Epidemiological Study in Antiviral Innate Immunity.

This chapter summarizes the epidemiological study design of natural immune epidemiology studies based on recent COVID-19-related research. The epidemiological studies on antiviral innate immunity have mainly included randomized controlled trials (RCTs) and observational studies. Importantly, this chapter will discuss how to use these methodologies to answer an epidemiological question of natural immunity in the viral infection process based on previous studies. An observational case- or cohort-based study of antiviral innate immunity may support this theoretical hypothesis but is not appropriate for clinical practice or treatment. RCTs are the gold standard for epidemiological studies and occupy a greater role in the hierarchy of evidence.

Exploring antiviral effect and mechanism of Jinye Baidu granules（JYBD）against influenza A virus through network pharmacology and in vitro and invivo experiments.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinye Baidu granules (JYBD) have been used to treat acute respiratory tract infections and demonstrated clinical efficacy for the treatment of emerging or epidemic respiratory viruses such as SARS-CoV-2 and influenza virus. AIM OF THE STUDY: This study is to investigate the antiviral effect of JYBD against influenza A viruses (IAV) in vitro and in vivo and elucidate its underlying mechanism. MATERIALS AND METHODS: Ultra-high-performance liquid chromatography connected with Orbitrap mass spectrometer (UHPLC-Orbitrap MS) was employed to describe the chemical profile of JYBD. The potential pathways and targets involved in JYBD against IAV infection were predicted by network pharmacology. The efficacy and mechanism of JYBD were validated through both in vivo and in vitro experiments. Moreover, combination therapy with JYBD and the classic anti-influenza drugs was also investigated. RESULTS: A total of 126 compounds were identified by UHPLC-Orbitrap MS, of which 9 compounds were unambiguously confirmed with reference standards. JYBD could significantly inhibit the replication of multiple strains of IAV, especially oseltamivir-resistant strains. The results of qRT-PCR and WB demonstrated that JYBD could inhibit the excessive induction of pro-inflammatory cytokines induced by IAV infection and regulate inflammatory response through inhibiting JAK/STAT, NF-κB and MAPK pathways. Moreover, both JYBD monotherapy or in combination with oseltamivir could alleviate IAV-induced severe lung injury in mice. CONCLUSIONS: JYBD could inhibit IAV replication and mitigate virus-induced excessive inflammatory response. Combinations of JYBD and neuraminidase inhibitors conferred synergistic suppression of IAV both in vitro and in vivo. It might provide a scientific basis for clinical applications of JYBD against influenza virus infected diseases.

Accuracy study of Angiotensin 1-7 composite index test to predict pulmonary fibrosis and guide treatment.

BACKGROUND: Pulmonary fibrosis can develop after acute respiratory distress syndrome (ARDS). The hypothesis is we are able to measure phenotypes that lie at the origin of ARDS severity and fibrosis development. The aim is an accuracy study of prognostic circulating biomarkers. METHODS: A longitudinal study followed COVID-related ARDS patients with medical imaging, pulmonary function tests and biomarker analysis, generating 444 laboratory data. Comparison to controls used non-parametrical statistics; p < 0·05 was considered significant. Cut-offs were obtained through receiver operating curve. Contingency tables revealed predictive values. Odds ratio was calculated through logistic regression. RESULTS: Angiotensin 1-7 beneath 138 pg/mL defined Angiotensin imbalance phenotype. Hyper-inflammatory phenotype showed a composite index test above 34, based on high Angiotensin 1-7, C-Reactive Protein, Ferritin and Transforming Growth Factor-ß. Analytical study showed conformity to predefined goals. Clinical performance gave a positive predictive value of 95 % (95 % confidence interval, 82 %-99 %), and a negative predictive value of 100 % (95 % confidence interval, 65 %-100 %). Those severe ARDS phenotypes represented 34 (Odds 95 % confidence interval, 3-355) times higher risk for pulmonary fibrosis development (p < 0·001). CONCLUSIONS: Angiotensin 1-7 composite index is an early and objective predictor of ARDS evolving to pulmonary fibrosis. It may guide therapeutic decisions in targeted phenotypes.

Impact of the COVID-19 pandemic on the treatment of acute cholangitis caused by choledocholithiasis: A single-center retrospective study in Japan.

Objectives: This study aimed to determine the impact of the coronavirus disease 2019 (COVID-19) pandemic on the treatment of acute cholangitis caused by choledocholithiasis. Methods: The Japanese government declared a state of emergency in April 2020 due to the COVID-19 pandemic. We retrospectively reviewed the medical records of 309 patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) for acute cholangitis caused by choledocholithiasis between April 2017 and December 2022. Results: Patients were categorized into a pregroup (n = 134) and a postgroup (n = 175), depending on whether they were diagnosed before or after the state of emergency declaration. The total number of ERCP cases and the number of ERCP cases with endoscopic stone removals increased after the state of emergency declaration. Compared with the pregroup, the numbers of patients with performance status of 0-1 and surgically altered anatomy increased, whereas the numbers of patients taking oral antiplatelets or anticoagulants and those with cerebrovascular disease decreased in the postgroup. The number of single-stage endoscopic stone removals increased and hospital stays were significantly shorter in the postgroup. No differences in adverse event rates were detected between the two groups. Conclusions: Although our hospital provides tertiary care, the number of patients with cholangitis in good general condition and no underlying disease increased after the state of emergency declaration. The COVID-19 pandemic resulted in an increase in the number of single-stage endoscopic treatments and shortened hospital stays for patients with acute cholangitis caused by choledocholithiasis. No safety issues with ERCP were detected, even during the pandemic.

Exploring the HONO source during the COVID-19 pandemic in a megacity in China.

HONO is a critical precursor of •OH, but its sources are controversial due to its complex formation mechanism. This study conducted comprehensive observations in Zhengzhou from April 26 to May 11, 2022. Low NOx concentrations were observed during the Covid epidemic period (EP) (10.4 ± 3.0 ppb), compared to the pre-epidemic period (PEP) (12.5 ± 3.8 ppb). The mean HONO concentration during EP (0.53 ± 0.34 ppb) was 0.09 ppb lower than that during PEP (0.62 ± 0.53 ppb). The decrease in HONO concentration during EP came mainly at night due to the reduction in the direct emission (Pemi) (0.03 ppb/hr), the homogeneous reaction between •OH and NO (POH+NO) (0.02 ppb/hr), and the heterogeneous conversion of NO2 on the ground (0.01 ppb/hr). Notably, there was no significant change in daytime HONO concentration. The daytime HONO budget indicated that the primary HONO sources during PEP were the nitrate photolysis (Pnitrate), followed by the POH+NO, Pemi, the photo-enhanced reaction of NO2 on the ground (Pground+hv) and aerosol surface (Paerosol+hv). The primary HONO sources were Pnitrate, POH+NO, Pemi, and Paerosol+hv during EP, respectively. The missing source has a high correlation with solar radiation, there might be other photo-related HONO sources or the contributions of photosensitized reactions were underestimated. In the extremely underestimated cases, HONO production rates from the Pnitrate, Pground+hv, and Paerosol+hv increased by 0.17, 0.10, and 0.10 ppb/hr during PEP, 0.23, 0.13, and 0.16 ppb/hr during EP, and Pnitrate was still the primary source during both PEP and EP.

Programa de controle do tabagismo em Mato Grosso do Sul: oferta, adesão e efetividade / Smoking control program in Mato Grosso do Sul: offer, adherence and effectiveness / Programa de control del tabaquismo en Mato Grosso do Sul: oferta, adherencia y efectividad

Objetivo: O estudo teve por objetivo avaliar o Programa Nacional de Controle do Tabagismo (PNCT) em Mato Grosso do Sul, taxas de cobertura, abandono, cessação, uso de medicamentos, rede de serviços de saúde e as razões pelas quais algumas Equipes de Saúde da Família de Campo Grande ainda não aderiram ao programa. Métodos: Trata-se de uma pesquisa descritiva, com abordagem quantitativa, baseada em dados primários e secundários sobre o PNCT em Mato Grosso do Sul. Os dados primários foram obtidos por meio de questionário aplicado aos profissionais das Equipes de Saúde da Família (ESF) de Campo Grande, sem oferta do programa e avaliados quanto à frequência e presença de correlação entre as variáveis analisadas utilizando V de Cramer e teste de χ2. Os dados secundários foram obtidos do consolidado do Instituto Nacional de Câncer José Alencar Gomes da Silva com os registros produzidos pelos serviços. Resultados: As taxas de adesão, efetividade e apoio farmacológico na capital e interior foram: 66,80 e 59,79%; 20,58 e 34,91%; 32,14 e 99,86%, respectivamente. A oferta do programa ocorreu em 49,37% municípios e 43,85% das Unidades Básicas de Saúde (UBS) estimadas. Houve correlações entre ser capacitado e implantar o programa; treinamento de ingresso e oferta na UBS. As dificuldades relatadas pelos profissionais foram a pandemia de COVID-19, a sobrecarga e/ou equipe pequena e/ou falta de tempo e a ausência de capacitação/treinamento. Conclusões: O PNCT em Mato Grosso do Sul apresenta baixa cobertura e oferta restrita na rede de saúde, além do desempenho mediano de assistência aos tabagistas. Evidencia-se a necessidade de investimento em capacitação/treinamento, prioritariamente para as ESF de Campo Grande, dando-lhes condições de responder às necessidades de promoção da saúde, reconhecendo o programa como de maior custo-efetividade.

Objective: The objective of this study was to evaluate the National Tobacco Control Program (PNCT) in Mato Grosso do Sul, coverage rates, dropout, cessation, use of medication, the health services network and the reasons why Family Health Teams in Campo Grande have not yet joined the program. Methods: This was a descriptive study with a quantitative approach, based on primary and secondary data on the PNCT in Mato Grosso do Sul. The primary data were obtained by means of a questionnaire administered to Family Health Teams (ESF) in Campo Grande, which did not offer the program and evaluated the frequency and presence of correlation between the variables analyzed using Cramer's V test and the χ2 test. The secondary data were obtained from the consolidated records of the José Alencar Gomes da Silva National Cancer Institute with the records produced by the services. Results: The rates of adherence, effectiveness and pharmacological support in the capital and interior were: 66.80 and 59.79%; 20.58 and 34.91%; and 32.14 and 99.86%, respectively. The program was offered in 49.37% of the municipalities and 43.85% of the Basic Health Units (UBS) estimated. There were correlations between being trained and implementing the program and entry training and provision in the UBS. The difficulties reported by professionals were the COVID-19 pandemic, overload and/or a small team and/or lack of time and the absence of training. Conclusions: The PNCT in Mato Grosso do Sul has low coverage and restricted supply in the health network, in addition to average performance in assisting smokers. There is a clear need to invest in capacitation/training, primarily for the ESF in Campo Grande, enabling them to respond to the needs of health promotion, recognizing the program as more cost-effective.

Objetivo: El objetivo de este estudio fue evaluar el Programa Nacional de Control del Tabaco (PNCT) en Mato Grosso do Sul, las tasas de cobertura, el abandono, la cesación, el uso de medicamentos, la red de servicios de salud y las razones por las que los Equipos de Salud de la Familia en Campo Grande aún no se han unido al programa. Métodos: Se trata de un estudio descriptivo con abordaje cuantitativo, basado en datos primarios y secundarios sobre el PNCT en Mato Grosso do Sul. Los datos primarios se obtuvieron por medio de un cuestionario aplicado a los Equipos de Salud de la Familia (ESF) de Campo Grande, que no ofrecían el programa y evaluaron la frecuencia y la presencia de correlación entre las variables analizadas utilizando la V de Cramer y la prueba de la χ2. Los datos secundarios se obtuvieron de los registros consolidados del Instituto Nacional del Cáncer José Alencar Gomes da Silva con los registros producidos por los servicios. Resultados: Las tasas de adherencia, eficacia y apoyo farmacológico en la capital y en el interior fueron: 66,80 y 59,79%; 20,58 y 34,91%; 32,14 y 99,86%, respectivamente. El programa fue ofrecido en el 49,37% de los municipios y en el 43,85% de las Unidades Básicas de Salud (UBS) estimadas. Hubo correlación entre estar capacitado e implementar el programa; capacitación de entrada y oferta en las UBS. Las dificultades relatadas por los profesionales fueron la pandemia del COVID-19, la sobrecarga y/o un equipo pequeño y/o la falta de tiempo y la ausencia de capacitación. Conclusiones: El PNCT en Mato Grosso do Sul tiene baja cobertura y oferta restringida en la red de salud, además de un desempeño medio en la asistencia a los fumadores. Hay una clara necesidad de invertir en la creación de capacidad / formación, principalmente para la ESF en Campo Grande, lo que les permite responder a las necesidades de promoción de la salud, reconociendo el programa como más rentable.

Prevalência de Influenza A, vírus sincicial respiratório eSARS-CoV-2 em pacientes com síndrome respiratóriaaguda grave em Passo Fundo, Rio Grande do Sul / Prevalence of Influenza A, respiratory syncytial virus andSARS-CoV-2 in patients with severe acute respiratorysyndrome in Passo Fundo, Rio Grande do Sul

A síndrome respiratória aguda grave (SRAG) é caracterizada por sintomas de febre alta, tosse e dispneia, e, na maioria dos casos, relacionada a uma quantidade reduzida de agentes infecciosos. O objetivo foi avaliar a prevalência dos vírus respiratórios Influenza A (FluA), vírus sincicial respiratório (RSV) e do novo coronavírus (SARS-CoV-2) em pacientes com internação hospitalar por SRAG. Estudo transversal, com pacientes em internação hospitalar com SRAG entre novembro de 2021 e maio de 2022. Dados sociodemográficos e clínicos e amostras da nasofaringe foram coletados/as, as quais foram submetidas à extração de RNA e testadas quanto à positividade para Influenza A, RSV e SARS-CoV-2 por meio da técnica de PCR em tempo real pelo método SYBR Green. Foram incluídos 42 pacientes, sendo 59,5% do sexo feminino, 57,1% idosos, 54,8% com ensino fundamental. A maior parte dos pacientes reportou hábito tabagista prévio ou atual (54,8%), não etilista (73,8%) e 83,3% deles apresentavam alguma comorbidade, sendo hipertensão arterial sistêmica e diabetes mellitus tipo 2 as mais prevalentes. Um total de 10,5% dos pacientes testou positivo para FluA, nenhuma amostra positiva para RSV e 76,3% positivos para SARS-CoV-2. Na população estudada, SRAG com agravo hospitalar foi observado em maior proporção, em mulheres, idosos e pessoas com comorbidades, embora sem significância estatística, sendo o novo coronavírus o agente etiológico mais relacionado, o que evidencia a patogenicidade desse agente e suas consequências ainda são evidentes após quase 2 anos de período pandêmico.

Severe acute respiratory syndrome (SARS) is characterized by symptoms of high fever, cough and dyspnea, and is in most cases related to a reduced amount of infectious agents. The objective was to assess the prevalence of respiratory viruses Influenza A (FluA), respiratory syncytial virus (RSV) and the new coronavirus (SARS-CoV-2) in patients hospitalized for SARS. Cross-sectional study, with patients hospitalized with SARS between November 2021 and May 2022. Sociodemographic and clinical data and nasopharyngeal samples were collected, which were subjected to RNA extraction and tested for positivity for Influenza A, RSV and SARS-CoV-2 using the real-time PCR technique using the SYBR Green method. 42 patients were included, 59.5% female, 57.1% elderly, 54.8% with primary education. Most patients reported previous or current smoking habits (54.8%), non-drinkers (73.8) and 83.3% of them had some comorbidity, with systemic arterial hypertension and type 2 diabetes mellitus being the most prevalent. A total of 10.5% of patients tested positive for FluA, no samples positive for RSV, and 76.3% positive for SARS-CoV-2. In the studied population, SARS with hospital injury was observed more frequently in women and the elderly, with associated comorbidities, with the new coronavirus being the most related etiological agent, which shows, although not statistically significant, that the pathogenicity of this agent and its consequences are still evident after almost 2 years of period pandemic.

Comparative analysis of the incidence of enteroparasitosis andthe COVID-19 pandemic profile in the city of Bananeiras - PB / Análise comparativa da incidência de enteroparasitoses e doperfil pandêmico da COVID-19 na cidade de Bananeiras - PB

Enteroparasitosis are diseases caused by parasitic agents present in the environment and in the gastrointestinal tract of living beings. In addition, they are still considered neglected diseases, but of great importance for public health, especially when they are related to secondary infections and currently their co-infection profile with COVID-19. The interaction of protozoa and/or helminths with the SARS-CoV-2 virus is timely and its signs and symptoms are confused with other pathogen relationships. In this way, this study aims to correlate the incidence of enteroparasitosis and COVID-19, in the pandemic period from 2020 to April 2022. This is a documentary and exploratory study of secondary data from laboratory tests of patients who were treated and diagnosed with COVID-19 and enteroparasitosis at Hospital Doutor Cloves Bezerra Cavalcante, Municipal Hospital of Bananeiras, Paraíba, Brazil. In the analysis of the database, a significant increase of approximately 48.85% in the incidence of COVID-19 cases from 2020 to 2021 stands out, remaining high until 2022. In contrast, cases of enteroparasites peaked at 48.74% in 2021, followed by an average reduction of 23.12%, with a deviation of 1.49%, in relation to the years 2020 and 2022. It was concluded that COVID-19 is predominantly associated with an increase in secondary infections, highlighting the crucial need to promote health education, improve basic sanitation and guarantee access to health services as essential components in combating the increase in parasitic infections, especially those related to viral pathologies.

As enteroparasitoses são enfermidades originadas por agentes parasitários presentes no meio ambiente e no trato gastrointestinal dos seres vivos. Ademais, ainda são consideradas doenças negligenciadas, porém de grande importância para a saúde pública, em especial, quando estão relacionadas com infecções secundárias e atualmente seu perfil de coinfecção com a COVID-19. A interação de protozoários e/ou helmintos com o vírus SARS-CoV-2 é oportuna e seus sinais e sintomas são confundidos com outras relações de patógenos. Desta maneira, este estudo visa correlacionar a incidência de enteroparasitoses e COVID-19, no período pandêmico de 2020 a abril de 2022. Trata--se de uma pesquisa documental e exploratória, de dados secundários dos exames laboratoriais de pacientes que foram atendidos e diagnosticados com COVID-19 e enteroparasitoses no Hospital Doutor Cloves Bezerra Cavalcante, Hospital Municipal de Bananeiras, Paraíba, Brasil. Na análise da base de dados, destaca-se um aumento significativo de aproximadamente 48,85% na incidência de casos de COVID-19 de 2020 a 2021, mantendo-se elevado até 2022. Em contraste, os casos de enteroparasitas atingiram um pico de 48,74% em 2021, seguido por uma redução média de 23,12%, com um desvio de 1,49%, em relação aos anos de 2020 e 2022. Conclui-se que a COVID-19 está predominantemente associada ao aumento de infecções secundárias, destacando a necessidade crucial de promover a educação em saúde, melhorar o saneamento básico e garantir o acesso aos serviços de saúde como componentes essenciais no combate ao aumento de infecções parasitárias, especialmente aquelas relacionadas a patologias virais.

Internet access during COVID-19 and depressive symptoms in middle-aged and older adults: Evidence from a quasi-experimental study in China.

BACKGROUND: Amid the COVID-19 pandemic, the mental health of middle-aged and older adults has become an increasing concern, and the role of the internet in addressing this public health crisis has drawn the attention of researchers. This study evaluated the impact of internet access during COVID-19 on depressive symptoms among middle-aged and older adults. METHODS: Data were derived from China Health and Retirement Longitudinal Study (CHARLS) 2018 and 2020. Difference-in-differences analysis was performed to compare changes in depressive symptoms between the internet users during COVID-19 and those who didn't have access to the internet before and during the pandemic. RESULTS: We found that internet access during COVID-19 pandemic significantly reduced middle-aged and older adults' depressive symptoms. Further investigation identified the underlying mechanisms through which internet access helps in alleviating depressive symptoms by reducing the likelihood of experiencing negative emotions about COVID-19. Heterogeneity analyses showed that rural residents and middle-aged individuals benefited more from internet access during the pandemic. CONCLUSIONS: Since internet access can alleviate middle-aged and older adults' depressive symptoms amidst public health crisis, policy makers should focus on enhancing their access to the internet.

Potential of 6'­hydroxy justicidin B from Justicia procumbens as a therapeutic agent against coronavirus disease 2019.

BACKGROUND: Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, remarkable advances have been made in vaccine development to reduce mortality. However, therapeutic interventions for COVID-19 are comparatively limited despite these intensive efforts. Furthermore, the rapid mutation capability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a characteristic of its RNA structure, has led to the emergence of multiple variants, necessitating a shift from a predominantly vaccine-centric approach to one that encompasses therapeutic strategies. 6'-Hydroxy justicidin B (6'-HJB), an arylnaphthalene lignan isolated from Justicia procumbens, a traditional Chinese medicine, is known for its antiviral properties. HYPOTHESIS/PURPOSE: The aim of the present study was to assess the effectiveness and safety of 6'-HJB against SARS-CoV-2 in order to determine its potential as a therapeutic agent against COVID-19. METHODS: The efficacy of 6'-HJB was evaluated both in vitro using Vero and Calu-3 cell lines and in vivo using ferrets. The safety assessment included toxicokinetics, safety pharmacology, and Good Laboratory Practice (GLP)-compliant toxicity evaluations following single- and repeated-dose toxicity studies in dogs. RESULTS: The anti-SARS-CoV-2 efficacy of 6'-HJB was evaluated through dose-response curve (DRC) analysis using immunofluorescence; 6'-HJB demonstrated superior inhibition of SARS-CoV-2 growth and lower cytotoxicity than remdesivir. In SARS-CoV-2-infected ferret, 6'-HJB showed efficacy comparable to that of the positive control, Truvada. Further GLP toxicity studies corroborated the safety profile of 6'-HJB. Single-dose and 4-week repeated oral toxicity studies in Beagle dogs demonstrated minimal harmful effects at the highest dosages. The lethal dose of 6'-HJB exceeded 2,000 mg kg-1 in Beagle dogs. Toxicokinetic and GLP safety pharmacology studies demonstrated no adverse effects of 6'-HJB on metabolic processes, respiratory or central nervous systems, or cardiac functions. CONCLUSION: This research highlights both the antiviral efficacy and safety profile of 6'-HJB, underscoring its potential as a novel COVID-19 treatment option. The potential of 6'-HJB was demonstrated using modern scientific methodologies and standards.

Expert providers implement integrated and coordinated care in opioid use disorder treatment.

BACKGROUND: Enhancing care integration and coordination to improve patient outcomes in opioid use disorder treatment is a growing focus in the field. Understanding of how the treatment system implements coordination and integration, particularly in the aftermath of the COVID-19 pandemic, remains limited. In this study, we explored the implementation of medications for opioid use disorder (MOUD) and the evolution of service delivery toward a more comprehensive approach. We examined providers' perspectives from high-achieving programs in Los Angeles County, the largest and most diverse U.S. county, including barriers to integrating and coordinating care and strategies for integrating MOUD service delivery. METHODS: We gathered qualitative interview data from 30 high-performing programs in Los Angeles County, each represented by a manager or supervisor. High performance was defined by empirical indicators of access, retention, and program completion. Our data collection and analysis followed the constructivist grounded theory approach, explicating the social processes used by participating managers during the pandemic and subsequent organizational shifts. This approach yielded 14 major and six minor codes. Interrater reliability tests yielded a pooled Cohen's kappa statistic of 93%. RESULTS: Expert providers exhibited a strong commitment to destigmatizing MOUD and worked to overcome obstacles in delivering care to clients by advocating its efficacy to fellow health care providers. Along with their endorsement of MOUD, they identified challenges in integrating and coordinating MOUD care. Barriers included stigma at both patient and provider levels, inadequate education about MOUD, limited access to MOUD, and the complexities of operating in a fragmented health care framework. Despite these challenges, high-performing providers used strategies to harmonize and align MOUD service delivery with health and social services. These included establishing service colocation, adopting a multidisciplinary team-based approach, forming partnerships with the community, offering telehealth services, integrating and sharing data, and embracing a harm reduction philosophy. DISCUSSION: Through the adoption of these strategies, providers enhanced care accessibility, boosted patient engagement, sustained retention in treatment, and enhanced treatment outcomes. Even among highly skilled treatment providers in Los Angeles County, barriers to integrating and coordinating care using MOUD remain intricate and multifaceted. Addressing these challenges necessitates a comprehensive strategy involving provider education and training, increased availability of MOUD, enhanced coordination and communication among health care providers, resolution of regulatory hurdles, and addressing patient hesitancy toward MOUD.

Structural review of SARS-CoV-2 antiviral targets.

The coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents the most disastrous infectious disease pandemic of the past century. As a member of the Betacoronavirus genus, the SARS-CoV-2 genome encodes a total of 29 proteins. The spike protein, RNA-dependent RNA polymerase, and proteases play crucial roles in the virus replication process and are promising targets for drug development. In recent years, structural studies of these viral proteins and of their complexes with antibodies and inhibitors have provided valuable insights into their functions and laid a solid foundation for drug development. In this review, we summarize the structural features of these proteins and discuss recent progress in research regarding therapeutic development, highlighting mechanistically representative molecules and those that have already been approved or are under clinical investigation.

Psychotropic drug prescribing before and during the COVID-19 pandemic among people with depressive and anxiety disorders: a multinational network study.

BACKGROUND: People with mental health conditions were potentially more vulnerable than others to the neuropsychiatric effects of the COVID-19 pandemic and the global efforts taken to contain it. The aim of this multinational study was to examine the changes in psychotropic drug prescribing during the pandemic among people with depressive and anxiety disorders. METHODS: This study included electronic medical records and claims data from nine databases in six countries (France, Germany, Italy, the UK, South Korea, and the USA) of patients with a diagnosis of depressive or anxiety disorders between 2016 and 2021. The outcomes were monthly prevalence rates of antidepressant, antipsychotic, and anxiolytic drug prescribing. The associations between the pandemic and psychotropic drug prescribing were examined with interrupted time series analyses for the total sample and stratified by sex and age group. People with lived experience were not involved in the research and writing process. FINDINGS: Between Jan 1, 2016 and Dec 31, 2020, an average of 16 567 914 patients with depressive disorders (10 820 956 females [65·31%] and 5 746 958 males [34·69%]) and 15 988 451 patients with anxiety disorders (10 688 788 females [66·85%] and 5 299 663 males [33·15%]) were identified annually. Most patients with depressive disorders and anxiety disorders were aged 45-64 years. Ethnicity data were not available. Two distinct trends in prescribing rates were identified. The first pattern shows an initial surge at the start of the pandemic (eg, antipsychotics among patients with depressive disorders in MDCD_US (rate ratio [RR] 1·077, 95% CI 1·055-1·100), followed by a gradual decline towards the counterfactual level (RR 0·990, 95% CI 0·988-0·992). The second pattern, observed in four databases for anxiolytics among patients with depressive disorders and two for antipsychotics among patients with anxiety disorders, shows an immediate increase (eg, antipsychotics among patients with anxiety disorders in IQVIA_UK: RR 1·467, 95% CI 1·282-1·675) without a subsequent change in slope (RR 0·985, 95% CI 0·969-1·003). In MDCD_US and IQVIA_US, the anxiolytic prescribing rate continued to increase among patients younger than 25 years for both disorders. INTERPRETATION: The study reveals persistently elevated rates of psychotropic drug prescriptions beyond the initial phase of the pandemic. These findings underscore the importance of enhanced mental health support and emphasise the need for regular review of psychotropic drug use among this patient group in the post-pandemic era. FUNDING: University Grants Committee, Research Grants Council, The Government of the Hong Kong Special Administrative Region.

Antipsychotic exposure and infection risk in people with schizophrenia spectrum disorders during the COVID-19 pandemic: a Danish nationwide registry study.

BACKGROUND: Infection risk and mortality are increased in schizophrenia spectrum disorders, which was corroborated during the COVID-19 pandemic. However, evidence is lacking regarding the additional impact of antipsychotic drugs, and the highly debated safety of clozapine treatment during large-scale infection outbreaks. Therefore, we aimed to investigate risk of COVID-19 and non-COVID respiratory infections during exposure to antipsychotics. METHODS: We used several nationwide Danish registers (National Prescription Registry, National Hospital Registry, Psychiatric Research Register, Microbiology Database, Vaccination Registry, Cause of Death Registry, and Database for Labour market Research) to investigate all individuals aged 18 years or older with a schizophrenia spectrum disorder (ICD-10: F20-F29) living in Denmark between Jan 1 and March 1, 2020. Antipsychotic exposure groups were defined as prevalent-users and incident-users. The full observation period was March 1, 2020 to Dec 31, 2021. Antipsychotic exposure was defined in a time-varying manner and compared with non-exposure. Risk was calculated for mild infection outcomes (positive SARS-CoV-2 PCR and anti-infective drug prescriptions) and severe infection outcomes (hospitalisation and death) related to COVID-19 and non-COVID-19 respiratory infections. Outcomes were adjusted for demographics, socio-economic factors, and comorbidity. FINDINGS: Of 85 083 individuals (44 293 men [52·1%] and 40 790 women [47·9%], median age 45·8 years [IQR 31·1-60·2]) with pre-existing schizophrenia spectrum disorders, 30 984 had antipsychotic exposure periods. Ethnicity data were not available. During antipsychotic exposure compared with non-exposed periods, assessing mild infection outcomes, risk of a positive SARS-CoV-2 test was decreased (hazard ratio 0·91 [95% CI 0·85-0·97]) and risk of redeeming an anti-infective drug was not statistically significantly different (1·01 [0·97-1·06]). For severe infection outcomes, COVID-19-related hospitalisation risk was increased (1·28 [1·07-1·52]) although COVID-19-related death was not statistically significantly increased (1·24 [0·82-1·86]). For non-COVID-19 respiratory infections, risk was increased both for hospitalisation (1·61 [1·44-1·79]) and death (1·61 [1·18-2·21]). Specifically, COVID-19 hospitalisation risk was increased in individuals older than 70 years, and non-COVID-19 hospitalisation risk increased in individuals older than 40 years and death risk in age groups of 50-59 years and 70-79 years. Based on homogeneity testing, no apparent excess risk of any outcome was observed with clozapine exposure compared with other antipsychotics. INTERPRETATION: During antipsychotic exposure compared with unexposed periods, risk of severe infection outcomes increases. It seems reasonable to initiate infection countermeasures, such as pneumococcal vaccination, in people older than 40 years with schizophrenia spectrum disorders, who commence or are treated with antipsychotics. We do not suggest the avoidance of specific antipsychotics but rather adherence to treatment guidelines and a call for increased vigilance regarding this at-risk group. FUNDING: Mental Health Services of the Capital Region of Denmark.

Comparison of 24 vs 72-hour octreotide infusion in acute esophageal variceal hemorrhage - a multi-center, randomized clinical trial.

BACKGROUND: Current guidelines lack clarity about the optimal duration of octreotide therapy for patients with esophageal variceal hemorrhage (EVH). To address this lack of evidence, we conducted a randomized clinical trial (RCT) of 24-hours versus 72-hours continuous infusion of octreotide for patients with EVH. METHODS: This multi-center, prospective RCT (NCT03624517), randomized patients with EVH to 24-hour versus 72-hour infusion of octreotide. Patients were required to undergo esophageal variceal band ligation prior to enrollment. The primary endpoint was rebleeding rate at 72 hours. The study was terminated early due to an inability to recruit during and after the COVID-19 epidemic. RESULTS: For patients randomized to 72-hours (n = 19) of octreotide vs 24-hours (n = 15), there were no differences in the need for transfusion, average pRBC units transfused per patient (3 units vs 2 units), infection (5% vs 0%), mechanical ventilation (11% vs 7%), or the need for vasopressors (5% vs 3%), respectively (none of these differences were statistically significantly different). There were 2 re-bleeding events in the 72-hour group (11%), and no re-bleeding events in the 24-hour group (p = 0.49). 8/15 of patients receiving 24 hours of octreotide were discharged at or before hospital day 3 while none in the 72-hour group was discharged before day 3 (p < 0.001). There was one death (in the 72-hour group) within 30 days. CONCLUSIONS: A 24-hour infusion is non-inferior to a 72-hour infusion of octreotide for prevention of re-bleeding in patients with EVH. We propose that shortened octreotide duration may help reduce hospital stay and related costs in these patients.

Quo Vadis, ECMO? Multidisciplinary Hybrid Extra Corporeal Membrane Oxygenation Rounds During the COVID-19 Pandemic.

The complex care of patients on extracorporeal membrane oxygenation (ECMO) requires a high level of collaboration between multiple medical specialties and allied health professionals. Effective and timely communication between team members is imperative in ensuring patient safety. The COVID-19 pandemic posed unique challenges in the care of patients on ECMO. Communication between team members was complicated by social distancing recommendations, increased patient volume, and staff turnover. In this article, we describe a hybrid approach to rounds that allowed team members to attend virtually or in-person to improve team communication. Weekly hybrid ECMO rounds were held to discuss patient cases and work collectively to establish patient centered goals for the following week. Critical care and surgical consultants, registered nurse ECMO specialists, RNs, perfusionists, respiratory therapists, physical and occupational therapists, pharmacists, ethics committee members, and patient family members were invited to attend hybrid ECMO rounds. After eight months of rounds, medical care team members were asked to provide feedback regarding the rounds format, strengths, and weaknesses. The most frequently identified strengths were improved multidisciplinary communication and continuity of care. This article demonstrates that hybrid virtual and in-person patient rounds are a feasible way for ECMO programs to improve team communication and overall patient care.

Trends in hip fracture surgery in the United States from 2016 to 2021: patient characteristics, clinical management, and outcomes.

INTRODUCTION: Hip fractures are a serious health concern and a major contributor to healthcare resource utilisation. We aimed to investigate nationwide trends in the USA in patient characteristics and outcomes in patients after hip fracture repair surgery. METHODS: From the Premier Healthcare dataset, we extracted patient encounters for surgical hip fracture repair from 2016 to 2021. Patient characteristics, comorbidities, complications, and anaesthetic and surgical details were analysed. Cochran-Armitage trend tests and simple linear regression were used to determine trends. RESULTS: We included 347 086 hip fracture repair encounters. Notable trends included the following: median patient age declined from 82 yr [interquartile range: 73-88 yr] to 81 yr [interquartile range: 73-88 yr], (P-value=0.002), the proportion of female patients decreased from 68% to 66.2% (P-value=0.019); internal fixation was the most common intervention initially, but with a declining percentage from 49.9% to 43.8% (P-value <0.001); in general, patients carried a greater comorbidity burden, with the proportion with three or more Elixhauser comorbidities increasing from 56.4% to 58.6% (P-value=0.006); general anaesthesia remained the most common anaesthetic technique, from 68.90% to 56.80% without a significant trend; per 1000 inpatient days, the most common complication remained acute renal failure; despite a higher comorbidity burden, no complication showed a statistically significant upward trend, and many showed downward trends. CONCLUSIONS: Over the 6-yr period from 2016 to 2021, a majority of hip fracture repairs continued to be performed under general anaesthesia but with that percentage declining over time. Notable trends included a lower percentage of female patients, an increase in femoral neck fractures, a higher comorbidity burden among patients, and a decrease in complications.

Depression and Quality of Life in Transplant Recipients During the COVID-19 Pandemic.

INTRODUCTION: Depression prevention is crucial for maintaining both physical and mental health and enhancing individuals' quality of life (QOL) post-transplantation. Despite the heightened susceptibility of post-transplant patients to COVID-19 infection, the relationship between depression and QOL during the pandemic remains unclear. This study aimed to (1) identify depression and QOL during the pandemic in kidney and liver transplant patients, and (2) explore the relationship between QOL and depression. DESIGN: This cross-sectional study involved patients aged 20 years or older who were at least 6 months post-transplantation. Depression and QOL were assessed using the Patient Health Questionnaire-9 and the 8-item Short-Form Health Survey, respectively. Logistic regression analysis was conducted to examine the relationship between QOL and depression. The study included 204 participants comprising 68 postkidney transplant and 136 postliver transplant patients. RESULTS: Among all participants, depressive symptoms were present 30% of the time, with 8.3% experiencing moderate or severe depression. Logistic regression analysis revealed that depression (mental component summary; OR = 2.419, P < .001, 95% CI: 1.862-2.915) and postoperative period (physical component summary; OR = 1.397, P = .008, 95% CI: 1.094-1.733) significantly influenced QOL. CONCLUSION: This study suggests that the prevention of depression in emerging infectious disease pandemics may contribute to maintaining the mental QOL of transplant recipients.

Four odorants for olfactory training are enough: a pilot study.

BACKGROUND:  Olfactory training (OT) is commonly used for the treatment of olfactory disorders. Nevertheless, there is an ongoing debate about the most effective OT regimen. We aimed to compare the effects of OT with 7 items (rose, lemon, eucalyptus, cloves, stewed apple, balm, mint) to 4-item-OT (rose, lemon, eucalyptus, cloves) over 3 months. Methods: Participants were 40 patients with olfactory dysfunction receiving 4-item-OT or 7-item-OT and 60 gender- and age-matched individuals with normal sense of smell receiving no OT, 4-item-OT, or 7-item-OT. Before and after the OT we assessed n-butanol odor thresholds, discrimination, and identification (TDI score), additionalthresholds for (R)-(-)-carvone, ß-damascenone, salicyclic acid benzylester, the degree of phantosmia and parosmia, cognitive function, and ratings of olfactory function. Results: In both patient groups, the TDI score increased with the use of OT, regardless of the number of odors used (p < 0.001; 3.48 ± 4.21 and lower than control groups). The clinically significant increase of 5.5 points in TDI score correlated with change of ratings of parosmia (r 0.62; p < 0.01) and with ratings of olfactory dysfunction (r = 0.51; p < 0.05). CONCLUSION:  Concluding, OT over a 3-months period with 4 or 7 odors appears to produce similar results, although the sample size has to be considered.

Impact of Cardiorespiratory Fitness on COVID-19-Related Outcomes: The Exercise Testing and Health Outcomes Study (ETHOS).

OBJECTIVE: To assess the association between cardiorespiratory fitness (CRF) and COVID-19-related health outcomes including mortality, hospitalization, and mechanical ventilation. PATIENTS AND METHODS: In a retrospective analysis of 750,302 patients included in the Exercise Testing and Health Outcomes Study, we identified 23,140 who had a positive result on COVID-19 testing between March 2020 and September 2021 and underwent a maximal exercise test in the Veterans Affairs Health Care System between October 1, 1999 to September 3, 2020. The association between CRF and risk for severe COVID-19 outcomes, including mortality, hospitalization due to COVID-19, and need for intubation was assessed after adjustment for 15 covariates. Patients were stratified into 5 age-specific CRF categories (Least-Fit, Low-Fit, Moderate-Fit, Fit, and High-Fit), based on peak metabolic equivalents achieved. RESULTS: During a median of follow-up of 100 days, 1643 of the 23,140 patients (7.1%) died, 4995 (21.6%) were hospitalized, and 927 (4.0%) required intubation for COVID-19-related reasons. When compared with the Least-Fit patients (referent), the Low-Fit, Moderate-Fit, Fit, and High-Fit patients had hazard ratios for mortality of 0.82 (95% CI, 0.72 to 0.93), 0.73 (95% CI, 0.63 to 0.86), 0.61 (95% CI, 0.53 to 0.72), and 0.54 (95% CI, 0.45 to 0.65), respectively. Patients who were more fit also had substantially lower need for hospital admissions and intubation. Similar patterns were observed for elderly patients and subgroups with comorbidities including hypertension, diabetes, cardiovascular disease, and chronic kidney disease; for each of these conditions, those in the High-Fit category had mortality rates that were roughly half those in the Low-Fit category. CONCLUSION: Among patients positive for COVID-19, higher CRF had a favorable impact on survival, need for hospitalization, and need for intubation regardless of age, body mass index, or the presence of comorbidities.