESIGN AND METHODS: We analyzed data pertaining to transfusion-related reactions from two randomized controlled trials in the U.S. that evaluated the efficacy of CCP versus control plasma in various ambulatory settings. Multivariable logistic regression was used to assess whether CCP was associated with transfusion reactions, after adjusting for potential confounders. RESULTS: The combined study reported 79/1351 (5.9%) adverse events during the transfusion visit, with the majority 62/1351 (4.6%) characterized by mild, allergic-type findings of urticaria, and/or pruritus consistent with minor allergic transfusion reactions; the other reported events were attributed to the patients' underlying disease, COVID-19, or vasovagal in nature. We found no difference in the likelihood of allergic transfusion reactions between those receiving CCP versus control plasma (adjusted odds ratio [AOR], 0.75; 95% CI, 0.43-1.31). Risk of urticaria and/or pruritus increased with a pre-existing diagnosis of asthma (AOR, 2.33; 95% CI, 1.16-4.67). We did not observe any CCP-attributed antibody disease enhancement in participants with COVID-19 or increased risk of infection. There were no life-threatening severe transfusion reactions and no patients required hospitalization related to transfusion-associated complications. DISCUSSION: Outpatient plasma administration was safely performed for nearly 1400 participants. CCP is a safe therapeutic option for outpatients at risk of hospitalization from COVID-19.
Assuntos
COVID-19 , Reação Transfusional , Urticária , Humanos , COVID-19/terapia , COVID-19/etiologia , Soroterapia para COVID-19 , Imunização Passiva/efeitos adversos , Pacientes Ambulatoriais , SARS-CoV-2 , Reação Transfusional/etiologia , Urticária/etiologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Idiop athic nephrotic syndrome (INS) is classified in children according to response to initial corticosteroid therapy into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS), and in adults according to histology into minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, there is well-recognised phenotypic overlap between these entities. Genome-wide association studies (GWAS) have shown a strong association between SSNS and variation at HLA, suggesting an underlying immunological basis. We sought to determine whether a risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of INS presenting in other ways. METHODS: We developed an SSNS genetic risk score (SSNS-GRS) from the five variants independently associated with childhood SSNS in a previous European GWAS. We quantified SSNS-GRS in independent cohorts of European individuals with childhood SSNS, non-monogenic SRNS, MCD, and FSGS, and contrasted them with SSNS-GRS quantified in individuals with monogenic SRNS, membranous nephropathy (a different immune-mediated disease-causing nephrotic syndrome), and healthy controls. RESULTS: The SSNS-GRS was significantly elevated in cohorts with SSNS, non-monogenic SRNS, MCD, and FSGS compared to healthy participants and those with membranous nephropathy. The SSNS-GRS in all cohorts with non-monogenic INS were also significantly elevated compared to those with monogenic SRNS. CONCLUSIONS: The shared genetic risk factors among patients with different presentations of INS strongly suggests a shared autoimmune pathogenesis when monogenic causes are excluded. Use of the SSNS-GRS, in addition to testing for monogenic causes, may help to classify patients presenting with INS. A higher resolution version of the Graphical abstract is available as Supplementary information.
Assuntos
Glomerulonefrite Membranosa , Glomerulosclerose Segmentar e Focal , Nefrose Lipoide , Síndrome Nefrótica , Criança , Humanos , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/genética , Nefrose Lipoide/diagnóstico , Nefrose Lipoide/tratamento farmacológico , Nefrose Lipoide/genética , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/genética , Estudo de Associação Genômica Ampla , Esteroides , Fatores de RiscoRESUMO
BACKGROUND: It is unknown if probiotics exert pathogen-specific effects in children with diarrhea secondary to acute gastroenteritis. METHODS: Analysis of patient-level data from 2 multicenter randomized, placebo controlled trials conducted in pediatric emergency departments in Canada and the United States. Participants were 3-48 months with >3 diarrheal episodes in the preceding 24 hours and were symptomatic for <72 hours and <7 days in the Canadian and US studies, respectively. Participants received either placebo or a probiotic preparation (Canada-Lactobacillus rhamnosus R0011/Lactobacillus helveticus R0052; US-L. rhamnosus GG). The primary outcome was post-intervention moderate-to-severe disease (ie, ≥9 on the Modified Vesikari Scale [MVS] score). RESULTS: Pathogens were identified in specimens from 59.3% of children (928/1565). No pathogen groups were less likely to experience an MVS score ≥9 based on treatment allocation (test for interaction = 0.35). No differences between groups were identified for adenovirus (adjusted relative risk [aRR]: 1.42; 95% confidence interval [CI]: .62, 3.23), norovirus (aRR: 0.98; 95% CI: .56, 1.74), rotavirus (aRR: 0.86; 95% CI: .43, 1.71) or bacteria (aRR: 1.19; 95% CI: .41, 3.43). At pathogen-group and among individual pathogens there were no differences in diarrhea duration or the total number of diarrheal stools between treatment groups, regardless of intervention allocation or among probiotic sub-groups. Among adenovirus-infected children, those administered the L. rhamnosus R0011/L. helveticus R0052 product experienced fewer diarrheal episodes (aRR: 0.65; 95% CI: .47, .90). CONCLUSIONS: Neither probiotic product resulted in less severe disease compared to placebo across a range of the most common etiologic pathogens. The preponderance of evidence does not support the notion that there are pathogen specific benefits associated with probiotic use in children with acute gastroenteritis. CLINICAL TRIALS REGISTRATION: NCT01773967 and NCT01853124.
Assuntos
Serviços Médicos de Emergência , Gastroenterite , Lacticaseibacillus rhamnosus , Lactobacillus helveticus , Probióticos , Canadá/epidemiologia , Criança , Diarreia/complicações , Método Duplo-Cego , Gastroenterite/microbiologia , Gastroenterite/terapia , Humanos , Lactente , Probióticos/uso terapêuticoRESUMO
We conducted a retrospective cohort study to assess the effect vaccination with the live-attenuated recombinant vesicular stomatitis virus-Zaire Ebola virus vaccine had on deaths among patients who had laboratory-confirmed Ebola virus disease (EVD). We included EVD-positive patients coming to an Ebola Treatment Center in eastern Democratic Republic of the Congo during 2018-2020. Overall, 25% of patients vaccinated before symptom onset died compared with 63% of unvaccinated patients. Vaccinated patients reported fewer EVD-associated symptoms, had reduced time to clearance of viral load, and had reduced length of stay at the Ebola Treatment Center. After controlling for confounders, vaccination was strongly associated with decreased deaths. Reduction in deaths was not affected by timing of vaccination before or after EVD exposure. These findings support use of preexposure and postexposure recombinant vesicular stomatitis virus-Zaire Ebola virus vaccine as an intervention associated with improved death rates, illness, and recovery time among patients with EVD.
Assuntos
Vacinas contra Ebola , Ebolavirus , Doença pelo Vírus Ebola , Estomatite Vesicular , Animais , República Democrática do Congo/epidemiologia , Ebolavirus/genética , Doença pelo Vírus Ebola/diagnóstico , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/prevenção & controle , Humanos , Estudos Retrospectivos , Vacinação , Vacinas Atenuadas , Estomatite Vesicular/induzido quimicamente , Vesiculovirus/genéticaRESUMO
Rapid diagnostic tools for children with Ebola virus disease (EVD) are needed to expedite isolation and treatment. To evaluate a predictive diagnostic tool, we examined retrospective data (2014-2015) from the International Medical Corps Ebola Treatment Centers in West Africa. We incorporated statistically derived candidate predictors into a 7-point Pediatric Ebola Risk Score. Evidence of bleeding or having known or no known Ebola contacts was positively associated with an EVD diagnosis, whereas abdominal pain was negatively associated. Model discrimination using area under the curve (AUC) was 0.87, which outperforms the World Health Organization criteria (AUC 0.56). External validation, performed by using data from International Medical Corps Ebola Treatment Centers in the Democratic Republic of the Congo during 2018-2019, showed an AUC of 0.70. External validation showed that discrimination achieved by using World Health Organization criteria was similar; however, the Pediatric Ebola Risk Score is simpler to use.
Assuntos
Ebolavirus , Doença pelo Vírus Ebola , Área Sob a Curva , Criança , República Democrática do Congo/epidemiologia , Surtos de Doenças , Doença pelo Vírus Ebola/diagnóstico , Doença pelo Vírus Ebola/epidemiologia , Humanos , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. METHODS: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. RESULTS: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. CONCLUSIONS: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).
Assuntos
Alanina/análogos & derivados , Anticorpos Monoclonais/uso terapêutico , Antivirais/uso terapêutico , Doença pelo Vírus Ebola/tratamento farmacológico , Ribonucleotídeos/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Adolescente , Adulto , Alanina/efeitos adversos , Alanina/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Antivirais/efeitos adversos , Criança , Pré-Escolar , República Democrática do Congo/epidemiologia , Surtos de Doenças , Ebolavirus/genética , Feminino , Doença pelo Vírus Ebola/mortalidade , Humanos , Lactente , Recém-Nascido , Infusões Intravenosas , Masculino , RNA Viral/sangue , Ribonucleotídeos/efeitos adversos , Método Simples-Cego , Adulto JovemRESUMO
Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare, life-threatening disorder, mediated through severe ADAMTS13 deficiency causing multi-system micro-thrombi formation, and has specific human leukocyte antigen associations. We undertook a large genome-wide association study to investigate additional genetically distinct associations in iTTP. We compared two iTTP patient cohorts with controls, following standardized genome-wide quality control procedures for single-nucleotide polymorphisms and imputed HLA types. Associations were functionally investigated using expression quantitative trait loci (eQTL), and motif binding prediction software. Independent associations consistent with previous findings in iTTP were detected at the HLA locus and in addition a novel association was detected on chromosome 3 (rs9884090, P=5.22x10-10, odds ratio 0.40) in the UK discovery cohort. Meta-analysis, including the French replication cohort, strengthened the associations. The haploblock containing rs9884090 is associated with reduced protein O-glycosyltransferase 1 (POGLUT1) expression (eQTL P<0.05), and functional annotation suggested a potential causative variant (rs71767581). This work implicates POGLUT1 in iTTP pathophysiology and suggests altered post-translational modification of its targets may influence disease susceptibility.
Assuntos
Púrpura Trombocitopênica Idiopática , Púrpura Trombocitopênica Trombótica , Proteína ADAMTS13/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Glucosiltransferases/genética , Humanos , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Trombótica/genéticaRESUMO
Convalescent plasma, collected from donors who have recovered from a pathogen of interest, has been used to treat infectious diseases, particularly in times of outbreak, when alternative therapies were unavailable. The COVID-19 pandemic revived interest in the use of convalescent plasma. Large observational studies and clinical trials that were executed during the pandemic provided insight into how to use convalescent plasma, whereby high levels of antibodies against the pathogen of interest and administration early within the time course of the disease are critical for optimal therapeutic effect. Several studies have shown outpatient administration of COVID-19 convalescent plasma (CCP) to be both safe and effective, preventing clinical progression in patients when administered within the first week of COVID-19. The United States Food and Drug Administration expanded its emergency use authorization (EUA) to allow for the administration of CCP in an outpatient setting in December 2021, at least for immunocompromised patients or those on immunosuppressive therapy. Outpatient transfusion of CCP and infusion of monoclonal antibody therapies for a highly transmissible infectious disease introduces nuanced challenges related to infection prevention. Drawing on our experiences with the clinical and research use of CCP, we describe the logistical considerations and workflow spanning procurement of qualified products, infrastructure, staffing, transfusion, and associated management of adverse events. The purpose of this description is to facilitate the efforts of others intent on establishing outpatient transfusion programs for CCP and other antibody-based therapies.
Assuntos
COVID-19 , COVID-19/terapia , Humanos , Imunização Passiva , Pacientes Ambulatoriais , Pandemias , SARS-CoV-2 , Estados Unidos , Soroterapia para COVID-19RESUMO
COVID-19 has stretched the U.S. social safety net and prompted federal legislation designed to ameliorate the pandemic's health and economic impacts. We surveyed a nationally representative cohort of 1222 U.S. adults in April 2020 and November 2020 to evaluate changes in public opinion about 11 social safety net policies and the role of government over the course of the pandemic. A majority of U.S. adults supported six policies at both time points, including policies guaranteeing two weeks of paid sick leave; enacting universal health insurance; increasing the federal minimum wage; and increasing government spending on construction projects, business tax credits, and employment education and training. From April to November 2020, public support was stable for nine of the 11 policies but declined nearly 10 percentage points for policies guaranteeing two weeks paid sick leave (from 76% support in April 2020 to 67% support in November 2020) and extending unemployment insurance benefits (51% to 42%). Declines in support for these two policies were concentrated among those with higher incomes, more education, in better health status, the employed, and those with health insurance. The share of respondents believing in a strong role of government also declined from 33% in April to 26% in November 2020 (p > 0.05). Despite these shifts, we observed consistent majority support for several policies enacted during the pandemic, including guaranteeing paid sick leave and business tax credits, as well as employment-related policies.
Assuntos
COVID-19 , Adulto , Humanos , Pandemias/prevenção & controle , Política Pública , SARS-CoV-2 , Licença MédicaRESUMO
Mask wearing and social distancing have been essential public health guidelines throughout the COVID-19 pandemic, but faced resistance from skeptical subgroups in the United States, including Republicans and evangelicals. We examined the effects of participation in ideologically heterogeneous civic associations on attitudes toward public health measures during the COVID-19 pandemic, particularly among partisan and religious subgroups most resistant to public health guidelines. We analyzed panel survey data from a nationally representative cohort of 1222 U.S. adults collected in April, July, and November 2020, and July/August 2021. Data on the importance of social distancing and mask wearing were collected in November 2020. Evangelicals and Republicans who participated in ideologically diverse civic associations were more likely to support mask wearing compared to those participating in ideologically homogenous associations (difference in predicted policy support on a 0-1 scale: 0.084, p ≤ .05 and 0.020, p ≤ .05, respectively). Evangelicals in ideologically diverse associations were also more likely to support social distancing compared to those in ideologically homogenous associations (0.089, p ≤ .05). Participation in civic associations with ideologically heterogeneous members was associated with greater support for public health measures among skeptical subgroups. Encouraging exposure to diverse ideologies may bolster support for public health measures to mitigate COVID-19.
Assuntos
COVID-19 , Distanciamento Físico , Adulto , COVID-19/prevenção & controle , Humanos , Máscaras , Pandemias/prevenção & controle , SARS-CoV-2 , Estados UnidosRESUMO
STUDY OBJECTIVE: This study aimed to explore oral ondansetron usage and impact on outcomes in clinical practice. METHODS: This observational study was a planned secondary analysis of 2 trials conducted in 10 US and 6 Canadian institutions between 2014 and 2017. Children 3 to 48 months old with gastroenteritis and ≥3 episodes of vomiting in the 24 hours preceding emergency department (ED) presentation were included. Oral ondansetron was administered at the discretion of the provider. The principal outcomes were intravenous fluid administration and hospitalization at the index visit and during the subsequent 72 hours and diarrhea and vomiting frequency during the 24 hours following the ED visit. RESULTS: In total, 794 children were included. The median age was 16.0 months (interquartile range 10.0 to 26.0), and 50.1% (398/794) received oral ondansetron. In propensity-adjusted analysis (n=528), children administered oral ondansetron were less likely to receive intravenous fluids at the index visit (adjusted odds ratio [aOR] 0.50; 95% confidence interval [CI] 0.29 to 0.88). There were no differences in the frequencies of intravenous fluid administration within the first 72 hours (aOR 0.65; 95% CI 0.39 to 1.10) or hospitalization at the index visit (aOR 0.31; 95% CI 0.09 to 1.10) or the subsequent 72 hours (aOR 0.52; 95% CI 0.21 to 1.28). Episodes of vomiting (aRR 0.86; 95% CI 0.63 to 1.19) and diarrhea (aRR 1.11; 95% CI 0.93 to 1.32) during the 24 hours following ED discharge also did not differ. CONCLUSION: Among preschool-aged children with gastroenteritis seeking ED care, oral ondansetron administration was associated with a reduction in index ED visit intravenous fluid administration; it was not associated with intravenous fluids administered within 72 hours, hospitalization, or vomiting and diarrhea in the 24 hours following discharge.
Assuntos
Antieméticos/administração & dosagem , Serviço Hospitalar de Emergência , Gastroenterite/complicações , Ondansetron/administração & dosagem , Vômito/prevenção & controle , Doença Aguda , Administração Oral , Pré-Escolar , Diarreia/etiologia , Diarreia/prevenção & controle , Feminino , Hidratação , Hospitalização , Humanos , Lactente , Masculino , Pontuação de Propensão , Vômito/etiologiaRESUMO
BACKGROUND: Empiric antimalarial treatment is a component of protocol-based management of Ebola virus disease (EVD), yet this approach has limited clinical evidence for patient-centered benefits. METHODS: This retrospective cohort study evaluated the association between antimalarial treatment and mortality among patients with confirmed EVD. The data was collected from five International Medical Corps operated Ebola Treatment Units (ETUs) in Sierra Leone and Liberia from 2014 through 2015. The standardized protocol used for patient care included empiric oral treatment with combination artemether and lumefantrine, twice daily for three days; however, only a subset of patients received treatment due to resource variability. The outcome of interest was mortality, comparing patients treated with oral antimalarials within 48-h of admission to those not treated. Analysis was conducted with logistic regression to generate adjusted odds ratios (aORs). Multivariable analyses controlled for ETU country, malaria rapid diagnostic test result, age, EVD cycle threshold value, symptoms of bleeding, diarrhea, dysphagia and dyspnea, and additional standard clinical treatments. RESULTS: Among the 424 cases analyzed, 376 (88.7%) received early oral antimalarials. Across all cases, mortality occurred in 57.5% (244). In comparing unadjusted mortality prevalence, early antimalarial treated cases yielded 55.1% mortality versus 77.1% mortality for those untreated (p = 0.005). Multivariable analysis demonstrated evidence of reduced aOR for mortality with early oral antimalarial treatment versus non-treatment (aOR = 0.34, 95% Confidence Interval: 0.12, 0.92, p = 0.039). CONCLUSION: Early oral antimalarial treatment in an EVD outbreak was associated with reduced mortality. Further study is warranted to investigate this association between early oral antimalarial treatment and mortality in EVD patients.
Assuntos
Antimaláricos , Doença pelo Vírus Ebola , Malária , Antimaláricos/uso terapêutico , Estudos de Coortes , Doença pelo Vírus Ebola/tratamento farmacológico , Humanos , Malária/tratamento farmacológico , Estudos RetrospectivosRESUMO
OBJECTIVES: Although most acute gastroenteritis (AGE) episodes in children rapidly self-resolve, some children go on to experience more significant and prolonged illness. We sought to develop a prognostic score to identify children at risk of experiencing moderate-to-severe disease after an index emergency department (ED) visit. METHODS: Data were collected from a cohort of children 3 to 48âmonths of age diagnosed with AGE in 16 North American pediatric EDs. Moderate-to-severe AGE was defined as a Modified Vesikari Scale (MVS) score ≥9 during the 14-day post-ED visit. A clinical prognostic model was derived using multivariable logistic regression and converted into a simple risk score. The model's accuracy was assessed for moderate-to-severe AGE and several secondary outcomes. RESULTS: After their index ED visit, 19% (336/1770) of participants developed moderate-to-severe AGE. Patient age, number of vomiting episodes, dehydration status, prior ED visits, and intravenous rehydration were associated with MVS ≥9 in multivariable regression. Calibration of the prognostic model was strong with a P value of 0.77 by the Hosmer-Lemenshow goodness-of-fit test, and discrimination was moderate with an area under the receiver operator characteristic curve of 0.68 (95% confidence interval [CI] 0.65-0.72). Similarly, the model was shown to have good calibration when fit to the secondary outcomes of subsequent ED revisit, intravenous rehydration, or hospitalization within 72âhours after the index visit. CONCLUSIONS: After external validation, this new risk score may provide clinicians with accurate prognostic insight into the likely disease course of children with AGE, informing disposition decisions, anticipatory guidance, and follow-up care.
Assuntos
Gastroenterite , Criança , Serviço Hospitalar de Emergência , Hidratação , Gastroenterite/complicações , Gastroenterite/diagnóstico , Hospitalização , Humanos , Lactente , Fatores de RiscoRESUMO
BACKGROUND: To examine the relationship between civic association participation and psychological distress during the COVID-19 pandemic, particularly whether different forms of engagement mitigate the increased rates of psychological distress throughout 2020. METHODS: Panel survey data collected from a nationally representative cohort of 1222 U.S. adults. Data was collected in three waves in April, July, and November 2020. Psychological distress was measured using the validated Kessler-6 instrument in November 2020. RESULTS: Respondents belonging to political associations were more likely to experience psychological distress (difference in predicted level of psychological distress on a 0-1 scale: 0.098, p ≤ .05) relative to those in unknown associations. However, individuals in political associations who more frequently interacted with others had lower levels of psychological distress (-.065, p ≤ .05) compared to those in political associations with less frequent interactions. CONCLUSIONS: Civic engagement that facilitates interpersonal interactions may protect against psychological distress.
Assuntos
COVID-19 , Angústia Psicológica , Adulto , Humanos , Pandemias , Estresse Psicológico/epidemiologia , Estresse Psicológico/psicologia , Inquéritos e QuestionáriosRESUMO
[This corrects the article DOI: 10.1371/journal.pgen.1007329.].