What Is in the Neuromuscular Junction Literature?

ABSTRACT: This update covers recommendations for myasthenia gravis (MG) in patients with coronavirus 2019 disease as well as reports of the clinical features of patients with MG and coronavirus 2019. Updated advisory committee recommendations for the use of thymectomy in generalized MG are also provided. Other MG topics include lipoprotein receptor-4 and agrin antibody associations, factors influencing conversion of ocular to generalized MG, the use of rituximab for more recent onset disease, immunoglobulins for maintenance therapy, and fatigue and depression.

Early COVID-19 Hospitalizations Among New York State Residents with a History of Invasive Cancer.

Background: Individuals with a history of cancer may be more susceptible to severe COVID-19 due to immunosuppression, comorbidities, or ongoing treatment. We linked inpatient claims data on COVID-19 hospitalizations to cancer diagnoses from the New York State Cancer Registry (NYSCR) to examine associations between prior cancer diagnoses and hospitalizations for COVID-19, and factors associated with death at discharge after COVID-19 hospitalization. Methods: New York State (NYS) residents diagnosed with invasive cancer before July 1, 2021, who were alive on January 1, 2020, were identified from NYSCR data. We obtained claims data for discharge year 2020 and the first half of 2021 from NYS's Statewide Planning and Research Cooperative System (SPARCS), and we linked inpatient records with COVID-19 as the primary diagnosis to cancer data from the NYSCR using deterministic matching methods. We calculated descriptive statistics and conducted multivariable-adjusted logistic regression analyses to examine associations of cancer case characteristics with COVID-19 hospitalization and with vital status at discharge among patients with a history of cancer. All analyses were conducted in SAS 9.4. Results: Our analysis included 1,257,377 individuals with a history of cancer, 10,210 of whom had a subsequent primary COVID-19 hospitalization. Individuals with a history of cancer were 16% more likely to be hospitalized with COVID-19, compared to the general population of NYS, after adjusting for age and sex (95% CI, 14%-19%). Factors independently associated with COVID-19 hospitalization among cancer patients included older age, male sex, non-Hispanic Black race or Hispanic ethnicity, diagnosis with late-stage cancer or with multiple tumors, more recent cancer diagnosis, and New York City (NYC) residency at the time of cancer diagnosis. Factors independently associated with death at discharge among individuals with COVID-19 hospitalization and a prior cancer diagnosis included older age, male sex, non-Hispanic Black or non-Hispanic Asian/Pacific Islander race or Hispanic ethnicity, residence in NYC at the time of COVID-19 hospitalization, and an active cancer diagnosis claim code at the time of COVID-19 hospitalization. Conclusion: This claims-based study identified higher risks of COVID-19 hospitalization and death at discharge among individuals with a history of cancer, and particularly those in certain demographic and diagnostic groups.

Use of platelet-rich plasma for COVID-19-related olfactory loss: a randomized controlled trial.

INTRODUCTION: The current study evaluated the use of platelet-rich plasma (PRP), an autologous blood product with supraphysiologic concentrations of growth factors, in the treatment of prolonged coronavirus disease 2019 (COVID-19)-related smell loss. METHODS: This multi-institutional, randomized controlled trial recruited patients with COVID-19 who had objectively measured smell loss (University of Pennsylvania Smell Identification Test [UPSIT] ≤ 33) between 6 and 12 months. Patients were randomized to three intranasal injections of either PRP or sterile saline into their olfactory clefts. The primary outcome measure was change in Sniffin' Sticks score (threshold, discrimination, and identification [TDI]) from baseline. The secondary end point measures included responder rate (achievement of a clinically significant improvement, ≥5.5 points TDI), change in individual TDI olfaction scores, and change in subjective olfaction via a visual analog scale. RESULTS: A total of 35 patients were recruited and 26 completed the study. PRP treatment resulted in a 3.67-point (95% CI: 0.05-7.29, p = 0.047) greater improvement in olfaction compared with the placebo group at 3 months and a higher response rate (57.1% vs 8.3%, odds ratio 12.5 [95% exact bootstrap confidence interval, 2.2-116.7]). There was a greater improvement in smell discrimination following PRP treatment compared with placebo but no difference in smell identification or threshold. There was no difference in subjective scores between PRP and placebo. No adverse effects were reported. CONCLUSION: Olfactory function following COVID-19 can improve spontaneously after 6 months and can improve to a greater extent with PRP injection. These data build on the promise of PRP to be a safe potential treatment option for patients with COVID-19-related smell loss, and larger-powered studies will help further assess its efficacy.

[Regional Vascular Center in a COVID-19 pandemic: what changed in 2020 compared to 2019 in patients with ST Elevation Myocardial Infarction?]

AIM: To assess the effect of pandemic COVID-19 on the course of STEMI patients of the Regional Vascular Center in 2020, compared with the previous year. MATERIALS AND METHODS: Patients with acute coronary syndrome and, in particular, STEMI hospitalized at Regional Vascular Center in 2019 and 2020. RESULTS: In 2019, 981 patients with STEMI were admitted; in 2020 - 728 patients. The baseline clinical and demographic patients characteristics did not differ significantly. In 2020, the number of pneumonia has doubled, the number of mechanical ventilator support has increased by 20%; sepsis was diagnosed 5 times more often. However, patients in 2020 were less likely to develop delirium, minor and major bleeding. There were more patients admitted in the 1st day of the disease, and they were more frequently performed both primary angioplasty and angioplasty in general. Patients with STEMI in 2020 had more frequently registered pulmonary edema, cardiogenic shock and re-infarction. Lethality in the group of patients without angioplasty tended to be higher in 2020 compared with the previous year. None of 30 patients with COVID-19 died in our department, they were timely transferred either to COVID-hospital or to outpatient follow-up care. When analyzing various parameters during the spring and autumn periods, which were the peak periods for pneumonias in 2020, only mortality had a clear upward trend. CONCLUSION: The patient portrait of myocardial infarction in 2020 was dominated by pneumonia, sepsis, and re-infarction compared with the previous year. An upward trend in mortality was detected in those without angioplasty and those hospitalized in the spring and autumn wave of COVID-19. We believe that there are hidden mechanisms of pandemic effect on mortality in STEMI.

A Comparison of Long-Term Outcomes in Patients Managed With Venovenous Extracorporeal Membrane Oxygenation in the First and Second Waves of the COVID-19 Pandemic in the United Kingdom.

OBJECTIVES: Early studies of venovenous extracorporeal membrane oxygenation (ECMO) in COVID-19 have revealed similar outcomes to historical cohorts. Changes in the disease and treatments have led to differences in the patients supported on venovenous ECMO in the first and second waves. We aimed to compare these two groups in both the acute and follow-up phase. DESIGN: Retrospective single-center cohort study comparing mortality at censoring date (November 30, 2021) and decannulation, patient characteristics, complications and lung function and quality of life (QOL-by European Quality of Life 5 Dimensions 3 Level Version) at first follow-up in patients supported on venovenous ECMO between wave 1 and wave 2 of the COVID-19 pandemic. SETTING: Critical care department of a severe acute respiratory failure service. PATIENTS: Patients supported on ECMO for COVID-19 between wave 1 (March 17, 2020, to August 31, 2020) and wave 2 (January 9, 2020, to May 25, 2021). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred twenty-three patients were included in our analysis. Survival at censoring date (χ 2 , 6.35; p = 0.012) and decannulation (90.4% vs 70.0%; p < 0.001) was significantly lower in the second wave, while duration of ECMO run was longer (12.0 d [18.0-30.0 d] vs 29.5 d [15.5-58.3 d]; p = 0.005). Wave 2 patients had longer application of noninvasive ventilation (NIV) prior to ECMO and a higher frequency of barotrauma. Patient age and NIV use were independently associated with increased mortality (odds ratio 1.07 [1.01-1.14]; p = 0.025 and 3.37 [1.12-12.60]; p = 0.043, respectively). QOL and lung function apart from transfer coefficient of carbon monoxide corrected for hemoglobin was similar at follow-up across the waves. CONCLUSIONS: Most patients with COVID-19 supported on ECMO in both waves survived in the short and longer term. At follow-up patients had similar lung function and QOL across the two waves. This suggests that ECMO has an ongoing role in the management of a carefully selected group of patients with COVID-19.

How were we before? An analysis of the potential supply and inequality in the geographic access to critical resources for the COVID-19 treatment. / Como estávamos antes? Uma análise da oferta potencial e desigualdade de acesso geográfico aos recursos críticos para tratamento de COVID-19.

The objective was to analyze the situation of the Metropolitan Area of Brasília (AMB) before the onset of the COVID-19 pandemic, focusing on the availability and geographical accessibility of critical resources for the treatment of acute respiratory crises caused by the SARS-CoV-2 virus. Geographic mapping of the population within the territory and geolocation of health facilities and resources, construction of a relationship network between the potential demand simulated to the public health system and the supply of resources available in December 2019. The relationship analysis is based on the theory of complex networks crossing socioeconomic data available in the CENSUS and information from the National Registry of Health Establishments (CNES) and analyzing the micro relationship of census tracts with the stock and availability of health resources concerning Adult ICU Bed Type II/III and Respirators/Ventilators. The Federal District (DF) health facilities concentrate more than 75% of the relationships of potential access to critical resources for the treatment of COVID-19. Although the regions surrounding the DF, belonging to Goiás state, have the greatest relative vulnerability in the studied territory, they are also the most lacking in spatial accessibility and availability of resources, evidencing a care imbalance within the AMB region.

O objetivo deste artigo é analisar a situação da Área Metropolitana de Brasília (AMB) antes do início da pandemia de COVID-19 com foco na disponibilidade e acessibilidade de recursos críticos para o tratamento da crise aguda respiratória causada pelo vírus SARS-CoV-2. Mapeamento geográfico da população e geolocalização dos estabelecimentos e recursos de saúde, construção de rede de relacionamentos entre a demanda potencial ao sistema de saúde público e a oferta de recursos existente em dez/2019. Análise baseada na teoria de redes complexas cruzando dados socioeconômicos disponíveis no CENSO, dados do Cadastro Nacional de Estabelecimentos de Saúde (CNES) e o micro relacionamento dos setores censitários e suas populações com o estoque e disponibilidade de recursos do tipo Leito de UTI Adulto Tipo II/III e Respiradores Mecânicos. Estabelecimentos do Distrito Federal (DF) concentram mais de 75% dos relacionamentos de acesso potencial aos recursos críticos para o tratamento de COVID-19. Embora as regiões do entorno do DF, pertencentes ao Goiás, apresentem a maior vulnerabilidade relativa no território estudado, são também as mais carentes de acessibilidade e disponibilidade de recursos, evidenciando um desequilíbrio assistencial dentro da região da AMB.

How An Established Health System Ventures Forth: Ochsner Invests in the Future.

SUMMARY: The founding of Ochsner Ventures followed the natural evolution of more than a decade of growth and expansion of Ochsner Health's offerings and capabilities beyond traditional patient care. This growth has enabled the health system to bring critical services to underserved communities across the Gulf South. Ochsner Ventures supports promising companies both in and beyond the region while bringing forward new solutions to healthcare sector challenges and improving health outcomes, access, and equity. In a dynamic healthcare environment amid the persistent effects of the COVID-19 pandemic, Ochsner Health is executing a multiyear strategic plan to reinforce its mission and maintain a position of strength in the region. One aspect of the strategy focuses on the diversification and pursuit of new value by creating new revenue, additional savings, cost reductions, innovations, and amplifying existing assets and capabilities.

The Impact of Therapeutic Plasma Exchange on Inflammatory Markers and Acute Phase Reactants in Patients with Severe SARS-CoV-2 Infection.

Background and Objectives: Due to the poor prognosis and the very high mortality rate associated with severe SARS-CoV-2 infections, various regimens have been tried to stop the evolution of the inflammatory cascade, such as immunomodulatory therapy and plasma clearance of the acute phase reactants involved. Therefore, the objective of this review was to analyze the effects of using therapeutic plasma exchange (TPE), also known as plasmapheresis, on the inflammatory markers of critically ill COVID-19 patients admitted to the intensive care unit (ICU). Materials and Methods: A thorough scientific database search was performed, and it included a review of articles published on PubMed, Cochrane Database, Scopus, and Web of Science from the beginning of the COVID-19 pandemic in March 2020 until September 2022 that focused on the treatment of SARS-CoV-2 infections using plasma exchange for patients admitted to the ICU. The current study included original articles, reviews, editorials, and short or special communications regarding the topic of interest. Results: A total of 13 articles were selected after satisfying the inclusion criterion of three or more patients enrolled with clinically severe COVID-19 that were eligible for TPE. From the included articles, it was observed that TPE was used as a last-resort salvage therapy that can be regarded as an alternative treatment method when the standard management for these patients fails. TPE significantly decreased the inflammatory status as measured by Interleukin-6 (IL-6), C-reactive protein (CRP), lymphocyte count, and D-dimers, as well as improving the clinical status measured with PaO2/FiO2 and duration of hospitalization. The pooled mortality risk reduction after TPE was 20%. Conclusions: There are sufficient studies and evidence to show that TPE reduces inflammatory mediators and improves coagulation function and the clinical/paraclinical status. Nevertheless, although it was shown that TPE decreases the severe inflammatory status without significant complications, the improvement of survival rate remains unclear.

Mortality Among US Veterans Admitted to Community vs Veterans Health Administration Hospitals for COVID-19.

Importance: Veterans Health Administration (VHA) enrollees receive care for COVID-19 in both VHA and non-VHA (ie, community) hospitals, but little is known about the frequency or outcomes of care for veterans with COVID-19 in VHA vs community hospitals. Objective: To compare outcomes among veterans admitted for COVID-19 in VHA vs community hospitals. Design, Setting, and Participants: This retrospective cohort study used VHA and Medicare data from March 1, 2020, to December 31, 2021, on hospitalizations for COVID-19 in 121 VHA and 4369 community hospitals in the US among a national cohort of veterans (aged ≥65 years) enrolled in both the VHA and Medicare with VHA care in the year prior to hospitalization for COVID-19 based on the primary diagnosis code. Exposure: Admission to VHA vs community hospitals. Main Outcomes and Measures: The main outcomes were 30-day mortality and 30-day readmission. Inverse probability of treatment weighting was used to balance observable patient characteristics (eg, demographic characteristics, comorbidity, mechanical ventilation on admission, area-level social vulnerability, distance to VHA vs community hospitals, and date of admission) between VHA and community hospitals. Results: The cohort included 64 856 veterans (mean [SD] age, 77.6 [8.0] years; 63 562 men [98.0%]) dually enrolled in the VHA and Medicare who were hospitalized for COVID-19. Most (47 821 [73.7%]) were admitted to community hospitals (36 362 [56.1%] admitted to community hospitals via Medicare, 11 459 [17.7%] admitted to community hospitals reimbursed via VHA's Care in the Community program, and 17 035 [26.3%] admitted to VHA hospitals). Admission to community hospitals was associated with higher unadjusted and risk-adjusted 30-day mortality compared with admission to VHA hospitals (crude mortality, 12 951 of 47 821 [27.1%] vs 3021 of 17 035 [17.7%]; P < .001; risk-adjusted odds ratio, 1.37 [95% CI, 1.21-1.55]; P < .001). Readmission within 30 days was less common after admission to community compared with VHA hospitals (4898 of 38 576 [12.7%] vs 2006 of 14 357 [14.0%]; risk-adjusted hazard ratio, 0.89 [95% CI, 0.86-0.92]; P < .001). Conclusions and Relevance: This study found that most hospitalizations for COVID-19 among VHA enrollees aged 65 years or older were in community hospitals and that veterans experienced higher mortality in community hospitals than in VHA hospitals. The VHA must understand the sources of the mortality difference to plan care for VHA enrollees during future COVID-19 surges and the next pandemic.

[Clinical case of mucormycosis in patient COVID-19. Case report].

The COVID-19 epidemic is being revealed from a new angle every month. In particular, with the appearance of the delta strain, mucormycosis began to manifest in some patients, which had previously been extremely rare. Mucormycosis is a rare, aggressive infection caused by filamentous fungi of the Mucorales family and associated with high morbidity and mortality rates. The main risk factors for the mucormycosis in patients with COVID-19 are diabetes mellitus and diabetic ketoacidosis, uncontrolled hyperglycemia and massive use of glucocorticoids, vascular damage, thrombosis, lymphopenia, which often occur against the background of COVID-19 and make a person vulnerable to secondary or opportunistic fungal infection. We present a clinical case of mucormycosis in a 21-year-old female patient with COVID-19-associated severe pneumonia and concomitant type I diabetes mellitus. The patient was hospitalized and received standard therapy during inpatient treatment, including glucocorticosteroids in accordance with the severity of the course of COVID-19. On the 12th day from the hospitalization, the patient's condition deteriorated significantly, and the visible changes in the skin and soft tissues of the face, characteristic of mucormycosis appeared. Despite the drug therapy correction, the patient died because of the acute respiratory failure in combination with septic fungal damage of the brain stem.

Retrospective Analysis of the Outcome of Hospitalized COVID-19 Patients with Coexisting Metabolic Syndrome and HIV Using Multinomial Logistic Regression.

Globally, the coexistence of metabolic syndrome (MetS) and HIV has become an important public health problem, putting coronavirus disease 19 (COVID-19) hospitalized patients at risk for severe manifestations and higher mortality. A retrospective cross-sectional analysis was conducted to identify factors and determine their relationships with hospitalization outcomes for COVID-19 patients using secondary data from the Department of Health in Limpopo Province, South Africa. The study included 15,151 patient clinical records of laboratory-confirmed COVID-19 cases. Data on MetS was extracted in the form of a cluster of metabolic factors. These included abdominal obesity, high blood pressure, and impaired fasting glucose captured on an information sheet. Spatial distribution of mortality among patients was observed; overall (21-33%), hypertension (32-43%), diabetes (34-47%), and HIV (31-45%). A multinomial logistic regression model was applied to identify factors and determine their relationships with hospitalization outcomes for COVID-19 patients. Mortality among COVID-19 patients was associated with being older (≥50+ years), male, and HIV positive. Having hypertension and diabetes reduced the duration from admission to death. Being transferred from a primary health facility (PHC) to a referral hospital among COVID-19 patients was associated with ventilation and less chance of being transferred to another health facility when having HIV plus MetS. Patients with MetS had a higher mortality rate within seven days of hospitalization, followed by those with obesity as an individual component. MetS and its components such as hypertension, diabetes, and obesity should be considered a composite predictor of COVID-19 fatal outcomes, mostly, increased risk of mortality. The study increases our understanding of the common contributing variables to severe manifestations and a greater mortality risk among COVID-19 hospitalized patients by investigating the influence of MetS, its components, and HIV coexistence. Prevention remains the mainstay for both communicable and non-communicable diseases. The findings underscore the need for improvement of critical care resources across South Africa.

The effect of hyperbaric oxygen therapy on myocardial function in post-COVID-19 syndrome patients: a randomized controlled trial.

Post-COVID-19 condition refers to a range of persisting physical, neurocognitive, and neuropsychological symptoms following SARS-CoV-2 infection. Recent evidence revealed that post-COVID-19 syndrome patients may suffer from cardiac dysfunction and are at increased risk for a broad range of cardiovascular disorders. This randomized, sham-control, double-blind trial evaluated the effect of hyperbaric oxygen therapy (HBOT) on the cardiac function of post-COVID-19 patients with ongoing symptoms for at least three months after confirmed infection. Sixty patients were randomized to receive 40 daily HBOT or sham sessions. They underwent echocardiography at baseline and 1-3 weeks after the last protocol session. Twenty-nine (48.3%) patients had reduced global longitudinal strain (GLS) at baseline. Of them, 13 (43.3%) and 16 (53.3%) were allocated to the sham and HBOT groups, respectively. Compared to the sham group, GLS significantly increased following HBOT (- 17.8 ± 1.1 to - 20.2 ± 1.0, p = 0.0001), with a significant group-by-time interaction (p = 0.041). In conclusion, post-COVID-19 syndrome patients despite normal EF often have subclinical left ventricular dysfunction that is characterized by mildly reduced GLS. HBOT promotes left ventricular systolic function recovery in patients suffering from post COVID-19 condition. Further studies are needed to optimize patient selection and evaluate long-term outcomes.This study was registered with ClinicalTrials.gov, number NCT04647656 on 01/12/2020.

Digital Healthy Diet Literacy and Fear of COVID-19 as Associated with Treatment Adherence and Its Subscales among Hemodialysis Patients: A Multi-Hospital Study.

Treatment adherence (TA) is a critical issue and is under-investigated in hemodialysis patients. A multi-center study was conducted from July 2020 to March 2021 on 972 hemodialysis patients in eight hospitals in Vietnam to explore the factors associated with TA during the COVID-19 pandemic. Data were collected, including socio-demographics, an End-Stage Renal Disease Adherence Questionnaire (ESRD-AQ), 12-item short-form health literacy questionnaire (HLS-SF12), 4-item digital healthy diet literacy scale (DDL), 10-item hemodialysis dietary knowledge scale (HDK), 7-item fear of COVID-19 scale (FCoV-19S), and suspected COVID-19 symptoms (S-COVID19-S). Bivariate and multivariate linear regression models were used to explore the associations. Higher DDL scores were associated with higher TA scores (regression coefficient, B, 1.35; 95% confidence interval, 95%CI, 0.59, 2.12; p = 0.001). Higher FCoV-19S scores were associated with lower TA scores (B, -1.78; 95%CI, -3.33, -0.24; p = 0.023). In addition, patients aged 60-85 (B, 24.85; 95%CI, 6.61, 43.11; p = 0.008) with "very or fairly easy" medication payment ability (B, 27.92; 95%CI, 5.89, 44.95; p = 0.013) had higher TA scores. Patients who underwent hemodialysis for ≥5 years had a lower TA score than those who received <5 years of hemodialysis (B, -52.87; 95%CI, -70.46, -35.28; p < 0.001). These findings suggested that DDL and FCoV-19S, among other factors, should be considered in future interventions to improve TA in hemodialysis patients.

[Determining factors of survival in patients with severe coronavirus infection admitted to intensive care unit in the third and fourth waves of COVID-19 pandemic]. / A kórházi túlélést meghatározó tényezok a COVID­19-járvány 3. és 4. hulláma idején súlyos koronavírus-fertozéssel intenzív osztályra felvett betegekben.

INTRODUCTION: During COVID-19 pandemic, a high mortality rate (20-60%) of patients admitted to intensive care unit has been observed. Identification of risk factors can support the understanding of disease pathophysiology and the recognition of vulnerable patients, prognostication and selection of appropriate treatment. OBJECTIVE: Beyond characterisation of a local, critically ill COVID-19 population, analysis of the associations between demographic/clinical data and patient survival were investigated. METHOD: Retrospective, observational study has been performed by recording demographic, clinical data and outcome parameters on patients with severe respiratory insufficiency caused by COVID-19. RESULTS: 88 patients were enrolled. Median age was 65 years and 53% of patients were male, median BMI was 29 kg/m2. Noninvasive ventilation was used in 81%, endotracheal intubation in 45%, prone positioning in 59% of all cases. Vasopressor treatment was introduced in 44%, secondary bacterial infection was detected in 36% of all cases. Hospital survival rate was 41%. Risk factors for survival and the effect of evolving treatment protocols were analyzed with multivariable regression model. A better survival chance was associated to younger age, lower APACE II score and non-diabetic status. Effect of the treatment protocol was found to be significant (OR = 0.18 [95% CI: 0.04-0.76], p = 0.01976) after controlling for APACHE II, BMI, sex, two comorbidities and two pharmaceutical agents (tocilizumab, remdesivir). CONCLUSION: Survival rate was favourable if patients were younger, with lower APACHE II score and if non-diabetic. Low initial survival rate (15%) significantly improved (49%) in association with the protocol changes. We would like to facilitate Hungarian centres to publish their data and initiate a nationwide database to improve the management of severe COVID disease. Orv Hetil. 2023; 164(17): 651-658.

Novel SARS-CoV-2 entry inhibitors, 2-anilinoquinazolin-4(3H)-one derivatives, show potency as SARS-CoV-2 antivirals in a human ACE2 transgenic mouse model.

The ongoing COVID-19 has not only caused millions of deaths worldwide, but it has also led to economic recession and the collapse of public health systems. The vaccines and antivirals developed in response to the pandemic have improved the situation markedly; however, the pandemic is still not under control with recurring surges. Thus, it is still necessary to develop therapeutic agents. In our previous studies, we designed and synthesized a series of novel 2-anilinoquinazolin-4(3H)-one derivatives, and demonstrated inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and MERS-CoV in vitro. We then conducted in vivo studies using modified compounds that are suitable for oral administration. These compounds demonstrated no toxicity in rats and inhibited viral entry. Here, we investigated the in vivo efficacy of these drug candidates against SARS-CoV-2. Three candidate drugs, 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (1), N-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N-(3,5-dichlorophenyl)acetamide (2), and N-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N-(3,5-difluorophenyl)acetamide (3) were administered orally to hACE2 transgenic mice at a dose of 100 mg/kg. All three drugs improved survival rate and reduced the viral load in the lungs. These results show that the derivatives possess in vivo antiviral efficacy similar to that of molnupiravir, which is currently being used to treat COVID-19. Overall, our data suggest that 2-anilinoquinazolin-4(3H)-one derivatives are promising as potential oral antiviral drug candidates against SARS-CoV-2 infection.

Delivery platforms for broadly neutralizing antibodies.

PURPOSE OF REVIEW: Passive administration of broadly neutralizing antibodies (bNAbs) is being evaluated as a therapeutic approach to prevent or treat HIV infections. However, a number of challenges face the widespread implementation of passive transfer for HIV. To reduce the need of recurrent administrations of bNAbs, gene-based delivery approaches have been developed which overcome the limitations of passive transfer. RECENT FINDINGS: The use of DNA and mRNA for the delivery of bNAbs has made significant progress. DNA-encoded monoclonal antibodies (DMAbs) have shown great promise in animal models of disease and the underlying DNA-based technology is now being tested in vaccine trials for a variety of indications. The COVID-19 pandemic greatly accelerated the development of mRNA-based technology to induce protective immunity. These advances are now being successfully applied to the delivery of monoclonal antibodies using mRNA in animal models. Delivery of bNAbs using viral vectors, primarily adeno-associated virus (AAV), has shown great promise in preclinical animal models and more recently in human studies. Most recently, advances in genome editing techniques have led to engineering of monoclonal antibody expression from B cells. These efforts aim to turn B cells into a source of evolving antibodies that can improve through repeated exposure to the respective antigen. SUMMARY: The use of these different platforms for antibody delivery has been demonstrated across a wide range of animal models and disease indications, including HIV. Although each approach has unique strengths and weaknesses, additional advances in efficiency of gene delivery and reduced immunogenicity will be necessary to drive widespread implementation of these technologies. Considering the mounting clinical evidence of the potential of bNAbs for HIV treatment and prevention, overcoming the remaining technical challenges for gene-based bNAb delivery represents a relatively straightforward path towards practical interventions against HIV infection.

Hemodynamic Effects of Awake Prone Positioning With COVID-19 Acute Respiratory Failure.

INTRODUCTION: Awake prone positioning (PP) reduces need for intubation for patients with COVID-19 with acute respiratory failure. We investigated the hemodynamic effects of awake PP in non-ventilated subjects with COVID-19 acute respiratory failure. METHODS: We conducted a single-center prospective cohort study. Adult hypoxemic subjects with COVID-19 not requiring invasive mechanical ventilation receiving at least one PP session were included. Hemodynamic assessment was done with transthoracic echocardiography before, during, and after a PP session. RESULTS: Twenty-six subjects were included. We observed a significant and reversible increase in cardiac index (CI) during PP compared to supine position (SP): 3.0 ± 0.8 L/min/m2 in PP, 2.5 ± 0.6 L/min/m2 before PP (SP1), and 2.6 ± 0.5 L/min/m2 after PP (SP2, P < .001). A significant improvement in right ventricular (RV) systolic function was also evidenced during PP: The RV fractional area change was 36 ± 10% in SP1, 46 ± 10% during PP, and 35 ± 8% in SP2 (P < .001). There was no significant difference in PaO2 /FIO2 and breathing frequency. CONCLUSION: CI and RV systolic function are improved by awake PP in non-ventilated subjects with COVID-19 with acute respiratory failure.

High-titer convalescent plasma plus nirmatrelvir/ritonavir treatment for non-resolving COVID-19 in six immunocompromised patients.

OBJECTIVES: Immunocompromised patients have an increased risk of severe or prolonged COVID-19. Currently available drugs are registered to treat COVID-19 during the first 5 to 7 days after symptom onset. Data on the effectivity in immunocompromised patients with chronic non-resolving COVID-19 are urgently needed. Here, we report the outcome of patients treated with nirmatrelvir/ritonavir together with high-titer convalescent plasma (CP) in six immunocompromised patients with non-resolving COVID-19. METHODS: Immunocompromised patients with persisting COVID-19 (positive PCR with Ct values <30 for ≥20 days) received off-label therapy with nirmatrelvir/ritonavir. It was combined with CP containing BA.5 neutralizing titers of ≥1/640 whenever available. Follow-up was done by PCR and sequencing on nasopharyngeal swabs on a weekly basis until viral genome was undetectable consecutively. RESULTS: Five immunocompromised patients were treated with high-titer CP and 5 days of nirmatrelvir/ritonavir. One patient received nirmatrelvir/ritonavir monotherapy. Median duration of SARS-CoV-2 PCR positivity was 70 (range 20-231) days before nirmatrelvir/ritonavir treatment. In four patients receiving combination therapy, no viral genome of SARS-CoV-2 was detected on day 7 and 14 after treatment while the patient receiving nirmatrelvir/ritonavir monotherapy, the day 7 Ct value increased to 34 and viral genome was undetectable thereafter. Treatment was unsuccessful in one patient. In this patient, sequencing after nirmatrelvir/ritonavir treatment did not show protease gene mutations. CONCLUSIONS: In immunocompromised patients with non-resolving COVID-19, the combination of nirmatrelvir/ritonavir and CP may be an effective treatment. Larger prospective studies are needed to confirm these preliminary results and should compare different treatment durations.

Association between distance to community health care facilities and COVID-19-related mortality across U.S. counties in the COVID-19-vaccine era.

OBJECTIVE: COVID-19 has caused tremendous damage to U.S. public health, but COVID vaccines can effectively reduce the risk of COVID-19 infections and related mortality. Our study aimed to quantify the association between proximity to a community healthcare facility and COVID-19 related mortality after COVID vaccines became publicly available and explore how this association varied across racial and ethnic groups. RESULTS: Residents living farther from a facility had higher COVID-19-related mortality across U.S. counties. This increased mortality incidence associated with longer distances was particularly pronounced in counties with higher proportions of Black and Hispanic populations.