Analysis: FDA's COVID-19 Accelerated Pathways

Current FDA programs to accelerate access In order to accelerate the product approval process, four regulatory programs currently exist to reduce development and review times for products that address unmet medical needs for the treatment of serious or life-threatening conditions. In May 2014, FDA issued a Final Guidance for Industry entitled, "Expedited Programs for Serious Conditions-Drugs and Biologics" which addresses fast track designation, breakthrough therapy designation, priority review designation and accelerated approval.3 In addition to this guidance document, under section 564 of the FD&C Act, 21 U.S.C. 360bbb3, in a situation where the Secretary of Health and Human Services (HHS) issues a declaration of emergency or threat justifying authorization of emergency use for a product caused by chemical, biological, radiological or nuclear (CBRN) agents, as well as an infectious disease, the Commissioner of the FDA may authorize an EUA of an unapproved product or an unapproved use of an approved product. In January 2017, the "Emergency Use Authorization of Medical Products and Related Authorities" guidance was finalized.4 Fast Track designation Section 112 of the Food and Drug Administration Modernization Act of 1997 (FDAMA), entitled "Expediting Study and Approval of Fast Track Drugs," mandates the facilitation of the development and processes to expedite review of therapeutics intended to treat serious or life-threatening conditions presenting with unmet medical needs. [...]a two-tiered system of review times, Standard Review and Priority Review was created.

Mental Mental health and risk of mortality and hospitalization in COVID-19 patients. Results from the PRECOVID Study in Spain (preprint)

The COVID-19 pandemic has created unprecedented challenges for health care systems globally. The identification of risk factors is crucial when optimizing medical resources for specific vulnerable population groups such as patients with mental disorders, who are specially at risk of poor COVID-19 outcomes. In this retrospective cohort study including 144,957 individuals with confirmed COVID-19 from the PRECOVID Study (Aragon, Spain), anxiety was the most frequent diagnosis. However, some differences were observed by sex: substance abuse, personality disorders and schizophrenia were more frequently diagnosed in men, while eating disorders, depression and mood, anxiety and cognitive disorders were more common among women. The presence of mental illness, specifically schizophrenia spectrum and cognitive disorders in men, and depression and mood disorders, substance abuse, anxiety and cognitive and personality disorders in women, increased the risk of mortality or hospitalization after COVID-19, in addition to other well-known risk factors such as age, morbidity and treatment burden. Identifying vulnerable patient profiles at risk of serious outcomes after COVID-19 based on their mental health status will be crucial to improve their access to the healthcare system and implement targeted public health prevention measures.

COVID-19 vaccines reduce mortality in hospitalized patients with oxygen requirements: Differences between vaccine subtypes. A multicontinental cohort study.

The aim of this study was to analyze whether the coronavirus disease 2019 (COVID-19) vaccine reduces mortality in patients with moderate or severe COVID-19 disease requiring oxygen therapy. A retrospective cohort study, with data from 148 hospitals in both Spain (111 hospitals) and Argentina (37 hospitals), was conducted. We evaluated hospitalized patients for COVID-19 older than 18 years with oxygen requirements. Vaccine protection against death was assessed through a multivariable logistic regression and propensity score matching. We also performed a subgroup analysis according to vaccine type. The adjusted model was used to determine the population attributable risk. Between January 2020 and May 2022, we evaluated 21,479 COVID-19 hospitalized patients with oxygen requirements. Of these, 338 (1.5%) patients received a single dose of the COVID-19 vaccine and 379 (1.8%) were fully vaccinated. In vaccinated patients, mortality was 20.9% (95% confidence interval [CI]: 17.9-24), compared to 19.5% (95% CI: 19-20) in unvaccinated patients, resulting in a crude odds ratio (OR) of 1.07 (95% CI: 0.89-1.29; p = 0.41). However, after considering the multiple comorbidities in the vaccinated group, the adjusted OR was 0.73 (95% CI: 0.56-0.95; p = 0.02) with a population attributable risk reduction of 4.3% (95% CI: 1-5). The higher risk reduction for mortality was with messenger RNA (mRNA) BNT162b2 (Pfizer) (OR 0.37; 95% CI: 0.23-0.59; p < 0.01), ChAdOx1 nCoV-19 (AstraZeneca) (OR 0.42; 95% CI: 0.20-0.86; p = 0.02), and mRNA-1273 (Moderna) (OR 0.68; 95% CI: 0.41-1.12; p = 0.13), and lower with Gam-COVID-Vac (Sputnik) (OR 0.93; 95% CI: 0.6-1.45; p = 0.76). COVID-19 vaccines significantly reduce the probability of death in patients suffering from a moderate or severe disease (oxygen therapy).

Gastrointestinal symptoms and complications in patients hospitalized due to COVID-19, an international multicentre prospective cohort study (TIVURON project).

BACKGROUND: Retrospective studies suggest that coronavirus disease (COVID-19) commonly involves gastrointestinal (GI) symptoms and complications. Our aim was to prospectively evaluate GI manifestations in patients hospitalized for COVID-19. METHODS: This international multicentre prospective cohort study recruited COVID-19 patients hospitalized at 31 centres in Spain, Mexico, Chile, and Poland, between May and September 2020. Patients were followed-up until 15 days post-discharge and completed comprehensive questionnaires assessing GI symptoms and complications. A descriptive analysis as well as a bivariate and multivariate analysis were performer using binary logistic regression. p<0.05 was considered significant. RESULTS: Eight hundred twenty-nine patients were enrolled; 129 (15.6%) had severe COVID-19, 113 (13.7%) required ICU admission, and 43 (5.2%) died. Upon admission, the most prevalent GI symptoms were anorexia (n=413; 49.8%), diarrhoea (n=327; 39.4%), nausea/vomiting (n=227; 27.4%), and abdominal pain (n=172; 20.7%), which were mild/moderate throughout the disease and resolved during follow-up. One-third of patients exhibited liver injury. Non-severe COVID-19 was associated with ≥2 GI symptoms upon admission (OR 0.679; 95% CI 0.464-0.995; p=0.046) or diarrhoea during hospitalization (OR 0.531; 95% CI 0.328-0.860; p=0.009). Multivariate analysis revealed that worse hospital outcomes were not independently associated with liver injury or GI symptoms. CONCLUSION: GI symptoms were more common than previously documented, and were mild, rapidly resolved, and not independently associated with COVID-19 severity. Liver injury was a frequent complication in hospitalized patients not independently associated with COVID-19 severity.

Cardiovascular vulnerability in COVID-19 elderly patients: getting into the biological mechanisms / Vulnerabilidad cardiovascular en adultos mayores con COVID-19: conociendo los mecanismos biológicos

The COVID-19 pandemic has had an important impact on older adults, conferring a worse prognosis. Older adults may have atypical presentations, which can delay the diagnosis of the disease, making its evolution more unfavorable. In addition to the cardiovascular damage mechanisms conferred by SARS-CoV-2 infection, the changes inherent in the aging cardiovascular and immune system favor the appearance of cardiovascular complications in a more relevant way in this population. The objective of this article will be to summarize the knowledge about cardiovascular involvement in older adults and explain its pathophysiological mechanisms, to alert about the early recognition and timely treatment of these complications.

La pandemia por COVID-19 ha impactado de forma importante en los adultos mayores, confiriéndoles un peor pronóstico. Los adultos mayores pueden tener presentaciones atípicas, las cuales pueden retrasar el diagnóstico de la enfermedad, haciendo su evolución más desfavorable. Además de los mecanismos de daño cardiovascular conferidos por la infección por SARS-CoV-2, los cambios inherentes al sistema cardiovascular e inmune ya envejecido, favorecen la aparición de complicaciones cardiovasculares de forma más relevante en esta población. El objetivo de este artículo será resumir los conocimientos sobre el involucro cardiovascular en adultos mayores y explicar los mecanismos fisiopatológicos de este, para alertar sobre el reconocimiento temprano y tratamiento oportuno de estas complicaciones.

Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.

Epidemiology and Outcomes of AKI Treated With Continuous Kidney Replacement Therapy: The Multicenter CRRTnet Study.

Rationale & Objective: Continuous kidney replacement therapy (CKRT) is the predominant form of acute kidney replacement therapy used for critically ill adult patients with acute kidney injury (AKI). Given the variability in CKRT practice, a contemporary understanding of its epidemiology is necessary to improve care delivery. Study Design: Multicenter, prospective living registry. Setting & Population: 1,106 critically ill adults with AKI requiring CKRT from December 2013 to January 2021 across 5 academic centers and 6 intensive care units. Patients with pre-existing kidney failure and those with coronavirus 2 infection were excluded. Exposure: CKRT for more than 24 hours. Outcomes: Hospital mortality, kidney recovery, and health care resource utilization. Analytical Approach: Data were collected according to preselected timepoints at intensive care unit admission and CKRT initiation and analyzed descriptively. Results: Patients' characteristics, contributors to AKI, and CKRT indications differed among centers. Mean (standard deviation) age was 59.3 (13.9) years, 39.7% of patients were women, and median [IQR] APACHE-II (acute physiologic assessment and chronic health evaluation) score was 30 [25-34]. Overall, 41.1% of patients survived to hospital discharge. Patients that died were older (mean age 61 vs. 56.8, P < 0.001), had greater comorbidity (median Charlson score 3 [1-4] vs. 2 [1-3], P < 0.001), and higher acuity of illness (median APACHE-II score 30 [25-35] vs. 29 [24-33], P = 0.003). The most common condition predisposing to AKI was sepsis (42.6%), and the most common CKRT indications were oliguria/anuria (56.2%) and fluid overload (53.9%). Standardized mortality ratios were similar among centers. Limitations: The generalizability of these results to CKRT practices in nonacademic centers or low-and middle-income countries is limited. Conclusions: In this registry, sepsis was the major contributor to AKI and fluid management was collectively the most common CKRT indication. Significant heterogeneity in patient- and CKRT-specific characteristics was found in current practice. These data highlight the need for establishing benchmarks of CKRT delivery, performance, and patient outcomes. Data from this registry could assist with the design of such studies.

Biosafety Practices When Working with Bats: A Guide to Field Research Considerations.

Introduction: Field work with bats is an important contribution to many areas of research in environmental biology and ecology, as well as microbiology. Work with bats poses hazards such as bites and scratches, and the potential for exposure to infectious pathogens such as rabies virus. It also exposes researchers to many other potential hazards inherent to field work, such as environmental conditions, delayed emergency responses, or challenging work conditions. Methods: This article discusses the considerations for a thorough risk assessment process around field work with bats, pre- and post-occupational health considerations, and delves into specific considerations for areas related to biosafety concerns-training, personal protective equipment, safety consideration in field methods, decontamination, and waste. It also touches on related legal and ethical issues that sit outside the realm of biosafety, but which must be addressed during the planning process. Discussion: Although the focal point of this article is bat field work located in northern and central America, the principles and practices discussed here are applicable to bat work elsewhere, as well as to field work with other animal species, and should promote careful considerations of how to safely conduct field work to protect both researchers and animals.

Reduced Cholesterol Levels during Acute Human Babesiosis.

BACKGROUND: Babesiosis, an intra-erythrocytic protozoan disease, is an emerging zoonotic parasitic disease worldwide. Cholesterol levels are correlated with severe infections, such as sepsis and COVID-19, and anecdotal reports suggest that high-density lipoprotein (HDL) cholesterol declines during acute babesiosis. Our aim was to describe the cholesterol levels in patients with acute babesiosis diagnosed in an endemic area in New York, hypothesizing that HDL levels correlate with the severity of infection. METHODS: We reviewed the medical records of adult patients with babesiosis diagnosed by identification of Babesia parasites on a thin blood smear and confirmed by polymerase chain reaction from 2013 to 2018, who also had available a lipid profile drawn at the time of clinical presentation. Additional lipid profile levels were considered as "baseline" if they were drawn within 2 months before or after the infection as part of routine care. RESULTS: A total of 39 patients with babesiosis had a lipid profile drawn on presentation. The patients were divided into two groups for comparison based on the treating physician's clinical decision: 33 patients who were admitted to the hospital and 8 patients who were evaluated as outpatients. A history of hypertension was more common in admitted patients (37% vs. 17%, p = 0.02). The median levels of low-density lipoprotein (LDL) and HDL were significantly reduced in admitted patients compared to non-admitted patients (46 vs. 76 mg/dL, p = 0.04; and 9 vs. 28.5 mg/dL, p = 0.03, respectively). In addition, LDL and HDL levels returned to baseline values following resolution of acute babesiosis. CONCLUSION: LDL and HDL levels are significantly reduced during acute babesiosis, suggesting that cholesterol depletion may predict disease severity. Pathogen and host factors may contribute to a reduction in serum cholesterol levels during acute babesiosis.

Stock market responses to COVID-19: The behaviors of mean reversion, dependence and persistence.

We examine stock market responses during the COVID-19 pandemic period using fractional integration techniques. The evidence suggests that stock markets generally follow a synchronized movement before and the stages of the pandemic shocks. We find while mean reversion significantly declines, the degree of persistence and dependence has been increased in the majority of the stock market indices in whole sample analysis covering the period of August 02, 2019 and July 09, 2020. This outcome implies increasing integration and possibly declining benefits of diversification for the global stock portfolio management.

Measuring Persistence in the US Equity Gender Diversity Index.

An analysis of the SPDR SSGA Gender Diversity Index ETF using fractional integration or I(d) techniques and daily data from 8 March 2016 to 8 January 2021, reveals that the series is highly persistent with an order of integration smaller than, though very close to 1. However, when estimating d recursively across subsamples, two peaks can be observed. The first peak appears in the sample with 679 observations (ending at 26 December 2018) and the second one occurs in the sample with 974 observations and ending at 28 February 2020, which shows the most significant change in d, moving from values within the I(1) interval to values significantly above 1. The findings indicate that the Covid-19 pandemic has had a significant impact on the persistence of the SPDR SSGA Gender Diversity Index ETF, increasing its magnitude and thus the level of persistence.

Investigation of an outbreak of COVID-19 among U.S. military personnel and beneficiaries stationed in the Republic of Korea, June-July 2021

On 28 May 2021, leisure travel restrictions in place to control coronavirus disease 2019 (COVID-19) were eased among vaccinated U.S. military personnel and beneficiaries stationed in South Korea (USFK) allowing access to bars and clubs which were off limits. We describe results from an investigation of the largest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak as of November 2021 among USFK personnel following this change in policy. Data such as SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) test results, demographic characteristics, symptom and vaccination histories, and genome sequences were analyzed. Of a total 207 new cases of COVID-19 diagnosed among USFK members from 15 June to 27 July 2021, 113 (57%) eligible cases were fully vaccinated, of whom 86 (76%) were symptomatic. RT-PCR cycling threshold values were similar among vaccinated and unvaccinated members. Whole genomic sequencing of 54 outbreak samples indicated all infections were due to the Delta variant. Phylogenetic analysis revealed two sources of SARS-CoV-2 accounted for 41% of infections among vaccinated and unvaccinated members. Vaccinated personnel were not at risk of severe illness;however, 86% experienced symptoms following infection. There were no hospitalizations among COVID-19 cases, most of whom were young military service members. Rescinded restrictions were reinstated to control the outbreak. Masking was mandated among all personnel predating U.S. national recommendations for indoor masking in high COVID-19 transmission areas. Increased vaccination with continued vigilance and extension of COVID-19 mitigation measures are warranted to contain the spread of SARS-CoV-2 variants of concern.

An mHealth tool for community health workers to improve caregiver knowledge of child health in the Amazon: An effectiveness-implementation hybrid evaluation

When community health workers (CHWs) are effective, they can teach healthy child rearing practices in their communities and improve child health and development outcomes. An effective mHealth tool can improve the capacity of CHWs to transmit knowledge to caregivers. This article evaluates the implementation of an mHealth tool in a CHW program in the Amazon of Peru. The intervention was designed, implemented, and evaluated with the guidance of multiple implementation science tools. A Hybrid Type 3 evaluation design was used to test the effectiveness of the implementation strategies and appropriateness of the intervention. The implementation outcomes: acceptability, adoption, dosage, and fidelity were analyzed with mixed methods approach to determine if the intervention was successfully installed in the CHW program. The service outcome, knowledge scores, was analyzed with an independent samples t-test and one way ANOVA to determine the effect of the program. The implementation strategies resulted in high degrees of acceptability, adoption, and fidelity of the mHealth tool. The surveillance component of the mHealth tools was not adequately adopted. The group of caregivers that received home visits with the mHealth tool (N = 48) had significantly higher knowledge scores (+1.26 standard deviations) than those in the control group (N = 138) (t(184) = -4.39, p<0.001). The COVID-19 pandemic significantly decreased the dosage of the intervention received by the participants. The CHEST App intervention is a promising tool to improve the capacity of CHWs during their home visits. Trial registered with ISRCTN on 11/29/2018 at https://doi.org/10.1186/ISRCTN43591826.

Visceral extra-abdominal panniculitis after COVID19.

"Retractile mesenteritis" was the first name given to a rare, benign, inflammatory disease that affects the adipose tissue of the intestinal mesentery and less frequently other locations. Now labeled as mesenteric panniculitis, the pathogenic mechanism remains unclear. Several stimuli could be involved, and it is sometimes associated with other conditions such as malignancy or autoimmune diseases. We present a case of mesenteric panniculitis with extensive abdominal and extra-abdominal involvement that developed a few months after SARS-COV2 infection, raising the hypothesis of this virus as a potential trigger for autoinflammatory and autoimmune diseases.

Is the Sars-CoV-2 virus a possible trigger agent for the development of achalasia?

BACKGROUND: Achalasia is an autoimmune disease whose probable causal agent is a neurotropic virus that chronically infects the myenteric plexus of the esophagus and induces the disease in a genetically susceptible host. The association between achalasia and coronaviruses has not been reported. AIMS: To evaluate the presence of the SARS-CoV-2 virus, the ACE2 expression, the tissue architecture, and immune response in the lower esophageal sphincter muscle (LESm) of achalasia patients who posteriorly had SARS-CoV-2 (achalasia-COVID-19) infection before laparoscopic Heller myotomy (LHM) and compare the findings with type II achalasia patients and transplant donors (controls) without COVID-19. METHODS: The LESm of 7 achalasia-COVID-19 patients (diagnosed by PCR), ten achalasia patients, and ten controls without COVID-19 were included. The presence of the virus was evaluated by in situ PCR and immunohistochemistry. ACE2 receptor expression and effector CD4 T cell and regulatory subsets were determined by immunohistochemistry. KEY RESULTS: Coronavirus was detected in 6/7 patients-COVID-19. The SARS-CoV-2 was undetectable in the LESm of the achalasia patients and controls. ACE2 receptor was expressed in all the patients and controls. One patient developed achalasia type II post-COVID-19. The percentage of Th22/Th17/Th1/pDCreg was higher in achalasia and achalasia-COVID-19 pre-HLM vs. controls. The Th2/Treg/Breg cell percentages were higher only in achalasia vs. controls. CONCLUSION & INFERENCES: SARS-CoV2 and its receptor expression in the LESm of achalasia patients who posteriorly had COVID-19 but not in the controls suggests that it could affect the myenteric plexus. Unlike achalasia, patients-COVID-19 have an imbalance between effector CD4 T cells and the regulatory mechanisms.

Differences in mortality rate among patients hospitalized with severe COVID-19 according to their body mass index.

Background: Obesity has been described as a risk factor for COVID-19 severity and mortality. Previous studies report a linear association between BMI and adverse outcomes, meanwhile in other critical illness, excessive fat tissue is related to improved survival. Whether different BMI is related with the survival of patients with severe COVID-19 deserves further analysis. Objective: To determine the mortality rate among hospitalized patients with severe COVID-19 stratified according to BMI. Methods: The clinical files of all patients hospitalized from March to December 2020 with a positive PCR test for SARS-CoV-2 discharged due to improvement or death, were analyzed. A mixed effects logistic regression was carried out to determine which clinical and biochemical characteristics and comorbidities were associated with in-hospital mortality. Results: The cohort consisted of 608 patients with a median age of 59 years (interquartile ranges, IQR 46-69 years), median BMI of 28.7 kg/m2 (IQR 25.4-32.4 kg/m2), 65.5% were male. In-hospital mortality rate was 43.4%. Of the cohort 0.8% had low weight, 20.9% normal weight, 36.0% overweight, 26.5% obesity grade I, 10.2% obesity grade II and 5.6% obesity grade III. Mortality rate was highest in patients with low weight (80%), followed by patients with obesity grade III (58.8%) and grade II (50.0%). Overweight and underweight/obesity grade III were associated with higher mortality (OR of 9.75 [1.01-1.10] and OR 4.08 [1.64-10.14]), after adjusting by sex and age. Conclusions: The patients in the underweight/overweight and grade 3 obesity categories are at higher risk of COVID-19 related mortality, compared to those with grade I or II obesity.

New, fast, and precise method of COVID-19 detection in nasopharyngeal and tracheal aspirate samples combining optical spectroscopy and machine learning.

Fast, precise, and low-cost diagnostic testing to identify persons infected with SARS-CoV-2 virus is pivotal to control the global pandemic of COVID-19 that began in late 2019. The gold standard method of diagnostic recommended is the RT-qPCR test. However, this method is not universally available, and is time-consuming and requires specialized personnel, as well as sophisticated laboratories. Currently, machine learning is a useful predictive tool for biomedical applications, being able to classify data from diverse nature. Relying on the artificial intelligence learning process, spectroscopic data from nasopharyngeal swab and tracheal aspirate samples can be used to leverage characteristic patterns and nuances in healthy and infected body fluids, which allows to identify infection regardless of symptoms or any other clinical or laboratorial tests. Hence, when new measurements are performed on samples of unknown status and the corresponding data is submitted to such an algorithm, it will be possible to predict whether the source individual is infected or not. This work presents a new methodology for rapid and precise label-free diagnosing of SARS-CoV-2 infection in clinical samples, which combines spectroscopic data acquisition and analysis via artificial intelligence algorithms. Our results show an accuracy of 85% for detection of SARS-CoV-2 in nasopharyngeal swab samples collected from asymptomatic patients or with mild symptoms, as well as an accuracy of 97% in tracheal aspirate samples collected from critically ill COVID-19 patients under mechanical ventilation. Moreover, the acquisition and processing of the information is fast, simple, and cheaper than traditional approaches, suggesting this methodology as a promising tool for biomedical diagnosis vis-à-vis the emerging and re-emerging viral SARS-CoV-2 variant threats in the future.