Sonographic Diaphragm Abnormalities are an Unexpectedly Frequent Feature of Long COVID Outpatients with Unexplained Dyspnea and Fatigue (preprint)

Purpose The primary aim of this study is to define the sonographic diaphragm phenotype of Long COVID rehabilitation outpatients with non-specific dyspnea and fatigue. We analyzed patients referred from a pulmonary post-COVID clinic that were lacking a specific cardiopulmonary diagnosis for their symptoms. Additionally, we report the functional outcomes of subset of patients who completed an outpatient cardiopulmonary physical therapy program.Methods This was a retrospective cohort study (n = 58) of consecutive patients referred for neuromuscular ultrasound assessment of diaphragm muscle using B-mode technique. Patients were recruited from a single academic hospital between February 25, 2021 and November 22, 2022.Results Sonographic abnormalities were identified in 57% (33/58) of patients, and in the vast majority of cases (33/33) was defined by a low diaphragm muscle thickness. Thinner diaphragm muscles are correlated with lower serum creatinine and creatine kinase values, but there was no association with markers of systemic inflammation. Thirty three patients participated in outpatient cardiopulmonary physical therapy that included respiratory muscle training, and 75.8% (25/33) had documented improvement.Conclusion In the outpatient rehabilitation setting, patients with Long COVID display low diaphragm muscle thickness, but intact muscle contractility, with surprising frequency on neuromuscular ultrasound. We speculate this represents a form of disuse atrophy. Also, these patients appear to have a favorable response to cardiopulmonary physical therapy that includes respiratory muscle training.

The first case of acute necrotizing encephalopathy associated with coronavirus disease in a child in Asia: a case report and literature review (preprint)

Background Acute necrotic encephalopathy（ANE） in children is a very rare complication of Severe Acute Respiratory Syndrome Coronavirus 2（SARS-CoV-2） infection, which has rarely been reported worldwide. Case presentation A 45-day-old girl was admitted to our hospital with fever and listlessness. A nose swab tested positive for novel coronavirus nucleic acid, and her cerebrospinal fluid was positive for SARS-CoV-2. An early head magnetic resonance imaging (MRI) scan indicated multiple abnormal signals in her bilateral cerebral hemispheres, and encephalitis was diagnosed. Twenty-three days after hospitalization, bilateral cerebral atrophy-like changes were observed by MRI, with multiple softening lesions in the bilateral cerebral hemispheres, accompanied by convulsions. She was admitted to hospital for mechanically-assisted ventilation, and her condition improved after treatment of her symptoms, including anti-epileptic medication, anti-infection drugs, glucocorticoids, and immunoglobulins. Conclusions Acute necrotic encephalopathy associated with novel coronavirus infection in children should be detected and treated as early as possible. Satisfactory short-term efficacy can be obtained, but long-term neurological sequelae often linger.

Stress as worsening of the signs and symptoms of the geographic tongue during the COVID-19 pandemic: a pilot study.

BACKGROUND: Geographic Tongue (GT) is a benign inflammatory disorder of unknown etiology, which is characterized by the loss of epithelium due to the atrophy of filiform papillae. It usually occurs on the dorsum of the tongue and may extend to its lateral edges. It appears as an erythematous area surrounded by whitish and slightly elevated margins. In most cases, the condition is asymptomatic, although some individuals may report symptoms that include a burning sensation of the tongue. OBJECTIVE: Assess whether there was a change in the clinical aspect of Geographic Tongue (GT) during the COVID-19 pandemic. METHODS: Thirty-two participants were recruited from Dentistry School Universidade Federal Fluminense. Anamnesis and oral examination were performed to collect medical history. The participants were split into two groups: control group (no GT) n = 20 and test group (with GT) n = 12. In the second step, nine participants from a 12 (75%) of the test group were contacted by phone and answered a questionnaire about changes in the signs and symptoms of GT during the pandemic. The subjects were subdivided into two groups: GT with and without signs and symptoms exacerbation. RESULTS: In the first phase of the research, no statistical difference between control and test groups was observed regarding clinical criteria such as age (p + 0.72), gender (p = 0.24), and systemic diseases (p = 0.58). In the second phase, there was a statistical difference between GT groups with or without symptom exacerbation in terms of age and stress as a factor of the oral symptoms (p = 0.3 and 0.2), respectively. Younger patients showed a worsening of the oral lesions related to GT (p = 0.3) and reported stress during the pandemic (p = 0.02). CONCLUSION: Younger patients were more susceptible to stress and presented more exacerbation of the oral lesions related to GT.

Multiple sclerosis as a model to investigate SARS-CoV-2 effect on brain atrophy.

INTRODUCTION: Data on structural brain changes after infection with SARS-CoV-2 is sparse. We postulate multiple sclerosis as a model to study the effects of SARS-CoV-2 on brain atrophy due to the unique availability of longitudinal imaging data in this patient group, enabling assessment of intraindividual brain atrophy rates. METHODS: Global and regional cortical gray matter volumes were derived from structural MRIs using FreeSurfer. A linear model was fitted to the measures of the matching pre-SARS-CoV-2 images with age as an explanatory variable. The residuals were used to determine whether the post-SARS-CoV-2 volumes differed significantly from the baseline. RESULTS: Fourteen RRMS patients with a total of 113 longitudinal magnetic resonance images were retrospectively analyzed. We found no acceleration of brain atrophy after infection with SARS-CoV-2 for global gray matter volume (p = 0.17). However, on the regional level, parahippocampal gyri showed a tendency toward volume reduction (p = 0.0076), suggesting accelerated atrophy during or after infection. CONCLUSIONS: Our results illustrate the opportunity of using longitudinal MRIs from existing MS registries to study brain changes associated with SARS-CoV-2 infections. We would like to address the global MS community with a call for action to use the available cohorts, reproduce the proposed analysis, and pool the results.

Post-intubation Laryngeal Disorders in COVID-19 Patients: A Prospective Study. (preprint)

Objective: To investigate post-intubation laryngeal complications in severe COVID-19 patients. Methods: From September 2020 to April 2021, consecutive patients presenting with laryngological symptoms following severe COVID-19 infection and related intubation were included. Demographic, age, gender, comorbidities, symptoms, intubation duration, tracheostomy features, and laryngeal findings were collected. Videolaryngostroboscopy findings were analyzed by two senior laryngologists in a blind manner. Results: Forty-three patients completed the evaluations. The intubation duration was <14 days in 22 patients (group 1) and >14 days in 21 patients (group 2). The following abnormalities were found on an average post-intubation time of 51.6 days: posterior glottic stenosis (N=14), posterior commissure hypertrophy (N=19) or laryngeal diffuse edema (N=10), granuloma (N=8), laryngeal necrosis (N=2), vocal fold atrophy (N=2), subglottic stenosis (N=1) and glottic flange (N=1). Sixteen patients required surgical treatment (N=17 procedures). The number of intubation days was significantly higher in patients with posterior glottic stenosis (26.1 ± 9.4) compared with those presenting posterior commissure hypertrophy (11.5 ± 2.9) or granuloma (15.1 ± 5.8; p<0.001). Fourteen patients required surgical management. Conclusion: Prolonged intubation used in severe COVID-19 patients is associated with significant laryngeal disorders. Patients with a history of >2-week intubation have a higher risk of posterior glottic stenosis.

Post-intubation Laryngeal Disorders in COVID-19 Patients: A Prospective Study. (preprint)

Objective: To investigate post-intubation laryngeal complications in severe COVID-19 patients. Methods: From September 2020 to April 2021, consecutive patients presenting with laryngological symptoms following severe COVID-19 infection and related intubation were included. Demographic, age, gender, comorbidities, symptoms, intubation duration, tracheostomy features, and laryngeal findings were collected. Videolaryngostroboscopy findings were analyzed by two senior laryngologists in a blind manner. Results: Forty-three patients completed the evaluations. The intubation duration was <14 days in 22 patients (group 1) and >14 days in 21 patients (group 2). The following abnormalities were found on an average post-intubation time of 51.6 days: posterior glottic stenosis (N=14), posterior commissure hypertrophy (N=19) or laryngeal diffuse edema (N=10), granuloma (N=8), laryngeal necrosis (N=2), vocal fold atrophy (N=2), subglottic stenosis (N=1) and glottic flange (N=1). Sixteen patients required surgical treatment (N=17 procedures). The number of intubation days was significantly higher in patients with posterior glottic stenosis (26.1 ± 9.4) compared with those presenting posterior commissure hypertrophy (11.5 ± 2.9) or granuloma (15.1 ± 5.8; p<0.001). Fourteen patients required surgical management. Conclusion: Prolonged intubation used in severe COVID-19 patients is associated with significant laryngeal disorders. Patients with a history of >2-week intubation have a higher risk of posterior glottic stenosis.

Comprehension of acoustically degraded speech in Alzheimer’s disease and primary progressive aphasia (preprint)

ABSTRACT Successful communication in daily life frequently depends on accurate decoding of speech signals that are acoustically degraded by challenging listening conditions. This process presents the brain with a demanding computational task that is vulnerable to neurodegenerative pathologies. However, despite recent intense interest in the link between hearing impairment and dementia, daily hearing measures (such as degraded speech comprehension) in these diseases remain poorly defined. Here we addressed this issue in a cohort of 19 patients with typical Alzheimer’s disease (AD) and 31 patients representing canonical syndromes of primary progressive aphasia (PPA), in relation to 25 healthy age-matched controls. As a model paradigm for the acoustically degraded speech signals of daily life, we used noise-vocoding: synthetic division of the speech signal into a variable number of frequency channels constituted from amplitude-modulated white noise, such that fewer channels convey less spectrotemporal detail thereby reducing intelligibility. We investigated the impact of noise-vocoding on recognition of spoken three-digit numbers and used psychometric modelling to ascertain the threshold number of noise-vocoding channels required for 50% intelligibility by each participant. Associations of noise-vocoded speech intelligibility threshold with general demographic, clinical and neuropsychological characteristics and regional grey matter volume (defined by voxel-based morphometry of patients’ brain MR images) were also assessed. Compared with healthy older controls, all patient groups had a significantly higher mean noise-vocoded speech intelligibility threshold, particularly marked in logopenic variant and nonfluent-agrammatic variant PPA and significantly higher in AD than in semantic variant PPA (all p<0.05). Noise-vocoded intelligibility threshold discriminated dementia syndromes (in particular, Alzheimer’s disease) well from healthy controls. Further, this central hearing measure correlated with overall disease severity but not with measures of peripheral hearing or clear speech perception. Neuroanatomically, after correcting for multiple voxel-wise comparisons in pre-defined regions of interest, impaired noise-vocoded speech comprehension across dementia syndromes was significantly associated (p<0.05) with atrophy of left planum temporale, angular gyrus and anterior cingulate gyrus: a cortical network widely implicated in processing degraded speech signals. Taken together, our findings suggest that the comprehension of acoustically altered speech captures a central process relevant to daily hearing and communication in major dementia syndromes, with novel diagnostic and therapeutic implications.

COVID-19 patients in the COVID-19 Recovery and Engagement (CORE) Clinics in the Bronx (preprint)

BACKGROUND: Early in the pandemic, we established COVID-19 Recovery and Engagement (CORE) Clinics in the Bronx and implemented a detailed evaluation protocol was implemented to assess physical, emotional, and cognitive function, pulmonary function tests, and imaging for COVID-19 survivors. Here we report our findings five months post-acute COIVD-19. METHODS: Main outcomes and measures included pulmonary function tests, imaging tests, and a battery of symptom, physical, emotional, and cognitive assessments 5 months post-acute COVID-19. FINDINGS: Dyspnea, fatigue, decreased exercise tolerance, brain fog, and shortness of breath were the most common symptoms but there were generally no significant differences between hospitalized and non-hospitalized cohorts (p>0.05). Many patients had abnormal physical, emotional, and cognitive scores, but most functioned independently; there were no significant differences between hospitalized and non-hospitalized cohorts (p>0.05). Six-minute walk test, lung ultrasound, and diaphragm excursion were abnormal but only in the hospitalized cohort. Pulmonary function tests showed moderately restrictive pulmonary function only in the hospitalized cohort but no obstructive pulmonary function. Newly detected major neurological events, microvascular disease, atrophy, and white-matter changes were rare, but lung opacity and fibrosis-like findings were common after acute COVID-19. INTERPRETATION: Many COVID-19 survivors experienced moderately restrictive pulmonary function, and significant symptoms across the physical, emotional, and cognitive health domains. Newly detected brain imaging abnormalities were rare, but lung imaging abnormalities were common. This study provides insights into post-acute sequelae following SARS-CoV-2 infection in neurological and pulmonary systems which may be used to support at-risk patients, develop effective screening methods and interventions.

An alternative mechanism for skeletal muscle dysfunction in long-term post-viral lung disease (preprint)

ABSTRACT Chronic lung disease is often accompanied by disabling extrapulmonary symptoms, notably skeletal muscle dysfunction and atrophy. Moreover, the severity of respiratory symptoms correlates with decreased muscle mass and in turn lowered physical activity and survival rates. Previous models of muscle atrophy in chronic lung disease often modeled COPD and relied on cigarette smoke exposure and LPS-stimulation, but these conditions independently affect skeletal muscle even without accompanying lung disease. Moreover, there is an emerging and pressing need to understand the extrapulmonary manifestations of long-term post-viral lung disease (PVLD) as found in Covid-19. Here, we examine the development of skeletal muscle dysfunction in the setting of chronic pulmonary disease using a mouse model of PVLD caused by infection due to the natural pathogen Sendai virus. We identify a significant decrease in myofiber size when PVLD is maximal at 49 d after infection. We find no change in the relative types of myofibers, but the greatest decrease in fiber size is localized to fast-twitch type IIB myofibers based on myosin heavy chain immunostaining. Remarkably, all biomarkers of myocyte protein synthesis and degradation (total RNA, ribosomal abundance, and ubiquitin-proteasome expression) were stable throughout the acute infectious illness and chronic post-viral disease process. Together, the results demonstrate a distinct pattern of skeletal muscle dysfunction in a mouse model of long-term PVLD. The findings thereby provide new insight into prolonged limitations in exercise capacity in patients with chronic lung disease after viral infections and perhaps other types of lung injury.

Identification of the co-differentially expressed hub genes involved in the endogenous protective mechanism against ventilator-induced diaphragm dysfunction.

BACKGROUND: In intensive care units (ICU), mechanical ventilation (MV) is commonly applied to save patients' lives. However, ventilator-induced diaphragm dysfunction (VIDD) can complicate treatment by hindering weaning in critically ill patients and worsening outcomes. The goal of this study was to identify potential genes involved in the endogenous protective mechanism against VIDD. METHODS: Twelve adult male rabbits were assigned to either an MV group or a control group under the same anesthetic conditions. Immunostaining and quantitative morphometry were used to assess diaphragm atrophy, while RNA-seq was used to investigate molecular differences between the groups. Additionally, core module and hub genes were analyzed using WGCNA, and co-differentially expressed hub genes were subsequently discovered by overlapping the differentially expressed genes (DEGs) with the hub genes from WGCNA. The identified genes were validated by western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: After a VIDD model was successfully built, 1276 DEGs were found between the MV and control groups. The turquoise and yellow modules were identified as the core modules, and Trim63, Fbxo32, Uchl1, Tmprss13, and Cst3 were identified as the five co-differentially expressed hub genes. After the two atrophy-related genes (Trim63 and Fbxo32) were excluded, the levels of the remaining three genes/proteins (Uchl1/UCHL1, Tmprss13/TMPRSS13, and Cst3/CST3) were found to be significantly elevated in the MV group (P < 0.05), suggesting the existence of a potential antiproteasomal, antiapoptotic, and antiautophagic mechanism against diaphragm dysfunction. CONCLUSION: The current research helps to reveal a potentially important endogenous protective mechanism that could serve as a novel therapeutic target against VIDD.

IDIOPATHIC MULTIFOCAL CHOROIDITIS WITH SERPIGINOUS-LIKE PERIPAPILLARY CHORIORETINAL ATROPHY.

PURPOSE: To report nine cases of multifocal choroiditis with serpiginous-like peripapillary chorioretinal atrophy. METHODS: A retrospective observational case series of eyes with multifocal choroiditis with serpiginous-like peripapillary chorioretinal atrophy. Multimodal imaging findings were reviewed and presented. RESULTS: Fifteen eyes of 9 patients (6 women and 3 men), with a mean age of 48.1 years (median, 46 years; range, 23-74 years), presented with multifocal choroiditis serpiginous-like peripapillary chorioretinal atrophy. All 15 eyes presented with serpiginoid peripapillary changes and had discrete patches of atrophy or punched-out scars in the posterior pole or periphery. Eleven eyes (73.3%) had cone-shaped retinal pigment epithelium elevations on optical coherence tomography, 10 eyes (66.7%) had mild vitritis, and 4 eyes (26.7%) had peripheral curvilinear streak lesions. Three eyes (20%) had choroidal neovascularization. All patients responded well to treatment with systemic immunosuppression, local corticosteroid injections, and/or intravitreal anti-vascular endothelial growth factor injections. CONCLUSION: Multifocal choroiditis may present with peripapillary chorioretinal changes resembling a serpiginous-like choroiditis in addition to the classic findings of patches of atrophy or punched-out scars in the posterior pole or periphery, cone-shaped retinal pigment epithelium elevated on optical coherence tomography and peripheral curvilinear streak lesions.

Development of transgenic models susceptible and resistant to SARS-CoV-2 infection in FVB background mice.

Coronavirus disease (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is currently spreading globally. To overcome the COVID-19 pandemic, preclinical evaluations of vaccines and therapeutics using K18-hACE2 and CAG-hACE2 transgenic mice are ongoing. However, a comparative study on SARS-CoV-2 infection between K18-hACE2 and CAG-hACE2 mice has not been published. In this study, we compared the susceptibility and resistance to SARS-CoV-2 infection between two strains of transgenic mice, which were generated in FVB background mice. K18-hACE2 mice exhibited severe weight loss with definitive lethality, but CAG-hACE2 mice survived; and differences were observed in the lung, spleen, cerebrum, cerebellum, and small intestine. A higher viral titer was detected in the lungs, cerebrums, and cerebellums of K18-hACE2 mice than in the lungs of CAG-hACE2 mice. Severe pneumonia was observed in histopathological findings in K18-hACE2, and mild pneumonia was observed in CAG-hACE2. Atrophy of the splenic white pulp and reduction of spleen weight was observed, and hyperplasia of goblet cells with villi atrophy of the small intestine was observed in K18-hACE2 mice compared to CAG-hACE2 mice. These results indicate that K18-hACE2 mice are relatively susceptible to SARS-CoV-2 and that CAG-hACE2 mice are resistant to SARS-CoV-2. Based on these lineage-specific sensitivities, we suggest that K18-hACE2 mouse is suitable for highly susceptible model of SARS-CoV-2, and CAG-hACE2 mouse is suitable for mild susceptible model of SARS-CoV-2 infection.

A pilot randomized controlled trial of vaginal estrogen on postpartum atrophy, perineal pain, and sexual function.

INTRODUCTION AND HYPOTHESIS: Vulvovaginal symptoms following perineal laceration may be worsened by atrophy related to decreased estrogen. Our objective was to evaluate the effect of local estrogen therapy in this setting. METHODS: We conducted a single-center, pilot, randomized, placebo-controlled trial of local estradiol in primiparous women with a second-degree or greater perineal laceration following a term vaginal delivery. Participants were randomized to twice weekly estradiol or placebo cream from delivery through 3 months postpartum. The primary outcome was a validated measure of vulvovaginal symptoms at 12 weeks postpartum. Secondary outcomes included measures of perineal pain, quality of life, sexual function, ease of use, likelihood of continued use, and adverse events. RESULTS: We planned to enroll 70 women; however, due to human subjects research restrictions related to the COVID-19 pandemic, enrollment was stopped early. A total of 59 women were randomized, 31 to the estradiol group and 28 to the placebo group. Nearly all participants (95%) were followed through 12 weeks with suggestion of marginal improvement in Vulvar Assessment Scale scores [-0.10; 90% CI = (-0.20, 0.01)] in those randomized to estradiol compared to placebo. Local estradiol was not associated with improvement in other measures, and only one non-serious adverse event was observed. CONCLUSIONS: In primiparous women with a perineal laceration, use of local estradiol showed minimal clinical benefit in vulvovaginal atrophy and related symptoms but appears to be acceptable and safe for postpartum use. Larger adequately powered trials enrolling a diverse group of postpartum women are needed to affirm these findings.

The Evolution of Vigilance and Its Atrophy Preceding the COVID-19 Global Pandemic.

Introduction: Recent infectious outbreaks preceding the COVID-19 crisis resulted in the evolution of vigilance for preparedness against the next pandemic. This vigilance was maintained to varying degrees in different jurisdictions. Objective: To evaluate the evolution of vigilance following previous epidemics and pandemics and the subsequent atrophy of vigilance prior to the COVID-19 global pandemic. Methods: We evaluated documentation discussing US, Canada, and South Korea from March 2002 to October 2021. Our policy search strategy was rooted in academic literature, government documents and media reports. Results: In the US, there were examples of atrophy of vigilance; however, there was clear understanding of pandemic readiness actions that were simply not executed amongst political chaos. In Canada, political mishaps were less evident at the time the pandemic unfolded. Nevertheless, atrophy was evident with erosion in preparedness programs following SARS. South Korea appeared least subjected to atrophy of vigilance. The more recent MERS outbreak prompted evolution of sustained vigilance and compliance with basic public health measures such as mask wearing. Recommendations: Policy options need to be explored and instituted that increase protection of preparedness programs through institutional safeguards and accountability measure.

Testicular torsion during the COVID-19 pandemic: Results of a multicenter study in northern Italy.

INTRODUCTION: The literature reported an increased avoidance of the Emergency Department (ED) during COrona VIrus Disease 19 (COVID-19) pandemic, causing a subsequent increase of morbidity and mortality for acute conditions. Testicular torsion is a surgical emergency, which can lead to the loss of the affected testicle if a delayed treatment occurs. As testicular loss is time-related, outcome was hypothesized to be negatively affected by the pandemic. OBJECTIVE: The aim is to investigate whether presentation, treatment and outcomes of children with testicular torsion were delayed during COVID-19. STUDY DESIGN: Medical records of pediatric patients operated for testicular torsion of six Paediatric Surgical Units in Northern Italy between January 2019 and December 2020 were retrospectively reviewed. Patients were divided as for ones treated during (dC) or before the pandemic (pC). To reflect possible seasonality, related to lockdown restrictions, winter and summer calendar blocks were also analysed. For all cohorts, demographic data, pre-operative evaluation, operative notes and post-operative outcomes were reviewed. Primary outcomes were referral time, time from diagnosis to surgery and ischemic time, while secondary outcomes were orchiectomy and atrophy rates. Statistic was conducted as appropriate. RESULTS: A total of 188 patients with acute testicular torsion were included in the study period, 89 in the pre-COVID-19 (pC) period and 99 during COVID-19 (dC). Time from symptom onset to the access to the Emergency Department (T1) was not different among the two populations (pC: 5,5 h, dC: 6 h, p 0.374), and similarly time from diagnosis to surgery (pC: 2,5 h, dC: 2,5 h, p 0.970) and ischemic time (pC: 8,2 h, dC: 10 h, p 0.655). T1 was <6 h in 46/99 patients (46%) pC and 45/89 patients (51%) dC (p = 0.88, Fisher's exact test). Subgroup analysis accounting for different lockdown measures, confirm the absence of any difference. Orchiectomies rate was 23% (23/99) dC and 21% (19/89) pC (p = 0.861, Fisher's exact test) and rate of post-operative atrophy was 9% dC (7/76) and 14% pC (10/70), p = 0,44, Fisher's exact test. DISCUSSION: Despite worldwide pediatric ED accesses reduction, we reported that neither ischemic time nor the long-term outcomes in children with testicular torsion increased during the COVID-19 pandemic. In the available literature, few studies investigated the topic and are controversial on the results. Similarly to our findings, some studies found that timing and orchiectomy rates were not significantly different during the pandemic, while others reported a correlation to pandemic seasonality. Furthermore, in the recent pediatric literature it has been reported a delayed testicular torsion diagnosis due to shame in informing parents. Strengths of this study are the large numerosity, its multicentric design and a long study period. Its main limitation is being retrospective. CONCLUSIONS: We reported our large cohort from one of the most heavily COVID-19-affected regions, finding that referral, intra-hospital protocols and ischemic time in testicular torsion were not increased during to the pandemic, as well as orchiectomy rate and atrophy.

The evidence behind the use of LASER for genitourinary syndrome of menopause, vulvovaginal atrophy, urinary incontinence and lichen sclerosus: A state-of-the-art review.

In recent years, LASER has been introduced as a minimally invasive treatment for a broad range of vaginal and vulvar symptoms and diseases. However, the efficacy and safety of vaginal and vulvar LASER has continuously been questioned. The aim of this study is to create an overview of the current literature and discuss the controversies within the use of LASER for genitourinary syndrome of menopause, vulvovaginal atrophy, urinary incontinence and lichen sclerosus. A search string was built in PubMed. The search was commenced on August 25, 2021 and closed on October 27, 2021. Two authors screened the studies in Covidence for inclusion according to the eligibility criteria in the protocol. The data were extracted from the studies and are reported in both text and tables. This review included 114 papers, of which 15 were randomized controlled trials (RCTs). The effect of LASER as a vaginal treatment was investigated for genitourinary syndrome of menopause in 36 studies (six RCTs), vulvovaginal atrophy in 34 studies (four RCTs) and urinary incontinence in 30 studies (two RCTs). Ten studies (three RCTs) investigated the effect of vulvar treatment for lichen sclerosus. Half of the included RCTs, irrespective of indication, did not find a significant difference in improvement in women treated with vaginal CO2 or Er:YAG LASER compared with their respective controls. However, most non-comparative studies reported significant improvement after exposure to vaginal or vulvar LASER across all indications. Included studies generally had a short follow-up period and only a single RCT followed their participants for more than 6 months post treatment. Adverse events were reported as mild and transient and 99 studies including 51 094 patients provided information of no serious adverse events. In conclusion, this review found that the effect of vaginal and vulvar LASER decreases with higher study quality where potential biases have been eliminated. We therefore stress that all patients who are treated with vaginal or vulvar LASER should be carefully monitored and that LASER for those indications as a treatment should be kept on a research level until further high-quality evidence is available.

SARS-CoV-2 and its variants, but not Omicron, induces thymic atrophy and impaired T cell development (preprint)

Pathogenic infections cause thymic atrophy, perturb thymic-T cell development and alter immunological response. Previous studies reported dysregulated T cell function and lymphopenia in coronavirus disease-19 (COVID-19) patients. However, immune-pathological changes, in the thymus, post severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have not been elucidated. Here, we report SARS-CoV-2 infects thymocytes, depletes CD4+CD8+ (double positive DP) T cell population associated with an increased apoptosis of thymocytes, which leads to severe thymic atrophy in K18-hACE2-Tg mice. CD44+CD25- T cells were found to be enriched in infected thymus, indicating an early arrest in the T cell developmental pathway. Further, Interferon gamma was crucial for thymic atrophy, as anti-IFN{gamma}; antibody neutralization rescued the loss of thymic involution. Therapeutic use of remdesivir (prototype anti-viral drug) was also able to rescue thymic atrophy. While Omicron variant of SARS-CoV2 caused marginal thymic atrophy, delta variant of SARS-CoV-2 exhibited most profound thymic atrophy characterized by severely depleted DP T cells. Recently characterized broadly SARS-CoV-2 neutralizing monoclonal antibody P4A2 was able to rescue thymic atrophy and restore thymic developmental pathway of T cells. Together, we provide the first report of SARS-CoV-2 associated thymic atrophy resulting from impaired T cell developmental pathway and also explains dysregulated T cell function in COVID-19.

Disrupted Peyer's Patch Microanatomy in COVID-19 Including Germinal Centre Atrophy Independent of Local Virus.

Confirmed SARS-coronavirus-2 infection with gastrointestinal symptoms and changes in microbiota associated with coronavirus disease 2019 (COVID-19) severity have been previously reported, but the disease impact on the architecture and cellularity of ileal Peyer's patches (PP) remains unknown. Here we analysed post-mortem tissues from throughout the gastrointestinal (GI) tract of patients who died with COVID-19. When virus was detected by PCR in the GI tract, immunohistochemistry identified virus in epithelium and lamina propria macrophages, but not in lymphoid tissues. Immunohistochemistry and imaging mass cytometry (IMC) analysis of ileal PP revealed depletion of germinal centres (GC), disruption of B cell/T cell zonation and decreased potential B and T cell interaction and lower nuclear density in COVID-19 patients. This occurred independent of the local viral levels. The changes in PP demonstrate that the ability to mount an intestinal immune response is compromised in severe COVID-19, which could contribute to observed dysbiosis.

Thymic Dysfunction and Atrophy in COVID-19 Disease Complicated by Inflammation, Malnutrition and Cachexia.

Background: The current COVID-19 pandemic has put millions of people, especially children at risk of protein-energy malnutrition (PEM) by pushing them into poverty and disrupting the global food supply chain. The thymus is severely affected by nutritional deficiencies and is known as a barometer of malnutrition. Aim: The present commentary provides a novel perspective on the role of malnutrition-induced thymic dysfunction, involution and atrophy on the risk and severity of disease in children during the COVID-19 pandemic. Methods: A review of pertinent indexed literature including studies examining the effects of malnutrition on the thymus and immune dysfunction in COVID-19. Results: Protein-energy malnutrition and micronutrient deficiencies of zinc, iron and vitamin A are known to promote thymic dysfunction and thymocyte loss in children. Malnutrition- and infection-induced thymic atrophy and immune dysfunction may increase the risk of first, progression of COVID-19 disease to more severe forms including development of multisystem inflammatory syndrome in children (MIS-C); second, slow the recovery from COVID-19 disease; and third, increase the risk of other infections. Furthermore, malnourished children may be at increased risk of contracting SARS-CoV-2 infection due to socioeconomic conditions that promote viral transmission amongst contacts and create barriers to vaccination. Conclusion: National governments and international organizations including WHO, World Food Program, and UNICEF should institute measures to ensure provision of food and micronutrients for children at risk in order to limit the health impact of the ongoing COVID-19 pandemic.