Showing papers in "Frontiers in Medicine in 2022"

SARS-CoV-2 Mutations and Their Impact on Diagnostics, Therapeutics and Vaccines

Abstract: With the high rate of COVID-19 infections worldwide, the emergence of SARS-CoV-2 variants was inevitable. Several mutations have been identified in the SARS-CoV-2 genome, with the spike protein as one of the mutational hot spots. Specific amino acid substitutions such as D614G and N501Y were found to alter the transmissibility and virulence of the virus. The WHO has classified the variants identified with fitness-enhancing mutations as variants of concern (VOC), variants of interest (VOI) or variants under monitoring (VUM). The VOCs pose an imminent threat as they exhibit higher transmissibility, disease severity and ability to evade vaccine-induced and natural immunity. Here we review the mutational landscape on the SARS-CoV-2 structural and non-structural proteins and their impact on diagnostics, therapeutics and vaccines. We also look at the effectiveness of approved vaccines, antibody therapy and convalescent plasma on the currently prevalent VOCs, which are B.1.17, B.1.351, P.1, B.1.617.2 and B.1.1.529. We further discuss the possible factors influencing mutation rates and future directions.

Endothelial Dysfunction in Hypertension: Current Concepts and Clinical Implications

Abstract: Endothelium plays a fundamental role in the cardiovascular system, forming an interface between blood and adjacent tissues by regulating the vascular tone through the synthesis of nitric oxide, prostaglandins and other relaxing factors. Endothelial dysfunction is characterized by vasoconstriction, cell proliferation and shifting toward a proinflammatory and prothrombic state. In hypertension endothelial dysfunction may be involved in the initiation and development of vascular inflammation, vascular remodeling, and atherosclerosis and is independently associated with increased cardiovascular risk. Different conditions such as impaired vascular shear stress, inflammation and oxidative stress, activation of the renin angiotensin system have been described as important pathophysiological mechanisms involved in the development of endothelial dysfunction. The release of extracellular vesicles by neighboring cells in the vascular wall has emerged as an important regulator of endothelial function and with potential antihypertensive properties and beneficial effects by counteracting the hypertension mediated organ damage. Furthermore, macrovesicles are emerging as an innovative therapeutic approach for vascular protection, allowing the delivery of bioactive molecules, such as miRNA and drugs interacting with the renin angiotensin system. In this review we summarize the available evidence about the pathophysiological implications of endothelial dysfunction in cardiovascular diseases, focusing on hypertension and its sequelae, and the potential innovative therapeutic strategies targeting the endothelium with the aim to improve vascular function and remodeling.

Gene Therapy Advances: A Meta-Analysis of AAV Usage in Clinical Settings

Abstract: Adeno-associated viruses (AAVs) are the safest and most effective gene delivery vehicles to drive long-term transgene expression in gene therapy. While animal studies have shown promising results, the translatability of AAVs into clinical settings has been partly limited due to their restricted gene packaging capacities, off-target transduction, and immunogenicity. In this study, we analysed over two decades of AAV applications, in 136 clinical trials. This meta-analysis aims to provide an up-to-date overview of the use and successes of AAVs in clinical trials, while evaluating the approaches used to address the above challenges. First, this study reveals that the speed of novel AAV development has varied between therapeutic areas, with particular room for improvement in Central Nervous System disorders, where development has been slow. Second, the lack of dose-dependent toxicity and efficacy data indicates that optimal dosing regimes remain elusive. Third, more clinical data on the effectiveness of various immune-modulation strategies and gene editing approaches are required to direct future research and to accelerate the translation of AAV-mediated gene therapy into human applications.

Guts Imbalance Imbalances the Brain: A Review of Gut Microbiota Association With Neurological and Psychiatric Disorders

Abstract: Over the last 10 years, there has been a growing interest in the relationship between gut microbiota, the brain, and neurologic-associated affections. As multiple preclinical and clinical research studies highlight gut microbiota’s potential to modulate the general state of health state, it goes without saying that gut microbiota plays a significant role in neurogenesis, mental and cognitive development, emotions, and behaviors, and in the progression of neuropsychiatric illnesses. Gut microbiota produces important biologic products that, through the gut-brain axis, are directly connected with the appearance and evolution of neurological and psychiatric disorders such as depression, anxiety, bipolar disorder, autism, schizophrenia, Parkinson’s disease, Alzheimer’s disease, dementia, multiple sclerosis, and epilepsy. This study reviews recent research on the link between gut microbiota and the brain, and microbiome’s role in shaping the development of the most common neurological and psychiatric illnesses. Moreover, special attention is paid to the use of probiotic formulations as a potential non-invasive therapeutic opportunity for prevention and management of neuropsychiatric-associated affections. Graphical Abstract

Effect of Pulmonary Rehabilitation for Patients With Post-COVID-19: A Systematic Review and Meta-Analysis

Abstract: Background Evidence increasingly suggested that impaired respiratory function remained in about 40% of patients with coronavirus disease 2019 (COVID-19) after discharge, jeopardizing their activities of daily living and quality of life (QoL) in a long term. Pulmonary rehabilitation (PR) can improve exercise capacity and QoL in individuals with chronic lung disease; however, evidence on the effect of PR for patients with post-COIVD-19 was scarce. This study aimed to conduct a systematic review and meta-analysis to evaluate the effect of PR on lung impairment for patients with post-COVID-19. Methods Five databases were searched for all the published trials of PR for patients with post-COVID-19 from 2019 to October 2021. Data were extracted using a standardized form. The risks of bias of included studies were assessed using the Cochrane risk of the bias assessment tool. Data were synthesized where possible; otherwise, qualitative analysis was done. Results Among 6,000 retrieved studies, 3 studies with 233 patients after COVID-19 were included. The pooled estimate of PR effect on 6-min walk test (6-MWT) (50.41, 95% CI 34.34 to 66.48; p < 0.0001) was in favor of the experiment group with clinical importance. It is found that PR could improve the symptom of dyspnea and QoL; however, its effect on pulmonary function test was inconsistent across studies. The risk of bias of included studies varied, with major concerns on the risk of blinding of participants and interventions performers. Conclusion The review showed that PR could improve exercise capacity measured by 6-MWT among patients with mild-to-moderate lung impairment after COVID-19. The interpretation of effects on lung function, dyspnea, and QoL should be cautious due to inadequate and conflicting data reported across studies. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289562, identifier: CRD42021289562.

Optimization of the SARS-CoV-2 ARTIC Network V4 Primers and Whole Genome Sequencing Protocol

Abstract: Introduction The ARTIC Network's primer set and amplicon-based protocol is one of the most widely used SARS-CoV-2 sequencing protocol. An update to the V3 primer set was released on 18th June 2021 to address amplicon drop-off observed among the Delta variant of concern. Here, we report on an in-house optimization of a modified version of the ARTIC Network V4 protocol that improves SARS-CoV-2 genome recovery in instances where the original V4 pooling strategy was characterized by amplicon drop-offs. Methods We utilized a matched set of 43 clinical samples and serially diluted positive controls that were amplified by ARTIC V3, V4 and optimized V4 primers and sequenced using GridION from the Oxford Nanopore Technologies'. Results We observed a 0.5% to 46% increase in genome recovery in 67% of the samples when using the original V4 pooling strategy compared to the V3 primers. Amplicon drop-offs at primer positions 23 and 90 were observed for all variants and positive controls. When using the optimized protocol, we observed a 60% improvement in genome recovery across all samples and an increase in the average depth in amplicon 23 and 90. Consequently, ≥95% of the genome was recovered in 72% (n = 31) of the samples. However, only 60–70% of the genomes could be recovered in samples that had <28% genome coverage with the ARTIC V3 primers. There was no statistically significant (p > 0.05) correlation between Ct value and genome recovery. Conclusion Utilizing the ARTIC V4 primers, while increasing the primer concentrations for amplicons with drop-offs or low average read-depth, greatly improves genome recovery of Alpha, Beta, Delta, Eta and non-VOC/non-VOI SARS-CoV-2 variants.

COVID-19 and Acute Kidney Injury: A Systematic Review

Abstract: Introduction Acute kidney injury (AKI) has been associated with an increased mortality rate among hospitalized patients with Coronavirus disease 2019 (COVID-19). The current review aimed to evaluate the symptoms, complications, and treatments performed to manage AKI in patients with COVID-19. Methods We searched PubMed/Medline, Web of Science, and Embase for the relevant scientific literature published up to February 1, 2022. The following keywords were used: “COVID-19”, “SARS-CoV-2”, and “Acute kidney injury”. Results Forty-four studies with a total number of 114 COVID-19 patients with AKI (Mean age: 53.6 years) were included in our systematic review. The most common comorbidities in patients with COVID-19 suffering from AKI were the history of diabetes, hypertension, and hyperlipidemia. Twelve out of the 44 included studies reported a history of chronic kidney disease (CKD) in this group of patients. Focal segmental glomerulosclerosis (FSGS) and acute tubular necrosis (ATN) were the most common pathological evidence. The average length of hospital stay was 19 days, and the average duration of need for mechanical ventilation was 3 days. Conclusions The current systematic review shows that AKI frequently complicates the course of COVID-19 hospitalizations and is associated with increased severity of illness, prolonged duration of hospitalization, and poor prognosis. Given the extent of the adverse impact of AKI, early detection of comorbidities and renal complications is essential to improve the outcomes of COVID-19 patients.

Systematic Review and Meta-Analysis of COVID-19 Vaccination Acceptance

Abstract: Introduction Vaccination is an essential intervention to curb the coronavirus disease 2019 (COVID-19) pandemic. This review aimed to estimate the pooled proportion of COVID-19 vaccine acceptance worldwide. Methods A systematic search of the MEDLINE (PubMed) database using “COVID-19,” “vaccine” and “acceptance” to obtain original research articles published between 2020 and July 2021. Only studies with full text and that were published in English were included. The Joanna Briggs Institute meta-analysis was used to assess the data quality. The meta-analysis was performed using generic inverse variance with a random-effects model using the Review Manager software. Results A total of 172 studies across 50 countries worldwide were included. Subgroup analyses were performed with regard to vaccine acceptance, regions, population, gender, vaccine effectiveness, and survey time. The pooled proportion of COVID-19 vaccine acceptance was 61% (95% CI: 59, 64). It was higher in Southeast Asia, among healthcare workers, in males, for vaccines with 95% effectiveness, and during the first survey. Conclusion COVID-19 vaccine acceptance needs to be increased to achieve herd immunity to protect the population from the disease. It is crucial to enhance public awareness of COVID-19 vaccination and improve access to vaccines. Systematic Review Registration PROSPERO 2021, identifier CRD42021268645.

Differences in Clinical Characteristics Between Delta Variant and Wild-Type SARS-CoV-2 Infected Patients

Abstract: Background: As delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevailed in the current coronavirus disease 2019 (COVID-19) pandemic, its clinical characteristics with the difference from those of wild-type strains have been little studied. Methods: We reported one cohort of 341 wild-type patients with COVID-19 admitted at Wuhan, China in 2020 and the other cohort of 336 delta variant patients with COVID-19 admitted at Yangzhou, China in 2021, with comparisons of their demographic information, medical history, clinical manifestation, and hematological data. Furthermore, within the delta variant cohort, patients with none, partial, and full vaccination were also compared to assess vaccine effectiveness. Findings: For a total of 677 patients with COVID-19 included in this study, their median age was 53.0 years [interquartile range (IQR): 38.0–66.0] and 46.8% were men. No difference was found in age, gender, and percentage of patients with the leading comorbidity between wild-type and delta variant cohorts, but delta variant cohort showed a lessened time interval between disease onset to hospitalization, a reduced portion of patients with smoking history, and a lowered frequency of clinical symptoms. For hematological parameters, most values demonstrated significant differences between wild-type and delta variant cohorts, while full vaccination rather than partial vaccination alleviated the disease condition. This reflected the viremic effect of delta variant when vaccination succeeds or fails to protect. Interpretation: Delta variant of SARS-CoV-2 may cause severe disease profiles, but timely diagnosis and full vaccination could protect patients with COVID-19 from worsened disease progression.

Considerations for Polymers Used in Ocular Drug Delivery

Abstract: Purpose Age-related eye diseases are becoming more prevalent. A notable increase has been seen in the most common causes including glaucoma, age-related macular degeneration (AMD), and cataract. Current clinical treatments vary from tissue replacement with polymers to topical eye drops and intravitreal injections. Research and development efforts have increased using polymers for sustained release to the eye to overcome treatment challenges, showing promise in improving drug release and delivery, patient experience, and treatment compliance. Polymers provide unique properties that allow for specific engineered devices to provide improved treatment options. Recent work has shown the utilization of synthetic and biopolymer derived biomaterials in various forms, with this review containing a focus on polymers Food and Drug Administration (FDA) approved for ocular use. Methods This provides an overview of some prevalent synthetic polymers and biopolymers used in ocular delivery and their benefits, brief discussion of the various types and synthesis methods used, and administration techniques. Polymers approved by the FDA for different applications in the eye are listed and compared to new polymers being explored in the literature. This article summarizes research findings using polymers for ocular drug delivery from various stages: laboratory, preclinical studies, clinical trials, and currently approved. This review also focuses on some of the challenges to bringing these new innovations to the clinic, including limited selection of approved polymers. Results Polymers help improve drug delivery by increasing solubility, controlling pharmacokinetics, and extending release. Several polymer classes including synthetic, biopolymer, and combinations were discussed along with the benefits and challenges of each class. The ways both polymer synthesis and processing techniques can influence drug release in the eye were discussed. Conclusion The use of biomaterials, specifically polymers, is a well-studied field for drug delivery, and polymers have been used as implants in the eye for over 75 years. Promising new ocular drug delivery systems are emerging using polymers an innovative option for treating ocular diseases because of their tunable properties. This review touches on important considerations and challenges of using polymers for sustained ocular drug delivery with the goal translating research to the clinic.

The Biological Functions and Clinical Significance of SARS-CoV-2 Variants of Corcern

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuing to evolve, emerging novel variants with spike protein mutations. Although most mutations emerged in the SARS-CoV-2 genome are neutral or mildly deleterious, a small number of mutations can affect virus phenotype that confers the virus a fitness advantage. These mutations can enhance viral replication, raise the risk of reinfection and blunt the potency of neutralizing antibodies triggered by previous infection and vaccination. Since December 2020, the SARS-CoV-2 has emerged five quickly spreading strains, designated variants of concern (VOCs), including the Alpha (B.1.1.7) variant, the Beta (B.1.351) variant, the Gamma (P.1) variant, the Delta (B.1.617.2) variant and the Omicron (B.1.1.529) variant. These variants have a high number of the mutations in the spike protein that promotes viral cell entry through the angiotensin-converting enzyme -2 (ACE2). Mutations that have arisen in the receptor binding domain (RBD) of the spike protein are of great concern due to their potential to evade neutralizing antibodies triggered by previous infection and vaccines. The Alpha variant emerged in the United Kingdom in the second half of 2020 that has spread quickly globally and acquired the E484K mutation in the United Kingdom and the United States. The Beta and Gamma variants emerged in South Africa and Brazil, respectively, that have additional mutations at positions E484 and K417 in the RBD. SARS-CoV-2 variants containing the combination of N501Y, E484K, and K417N/T mutations exhibit remarkably decreased sensitivity to neutralizing antibodies mediated by vaccination or previous infection. The Gamma variant may result in more severe disease than other variants do even in convalescent individuals. The Delta variant emerged in India in December 2020 and has spread to many countries including the United States and the United Kingdom. The Delta variant has 8 mutations in the spike protein, some of which can influence immune responses to the key antigenic regions of RBD. In early November 2021, the Omicron (B.1.1.529) variant was first detected in Botswana and South Africa. The Omicron variant harbors more than 30 mutations in the spike protein, many of which are located within the RBD, which have been associated with increased transmissibility and immune evasion after previous infection and vaccination. Additionally, the Omicron variant contains 3 deletions and one insertion in the spike protein. Recently, the Omicron variant has been classified into three sublineages, including BA.1, BA.2, and BA.3, with strikingly different genetic characteristics. The Omicron BA.2 sublineage has different virological landscapes, such as transmissibility, pathogenicity and resistance to the vaccine-induced immunity compared to BA.1 and BA.3 sublineages. Mutations emerged in the RBD of the spike protein of VOCs increase viral replication, making the virus more infectious and more transmissible and enable the virus to evade vaccine-elicited neutralizing antibodies. Unfortunately, the emergence of novel SARS-CoV-2 VOCs has tempered early optimism regarding the efficacy of COVID-19 vaccines. This review addresses the biological and clinical significance of SARS-CoV-2 VOCs and their impact on neutralizing antibodies mediated by existing COVID-19 vaccines.

COVID-Net CT-2: Enhanced Deep Neural Networks for Detection of COVID-19 From Chest CT Images Through Bigger, More Diverse Learning

Abstract: The COVID-19 pandemic continues to rage on, with multiple waves causing substantial harm to health and economies around the world. Motivated by the use of computed tomography (CT) imaging at clinical institutes around the world as an effective complementary screening method to RT-PCR testing, we introduced COVID-Net CT, a deep neural network tailored for detection of COVID-19 cases from chest CT images, along with a large curated benchmark dataset comprising 1,489 patient cases as part of the open-source COVID-Net initiative. However, one potential limiting factor is restricted data quantity and diversity given the single nation patient cohort used in the study. To address this limitation, in this study we introduce enhanced deep neural networks for COVID-19 detection from chest CT images which are trained using a large, diverse, multinational patient cohort. We accomplish this through the introduction of two new CT benchmark datasets, the largest of which comprises a multinational cohort of 4,501 patients from at least 16 countries. To the best of our knowledge, this represents the largest, most diverse multinational cohort for COVID-19 CT images in open-access form. Additionally, we introduce a novel lightweight neural network architecture called COVID-Net CT S, which is significantly smaller and faster than the previously introduced COVID-Net CT architecture. We leverage explainability to investigate the decision-making behavior of the trained models and ensure that decisions are based on relevant indicators, with the results for select cases reviewed and reported on by two board-certified radiologists with over 10 and 30 years of experience, respectively. The best-performing deep neural network in this study achieved accuracy, COVID-19 sensitivity, positive predictive value, specificity, and negative predictive value of 99.0%/99.1%/98.0%/99.4%/99.7%, respectively. Moreover, explainability-driven performance validation shows consistency with radiologist interpretation by leveraging correct, clinically relevant critical factors. The results are promising and suggest the strong potential of deep neural networks as an effective tool for computer-aided COVID-19 assessment. While not a production-ready solution, we hope the open-source, open-access release of COVID-Net CT-2 and the associated benchmark datasets will continue to enable researchers, clinicians, and citizen data scientists alike to build upon them.

Age-Related Risk Factors and Complications of Patients With COVID-19: A Population-Based Retrospective Study

Abstract: Objective: To study the differences in clinical characteristics, risk factors, and complications across age-groups among the inpatients with the coronavirus disease 2019 (COVID-19). Methods: In this population-based retrospective study, we included all the positive hospitalized patients with COVID-19 at Wuhan City from December 29, 2019 to April 15, 2020, during the first pandemic wave. Multivariate logistic regression analyses were used to explore the risk factors for death from COVID-19. Canonical correlation analysis (CCA) was performed to study the associations between comorbidities and complications. Results: There are 36,358 patients in the final cohort, of whom 2,492 (6.85%) died. Greater age (odds ration [OR] = 1.061 [95% CI 1.057–1.065], p < 0.001), male gender (OR = 1.726 [95% CI 1.582–1.885], p < 0.001), alcohol consumption (OR = 1.558 [95% CI 1.355–1.786], p < 0.001), smoking (OR = 1.326 [95% CI 1.055–1.652], p = 0.014), hypertension (OR = 1.175 [95% CI 1.067–1.293], p = 0.001), diabetes (OR = 1.258 [95% CI 1.118–1.413], p < 0.001), cancer (OR = 1.86 [95% CI 1.507–2.279], p < 0.001), chronic kidney disease (CKD) (OR = 1.745 [95% CI 1.427–2.12], p < 0.001), and intracerebral hemorrhage (ICH) (OR = 1.96 [95% CI 1.323–2.846], p = 0.001) were independent risk factors for death from COVID-19. Patients aged 40–80 years make up the majority of the whole patients, and them had similar risk factors with the whole patients. For patients aged <40 years, only cancer (OR = 17.112 [95% CI 6.264–39.73], p < 0.001) and ICH (OR = 31.538 [95% CI 5.213–158.787], p < 0.001) were significantly associated with higher odds of death. For patients aged >80 years, only age (OR = 1.033 [95% CI 1.008–1.059], p = 0.01) and male gender (OR = 1.585 [95% CI 1.301–1.933], p < 0.001) were associated with higher odds of death. The incidence of most complications increases with age, but arrhythmias, gastrointestinal bleeding, and sepsis were more common in younger deceased patients with COVID-19, with only arrhythmia reaching statistical difference (p = 0.039). We found a relatively poor correlation between preexisting risk factors and complications. Conclusions: Coronavirus disease 2019 are disproportionally affected by age for its clinical manifestations, risk factors, complications, and outcomes. Prior complications have little effect on the incidence of extrapulmonary complications.

Psychological Distress and Protective Behaviors During the COVID-19 Pandemic Among Different Populations: Hong Kong General Population, Taiwan Healthcare Workers, and Taiwan Outpatients

Abstract: Purpose The novel coronavirus disease 2019 (COVID-19) caused psychological distress and changed human living styles. However, rare studies have examined the psychological distress and protective behaviors across different populations. Therefore, the present study aimed to assess psychological distress, protective behaviors, and potential predictors of psychological distress and protective behaviors across the Hong Kong general population, Taiwan healthcare workers, and Taiwan outpatients. Methods A cross-sectional design was used to recruit participants from Hong Kong and Taiwan. Telephone interviews were carried out for Hong Kong participants (n = 1,067; 30.2% male participants); online surveys were used for Taiwan healthcare workers (n = 500; 8.0% male participants) and Taiwan outpatients (n = 192; 32.8% male participants). All the participants completed questions on psychological distress and protective behaviors. Multiple linear regressions and multivariable logistic regressions were employed to explore the potential predictors of psychological distress and protective behaviors, respectively. Results Hong Kong participants had significantly lower levels of psychological distress than Taiwan participants [mean (SD) = 0.16 (0.39) vs. 0.47 (0.59) in healthcare workers and 0.46 (0.65) in outpatients; p < 0.001]. Hong Kong participants (51.7%) and Taiwan outpatients had more people showing fear of COVID-19 (52.0%) than Taiwan healthcare providers (40.8%; p < 0.001). Moreover, Hong Kong participants engaged the most in protective behaviors, followed by Taiwan healthcare providers and Taiwan outpatients (p < 0.001). Moreover, being a female, fear of COVID-19 and worry about personal savings were associated with protective behaviors in general. Conclusions Despite the greater COVID-19 severity and fear of COVID-19 in Hong Kong, the general population in Hong Kong experienced less psychosocial distress with higher compliance to protective behaviors than the other groups in Taiwan.

Clinical Characteristics of COVID-19 Patients Infected by the Omicron Variant of SARS-CoV-2

Abstract: Currently, as the omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surges amid the coronavirus disease 2019 (COVID-19) pandemic, its clinical characteristics with intrinsic severity and the protection from vaccination have been understudied.We reported 169 COVID-19 patients that were infected with the omicron variant of SARS-CoV-2 and hospitalized in Suzhou, China, from February to March 2022, with their demographic information, medical/immunization history, clinical symptom, and hematological profile. At the same time, patients with none/partial (one-dose), full (two-dose) and three-dose vaccination were also compared to assess the vaccine effectiveness.For the omicron COVID-19 patients included in this study, their median age was 33.0 [interquartile range (IQR): 24.0-45.5], 53.3% were male and the median duration from illness onset to hospitalization was 2 days. Hypertension, bronchitis, and diabetes were the leading comorbidities among patients. While the common clinical symptoms included cough, fever, expectoration, and fatigue, etc., asymptomatic patients took up a significant portion (46.7%). For hematological parameters, most values revealed the alleviated pathogenicity induced by the omicron variant infection. No critically ill or deceased patients due to COVID-19 infection were reported in this study.Our results supported that the viremic effect of the omicron variant became milder than the previous circulating variants, while full vaccination or booster shot was greatly desired for an effective protection against clinical severity.

Online, Face-to-Face, or Blended Learning? Faculty and Medical Students' Perceptions During the COVID-19 Pandemic: A Mixed-Method Study

Abstract: COVID-19 pandemic forced educational institutions to adopt online methods which were inevitable to keep continuity of education across all academia after suspension of traditional educational systems. The aim of this study was to explore the experience of faculty and students of online and face-to-face learning, and their preference of the mode of learning after the pandemic.This is a mixed-method study. Quantitative data was collected through a survey from 194 medical students and 33 faculty members, while qualitative data was collected through two focus group discussions with 9 students and another two with 13 faculty members. Quantitative variables were presented as means and standard deviations. Paired samples t-test and Chi-square test were used. Thematic analysis of qualitative data was used to code, interpret, and make sense of data.Mean scores of responses of faculty members and students were higher for face-to-face and blended learning compared to online learning in all survey statements with statistically significant differences. More than half of the students (53.1%) preferred the face-to-face mode of learning, while most of the faculty members (60.6%) preferred the blended mode of learning. Qualitative analysis identified five themes, namely: "Transforming the way theoretical teaching sessions are given," "Face-to-face teaching at campus cannot be replaced for some types of education," "Interaction in online sessions is limited," "Problems and challenges of online examinations," and "Technical issues and challenges of online education." It revealed suggestions that at least 30% of the curriculum could be taught online post-COVID-19. Some aspects of clinically oriented teaching including history taking and case discussions can also be delivered online in the future. Faculty members and students reported that dealing with online education was not difficult, although the transition was not smooth.Medical students and faculty members were in favor of face-to-face and blended modes of learning. However, they perceived online mode of learning as an acceptable adaptation in theoretical teaching and in some clinically oriented teaching including history taking and clinical case discussions. Although face-to-face education in medicine is irreplaceable, the blended mode of learning remains an acceptable and practical solution for the post-COVID era.

Optic Nerve Ultrasound Evaluation in Animals and Normal Subjects

Abstract: In recent years, ultrasonographic measurement of the optic nerve sheath diameter (ONSD) has been widely used to identify the presence of increased intracranial pressure (ICP). Intracranial hypertension is a life-threatening condition that can be caused by various neurological and non-neurological disorders, and it is associated to poor clinical results. Ultrasonography could be used to qualitatively and efficiently detect ICP increases, but to reach this purpose, clear cut-off values are mandatory. The aim of this review is to provide a wide overview of the most important scientific publications on optic nerve ultrasound normal values assessment published in the last 30 years. A total of 42 articles selected from PubMed medical database was included in this review. Our analysis showed that ocular ultrasonography is considered to be a valuable diagnostic tool, especially when intracranial hypertension is suspected, but unfortunately this research provided conflicting results that could be due to the different ultrasound protocols. This is mainly caused by the use of B scan alone, which presents several limitations. The use of B-scan coupled with the standardized A-scan approach could give more accurate, and reliable ultrasound evaluation, assuring higher data objectivity.

Allergic Rhinitis: A Clinical and Pathophysiological Overview

Abstract: Allergic rhinitis (AR) represents a global health concern where it affects approximately 400 million people worldwide. The prevalence of AR has increased over the years along with increased urbanization and environmental pollutants thought to be some of the leading causes of the disease. Understanding the pathophysiology of AR is crucial in the development of novel therapies to treat this incurable disease that often comorbids with other airway diseases. Hence in this mini review, we summarize the well-established yet vital aspects of AR. These include the epidemiology, clinical and laboratory diagnostic criteria, AR in pediatrics, pathophysiology of AR, Th2 responses in the disease, as well as pharmacological and immunomodulating therapies for AR patients.

Dysbiosis of Oral and Gut Microbiomes in SARS-CoV-2 Infected Patients in Bangladesh: Elucidating the Role of Opportunistic Gut Microbes

Abstract: Coronavirus disease-2019 (COVID-19) is an infectious disease caused by SARS-CoV-2 virus. The microbes inhabiting the oral cavity and gut might play crucial roles in maintaining a favorable gut environment, and their relationship with SARS-CoV-2 infection susceptibility and severity is yet to be fully explored. This study investigates the diversity and species richness of gut and oral microbiota of patients with COVID-19, and their possible implications toward the severity of the patient's illness and clinical outcomes. Seventy-four (n = 74) clinical samples (gut and oral) were collected from 22 hospitalized patients with COVID-19 with various clinical conditions and 15 apparently healthy people (served as controls). This amplicon-based metagenomic sequencing study yielded 1,866,306 paired-end reads that were mapped to 21 phyla and 231 classified genera of bacteria. Alpha and beta diversity analyses revealed a distinct dysbiosis of the gut and oral microbial communities in patients with COVID-19, compared to healthy controls. We report that SARS-CoV-2 infection significantly reduced richness and evenness in the gut and oral microbiomes despite showing higher unique operational taxonomic units in the gut. The gut samples of the patients with COVID-19 included 46 opportunistic bacterial genera. Escherichia, Shigella, and Bacteroides were detected as the signature genera in the gut of patients with COVID-19 with diarrhea, whereas a relatively higher abundance of Streptococcus was found in patients with COVID-19 having breathing difficulties and sore throat (BDST). The patients with COVID-19 had a significantly lower abundance of Prevotella in the oral cavity, compared to healthy controls and patients with COVID-19 without diabetes, respectively. The altered metabolic pathways, including a reduction in biosynthesis capabilities of the gut and oral microbial consortia after SARS-CoV-2 infection, were also observed. The present study may, therefore, shed light on interactions of SARS-CoV-2 with resilient oral and gut microbes which might contribute toward developing microbiome-based diagnostics and therapeutics for this deadly pandemic disease.

Convergence of Biofilm Formation and Antibiotic Resistance in Acinetobacter baumannii Infection

Abstract: Acinetobacter baumannii (A. baumannii) is a leading cause of nosocomial infections as this pathogen has certain attributes that facilitate the subversion of natural defenses of the human body. A. baumannii acquires antibiotic resistance determinants easily and can thrive on both biotic and abiotic surfaces. Different resistance mechanisms or determinants, both transmissible and non-transmissible, have aided in this victory over antibiotics. In addition, the propensity to form biofilms (communities of organism attached to a surface) allows the organism to persist in hospitals on various medical surfaces (cardiac valves, artificial joints, catheters, endotracheal tubes, and ventilators) and also evade antibiotics simply by shielding the bacteria and increasing its ability to acquire foreign genetic material through lateral gene transfer. The biofilm formation rate in A. baumannii is higher than in other species. Recent research has shown how A. baumannii biofilm-forming capacity exerts its effect on resistance phenotypes, development of resistome, and dissemination of resistance genes within biofilms by conjugation or transformation, thereby making biofilm a hotspot for genetic exchange. Various genes control the formation of A. baumannii biofilms and a beneficial relationship between biofilm formation and “antimicrobial resistance” (AMR) exists in the organism. This review discusses these various attributes of the organism that act independently or synergistically to cause hospital infections. Evolution of AMR in A. baumannii, resistance mechanisms including both transmissible (hydrolyzing enzymes) and non-transmissible (efflux pumps and chromosomal mutations) are presented. Intrinsic factors [biofilm-associated protein, outer membrane protein A, chaperon-usher pilus, iron uptake mechanism, poly-β-(1, 6)-N-acetyl glucosamine, BfmS/BfmR two-component system, PER-1, quorum sensing] involved in biofilm production, extrinsic factors (surface property, growth temperature, growth medium) associated with the process, the impact of biofilms on high antimicrobial tolerance and regulation of the process, gene transfer within the biofilm, are elaborated. The infections associated with colonization of A. baumannii on medical devices are discussed. Each important device-related infection is dealt with and both adult and pediatric studies are separately mentioned. Furthermore, the strategies of preventing A. baumannii biofilms with antibiotic combinations, quorum sensing quenchers, natural products, efflux pump inhibitors, antimicrobial peptides, nanoparticles, and phage therapy are enumerated.

Advances and Trends in Omics Technology Development

Abstract: The human history has witnessed the rapid development of technologies such as high-throughput sequencing and mass spectrometry that led to the concept of “omics” and methodological advancement in systematically interrogating a cellular system. Yet, the ever-growing types of molecules and regulatory mechanisms being discovered have been persistently transforming our understandings on the cellular machinery. This renders cell omics seemingly, like the universe, expand with no limit and our goal toward the complete harness of the cellular system merely impossible. Therefore, it is imperative to review what has been done and is being done to predict what can be done toward the translation of omics information to disease control with minimal cell perturbation. With a focus on the “four big omics,” i.e., genomics, transcriptomics, proteomics, metabolomics, we delineate hierarchies of these omics together with their epiomics and interactomics, and review technologies developed for interrogation. We predict, among others, redoxomics as an emerging omics layer that views cell decision toward the physiological or pathological state as a fine-tuned redox balance.

Unmet Medical Needs in Chronic, Non-communicable Inflammatory Skin Diseases

Abstract: An estimated 20–25% of the population is affected by chronic, non-communicable inflammatory skin diseases. Chronic skin inflammation has many causes. Among the most frequent chronic inflammatory skin diseases are atopic dermatitis, psoriasis, urticaria, lichen planus, and hidradenitis suppurativa, driven by a complex interplay of genetics and environmental factors. Autoimmunity is another important cause of chronic skin inflammation. The autoimmune response may be mainly T cell driven, such as in alopecia areata or vitiligo, or B cell driven in chronic spontaneous urticaria, pemphigus and pemphigoid diseases. Rare causes of chronic skin inflammation are autoinflammatory diseases, or rheumatic diseases, such as cutaneous lupus erythematosus or dermatomyositis. Whilst we have seen a significant improvement in diagnosis and treatment, several challenges remain. Especially for rarer causes of chronic skin inflammation, early diagnosis is often missed because of low awareness and lack of diagnostics. Systemic immunosuppression is the treatment of choice for almost all of these diseases. Adverse events due to immunosuppression, insufficient therapeutic responses and relapses remain a challenge. For atopic dermatitis and psoriasis, a broad spectrum of innovative treatments has been developed. However, treatment responses cannot be predicted so far. Hence, development of (bio)markers allowing selection of specific medications for individual patients is needed. Given the encouraging developments during the past years, we envision that many of these challenges in the diagnosis and treatment of chronic inflammatory skin diseases will be thoroughly addressed in the future.

Bullous Pemphigoid Associated With COVID-19 Vaccines: An Italian Multicentre Study

Abstract: Bullous pemphigoid (BP) is an autoimmune bullous disease caused by circulating autoantibodies toward the hemidesmosomal antigens BP180 and BP230. Cases of BP have been described following vaccinations against tetanus, poliomyelitis, diphtheria, influenza, pneumococcus, meningococcus, hepatitis B and rabies. The putative mechanism by which COVID-19-vaccines may induce BP has not been clarified. An Italian multicentre study was conducted to collect clinical, histopathological and immunopathological data of patients with BP associated with COVID-19-vaccines. Twenty-one cases were collected, including 9 females and 12 males (M/F = 1.3) with a median age at diagnosis of 82 years. Seventeen patients received the COMIRNATY Pfizer-BioNTech vaccine, two the Moderna mRNA-1273 vaccine, one the ChAdOx1/nCoV-19-AstraZeneca/ Vaxzevria vaccine and one received the first dose with the ChAdOx1/nCoV-19-AstraZeneca/Vaxzevria vaccine and the second dose with the COMIRNATY Pfizer-BioNTech vaccine. Median latency time between the first dose of anti-SARS-CoV-2 vaccine and the onset of cutaneous manifestations was 27 days. Median BPDAI at onset was 42. Eleven out of seventeen patients (65%) had positive titres for anti-BP180 antibodies with a median value of 106.3 U/mL on ELISA; in contrast, only five out of seventeen (29%) were positive for anti-BP230 antibodies, with a median of 35.3 U/mL. In conclusion, in terms of mean age, disease severity at diagnosis and clinical phenotype vaccine-associated BP patients seem to be similar to idiopathic BP with an overall benign course with appropriate treatment. On the other hand, the slight male predominance and the reduced humoral response to BP230 represent peculiar features of this subset of patients.

Acute Vertigo After COVID-19 Vaccination: Case Series and Literature Review

Abstract: Objective: The aim of this study was to present some cases of acute vertigo potentially related to the coronavirus disease 2019 (COVID-19) vaccine and review the available literature about cochleovestibular dysfunction after the COVID-19 vaccination. Methods: In the period from May to July 2021, we evaluated 33 patients (mean age 54.3 ± 14.1) with “acute vertigo” post COVID-19 vaccination. A detailed medical history was taken on comorbidities, types of vaccines received, and symptoms associated. All patients underwent otoneurological evaluation, such as head impulse test, nystagmus evaluation, test of skew (HINTS) examination. Head shaking test-induced nystagmus, hyperventilation-induced nystagmus, and parossistic positional nystagmus were studied to search for vestibular impairment. Results: Symptoms included 16 patients (48.5%) with objective vertigo, 14 patients (42.4%) with subjective vertigo, and 3 patients (9.1%) with dizziness. Of the associated ear, nose, and throat (ENT) symptoms, the most expressed was tinnitus (18.2%). Bedside examination showed absent nystagmus in 7 patients (21.2%), 9 patients (27.3%) had horizontal or rotatory nystagmus, 17 patients (51.5%) had a vertical or oblique nystagmus, negative HST, or “central HINTS.” Discussion and Conclusions: The 9 patients had an evoked nystagmus pathognomonic for benign paroxysmal positional vertigo; in the remaining 17 cases, peripheral vestibular dysfunction could be excluded and central disorder may be suggested. Due to the prevalence of nystagmus of non-peripheral origin, a central nervous system involvement could not be excluded. However, due to the small sample size, a definite cause–effect relationship between vaccination and vertigo cannot be inferred. In light of expected third dose, large-scale and well-designed studies are needed to better define possible adverse reactions of the COVID-19 vaccine.

Real-Word Effectiveness of Global COVID-19 Vaccines Against SARS-CoV-2 Variants: A Systematic Review and Meta-Analysis

Abstract: Background Currently, promoted vaccinations against SARS-CoV-2 are being given out globally. However, the occurrence of numerous COVID-19 variants has hindered the goal of rapid mitigation of the COVID-19 pandemic by effective mass vaccinations. The real-word effectiveness of the current vaccines against COVID-19 variants has not been assessed by published reviews. Therefore, our study evaluated the overall effectiveness of current vaccines and the differences between the various vaccines and variants. Methods PubMed, Embase, Cochrane Library, medRxiv, bioRxiv, and arXiv were searched to screen the eligible studies. The Newcastle–Ottawa scale and the Egger test were applied to estimate the quality of the literature and any publication bias, respectively. The pooled incident rates of different variants after vaccination were estimated by single-arm analysis. Meanwhile, the pooled efficacies of various vaccines against variants were evaluated by two-arm analysis using odds ratios (ORs) and vaccine effectiveness (VE). Results A total of 6,118 studies were identified initially and 44 articles were included. We found that the overall incidence of variants post first/second vaccine were 0.07 and 0.03, respectively. The VE of the incidence of variants post first vaccine between the vaccine and the placebo or unvaccinated population was 40% and post second vaccine was 96%, respectively. The sub-single-arm analysis showed a low prevalence rate of COVID-19 variants after specific vaccination with the pooled incidence below 0.10 in most subgroups. Meanwhile, the sub-two-arm analysis indicated that most current vaccines had a good or moderate preventive effect on certain variants considering that the VE in these subgroups was between 66 and 95%, which was broadly in line with the results of the sub-single-arm analysis. Conclusion Our meta-analysis shows that the current vaccines that are used globally could prevent COVID-19 infection and restrict the spread of variants to a great extent. We would also support maximizing vaccine uptake with two doses, as the effectiveness of which was more marked compared with one dose. Although the mRNA vaccine was the most effective against variants according to our study, specific vaccines should be taken into account based on the local dominant prevalence of variants.

New Aspects of Kidney Fibrosis–From Mechanisms of Injury to Modulation of Disease

Abstract: Organ fibrogenesis is characterized by a common pathophysiological final pathway independent of the underlying progressive disease of the respective organ. This makes it particularly suitable as a therapeutic target. The Transregional Collaborative Research Center “Organ Fibrosis: From Mechanisms of Injury to Modulation of Disease” (referred to as SFB/TRR57) was hosted from 2009 to 2021 by the Medical Faculties of RWTH Aachen University and the University of Bonn. This consortium had the ultimate goal of discovering new common but also different fibrosis pathways in the liver and kidneys. It finally successfully identified new mechanisms and established novel therapeutic approaches to interfere with hepatic and renal fibrosis. This review covers the consortium's key kidney-related findings, where three overarching questions were addressed: (i) What are new relevant mechanisms and signaling pathways triggering renal fibrosis? (ii) What are new immunological mechanisms, cells and molecules that contribute to renal fibrosis?, and finally (iii) How can renal fibrosis be modulated?

Lower Rate of Daily Smokers With Symptomatic COVID-19: A Monocentric Self-Report of Smoking Habit Study

Abstract: Background: Identification of prognostic factors in COVID-19 remains a global challenge. The role of smoking is still controversial. Methods: PCR-positive in- and outpatients with symptomatic COVID-19 from a large French University hospital were systematically interviewed for their smoking status, use of e-cigarette, and nicotinic substitutes. The rates of daily smokers in in- and outpatients were compared using the same smoking habit questionnaire to those in the 2019 French general population, after standardisation for sex and age. Results: The inpatient group was composed of 340 patients, median age of 66 years: 203 men (59.7%) and 137 women (40.3%), median age of both 66 years, with a rate of 4.1% daily smokers (CI 95% [2.3–6.9]) (5.4% of men and 2.2% of women). The outpatient group was composed of 139 patients, median age of 44 years: 62 men (44.6%, median age of 43 years) and 77 women (55.4%, median age of 44 years). The daily smoker rate was 6.1% (CI 95% [2.7–11.6], 5.1% of men and 6.8% of women). Amongst inpatients, daily smokers represented 2.2 and 3.4% of the 45 dead patients and of the 29 patients transferred to ICU, respectively. The rate of daily smokers was significantly lower in patients with symptomatic COVID-19, as compared to that in the French general population after standardisation by age and sex, with standardised incidence ratios (SIRs) of 0.24 [0.12–0.48] for outpatients and 0.24 [0.14–0.40] for inpatients. Conclusions: Daily smoker rate in patients with symptomatic COVID-19 is lower as compared to the French general population

The Efficacy and Safety of Janus Kinase Inhibitors for Patients With COVID-19: A Living Systematic Review and Meta-Analysis

Abstract: Background Cytokine storm observed in patients with severe Coronavirus Disease 2019 (COVID-19) contributes to poor clinical outcomes and increased mortality. Janus kinases (JAKs) are important mediators in the cytokine storm. Therefore, we conduct a living systematic review and meta-analysis of the literature investigating efficacy and safety of JAK inhibitors for patients with COVID-19. Methods Databases were searched up to December 1, 2021 for interventional and observational studies comparing JAK inhibitor treatment with concurrent control in patients with COVID-19. Efficacy and safety outcomes were evaluated by pooled risk ratio (RR). Results Of 3,170 records retrieved, 15 studies were eligible and 13 were evaluated in the meta-analysis (n = 3,977). Based on data from three randomized controlled trials (RCTs), baricitinib treatment significantly decreased mortality by day 28 in hospitalized patients with COVID-19 (RR = 0.64, 95% CI 0.51–0.80) without increasing the incidence of adverse outcomes. In subgroup analysis, patients who required supplemental oxygen (RR = 0.62, 95% CI 0.41–0.95) or high-flow oxygen/non-invasive ventilation (RR = 0.59, 95% CI 0.42–0.85) at baseline benefited most. Pooled analysis of all eligible studies for JAK inhibitors (baricitinib, ruxolitinib, tofacitinib, and nezulcitinib) demonstrated a significant decrease in mortality (RR = 0.62, 95% CI 0.49–0.78) with no increase in the risk of adverse events. Conclusion Baricitinib probably decreases mortality in hospitalized adult patients with COVID-19, especially for patients who required supplemental oxygen or high-flow oxygen/non-invasive ventilation at baseline. The efficacy and safety of other JAK inhibitors, such as ruxolitinib, tofacitinib, and nezulcitinib, await more evidence. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021261414, identifier: CRD42021261414.

The Outcomes of XEN Gel Stent Implantation: A Systematic Review and Meta-Analysis

Abstract: Purpose XEN gel stents are used for the treatment of open-angle glaucoma (OAG), including primary and secondary glaucoma that are uncontrolled by previous medical therapy and cases with previous failed surgery. Our aim was to systematically review of the clinical data of currently published ab-interno XEN gel stents with an emphasis on intraocular pressure (IOP), antiglaucoma medication outcomes, and safety profiles. Methods We analyzed all of the publications (MEDLINE, EMBASE, Cochrane Library) on the ab-interno XEN gel stent to evaluate the reduction in IOP and antiglaucoma medications following the procedure. The primary outcomes measured for the meta-analysis were reduction in IOP and anti-glaucoma medications. The secondary outcome were adverse events. For each study, we used a random effects analysis model to calculate the mean difference and 95% confidence intervals for the continuous results (reduction in IOP and antiglaucoma medications) using the inverse variance statistical method. Results Five hundred twenty-seven articles were checked and 56 studies were found to be relevant with a total of 4,410 eyes. There was a significant reduction in IOP as well as in the number of medications required in patients treated with ab-interno XEN implant either alone or combined with cataract surgery. This new treatment for various types of glaucoma reduced the IOP by 35% to a final average close to 15 mmHg. This reduction was accompanied by a decrease in the number of antiglaucoma medications in all the studies, approximately 2 classes of medication at the price of more needlings. The overall complete success rate was 21.0–70.8% after 2 years using strict criteria originally designed to record success rate in filtration surgery. The incidence of complications vision-threatening was low at <1%. Conclusions XEN gel stent was effective and safe for primary and secondary OAG. Further studies should be performed to investigate the impact of ethnicity on the success and failure rate after XEN implantation.

Management of Medico-Legal Risks in Digital Health Era: A Scoping Review

Abstract: Artificial intelligence needs big data to develop reliable predictions. Therefore, storing and processing health data is essential for the new diagnostic and decisional technologies but, at the same time, represents a risk for privacy protection. This scoping review is aimed at underlying the medico-legal and ethical implications of the main artificial intelligence applications to healthcare, also focusing on the issues of the COVID-19 era. Starting from a summary of the United States (US) and European Union (EU) regulatory frameworks, the current medico-legal and ethical challenges are discussed in general terms before focusing on the specific issues regarding informed consent, medical malpractice/cognitive biases, automation and interconnectedness of medical devices, diagnostic algorithms and telemedicine. We aim at underlying that education of physicians on the management of this (new) kind of clinical risks can enhance compliance with regulations and avoid legal risks for the healthcare professionals and institutions.