Transient anti-interferon autoantibodies in the airways are associated with efficient recovery from COVID-19 (preprint)

Pre-existing anti-interferon alpha (anti-IFN-) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti-IFN- autoantibodies in the airways - the initial site of infection - can also determine disease outcomes. In this study, we developed a new multiparameter technology, flowBEAT, to quantify and profile the isotypes of anti-IFN- and anti-SARS-CoV-2 antibodies in longitudinal samples collected over 20 months from the airway and matching blood of 129 donors with mild, moderate, and severe COVID-19. We found unexpectedly that nasal anti-IFN- autoantibodies were induced post-infection onset in more than 70% of mild to moderate COVID-19 cases and associated with robust anti-SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti-IFN- autoantibodies followed the peak of host IFN- production and waned with disease recovery, revealing a regulated balance between IFN- and anti-IFN- response. Notably, only a subset of mild to moderate patients progressed to develop systemic anti-IFN-, which correlated with systemic inflammation and worsened symptoms. In contrast, patients with life-threatening COVID-19 sustained elevated anti-IFN- in both airways and blood, coupled with uncontrolled viral load and IFN- production. Our studies thereby reveal a novel protective role for nasal anti-IFN- autoantibodies in the immunopathology of COVID-19 and, more broadly, suggest that anti-IFN- may serve an important regulatory function to restore homeostasis following viral invasion of the respiratory mucosa.

Relationship Between Sexual Behaviors with Non-committed Relationship Partners and COVID-19 Restrictions and Notification Rates: Results from a Longitudinal Study of Gay and Bisexual Men in Australia.

Introduction: COVID-19 related lockdowns have impacted the sexual activity of gay and bisexual men (GBM). We investigated trends in sexual behaviors and the COVID-19 context in which they occurred (COVID-notification rates and jurisdictional restrictions) to understand changes in the duration and severity of periods of lockdown on the sexual behavior of Australian GBM. Methods: In an online, prospective observational study of 831 GBM from May 2020 to May 2021, we investigated associations between changes in sexual behavior among Australian GBM, lockdowns, and COVID-19 notification rates through weekly surveys from May 2020 to May 2021. Results: The mean age was 45.71 years (SD: 13.93). Most identified as gay (89.0%) and 10.2% were living with HIV. There was an overall increase in the mean weekly number of non-committed relationship partners (0.53-0.90, p < 0.001). The state of Victoria experienced a significant extended COVID-19 outbreak, accompanied by severe lockdown restrictions. In response, Victorian men's partner numbers shifted three times, while elsewhere there was an overall gradually increasing trend. Conclusions: Less severe outbreaks with shorter lockdown periods, involving fewer and geographically contained, COVID-19 notifications were accompanied by non-significant changes in sex with non-relationship partners than more severe outbreaks over extended periods and larger geographical areas. Supplementary Information: The online version contains supplementary material available at 10.1007/s13178-022-00733-8.

Rapid Emergence of Potentially Transmissible Severe Acute Respiratory Syndrome Coronavirus 2 With Resistance to Combination Monoclonal Antibody Therapy.

Prolonged coronavirus disease 2019 may generate new viral variants. We report an immunocompromised patient treated with monoclonal antibodies who experienced rebound of viral RNA and emergence of an antibody-resistant (>1000-fold) variant containing 5 mutations in the spike gene. The mutant virus was isolated from respiratory secretions, suggesting the potential for secondary transmission.

The COVID-19 experience of orthodontists in Jordan.

OBJECTIVES: To understand the impact of the COVID-19 pandemic on orthodontic clinical services in Jordan. MATERIALS AND METHODS: Google Forms electronic questionnaires were distributed between March and June 2021 using the WhatsApp platform of the Jordanian Orthodontic Society and via direct WhatsApp messages. The survey was identical and contemporaneous to that used in the United Kingdom. RESULTS: The survey yielded 127 unique responses, giving a response rate of 53.1%. The factors that had the greatest impact on service delivery were government guidance (78%), patients' fear of attending (70.1%), and increased cross-infection measures (65.4%). The survey revealed that there had been a perceived deterioration in oral hygiene (60.3%) and levels of compliance (61.9%) in patients in active treatment even though patients in treatment were prioritized during the pandemic. Also, 56.8% of respondents felt clinical staff should be vaccinated and undergo regular testing for COVID-19. Orthodontists within Jordan were optimistic regarding the speed at which clinical services would return to pre-pandemic levels of activity with 32.5% anticipating this would take less than 6 months. CONCLUSIONS: Patients in active orthodontic treatment, during COVID-19, have been prioritized but at the expense of new and review patients. Respondents in Jordan felt COVID-19 would have ongoing effects on clinical care, professional practice, and society. Most respondents supported the vaccination of orthodontic staff and were optimistic about the effect of a vaccination program on restoring clinical services.

SARS-CoV-2 airway infection results in the development of somatosensory abnormalities in a hamster model.

Although largely confined to the airways, SARS-CoV-2 infection has been associated with sensory abnormalities that manifest in both acute and chronic phenotypes. To gain insight on the molecular basis of these sensory abnormalities, we used the golden hamster model to characterize and compare the effects of infection with SARS-CoV-2 and influenza A virus (IAV) on the sensory nervous system. We detected SARS-CoV-2 transcripts but no infectious material in the cervical and thoracic spinal cord and dorsal root ganglia (DRGs) within the first 24 hours of intranasal virus infection. SARS-CoV-2-infected hamsters exhibited mechanical hypersensitivity that was milder but prolonged compared with that observed in IAV-infected hamsters. RNA sequencing analysis of thoracic DRGs 1 to 4 days after infection suggested perturbations in predominantly neuronal signaling in SARS-CoV-2-infected animals as opposed to type I interferon signaling in IAV-infected animals. Later, 31 days after infection, a neuropathic transcriptome emerged in thoracic DRGs from SARS-CoV-2-infected animals, which coincided with SARS-CoV-2-specific mechanical hypersensitivity. These data revealed potential targets for pain management, including the RNA binding protein ILF3, which was validated in murine pain models. This work elucidates transcriptomic signatures in the DRGs triggered by SARS-CoV-2 that may underlie both short- and long-term sensory abnormalities.

Lasting Declines in Couples' Social Network Interactions in the First Years of COVID.

Since the onset of COVID-19, a rise in loneliness has raised concerns about the social impact of lockdowns and distancing mandates. Yet, to date, the effects of the pandemic on social networks have been studied only indirectly. To evaluate how the pandemic affected social networks, the current analyses analyzed five waves of detailed social network interviews conducted before and during the first 18 months of the pandemic in a sample especially vulnerable to contracting the virus: mostly non-White couples (243 husbands and 250 wives) recruited from lower income neighborhoods. Pre-COVID interviews asked spouses to name 24 individuals with whom they interact regularly. Post-COVID interviews indicated a nearly 50% decline in face-to-face interactions and a nearly 40% decline in virtual interactions, with little recovery over the first 18 months of the pandemic. Compared with less affluent couples, those with higher incomes maintained more of their network relationships, especially when virtual interactions were taken into account.

Evaluation of the analytical sensitivity of ACON and LumiraDx SARS-CoV-2 rapid antigen tests using samples with presumed Omicron variant.

BACKGROUND: Analytical sensitivity of 2 rapid antigen tests was evaluated for detection of presumed SARS-CoV-2 Omicron variants and earlier variants of concern. METHODS: A total of 152 SARS-CoV-2 RNA positive samples (N and ORF1ab positive but S gene negative) were tested for SARS-CoV-2 antigen by ACON lateral flow and LumiraDx fluorescence immunoassays. Sensitivity within 3 viral load ranges was compared among these 152 samples and 194 similarly characterized samples collected prior to the circulation of the Delta variant (pre-Delta). RESULTS: Antigen was detected in >95% of pre-Delta and presumed Omicron samples for both tests at viral loads >500,000 copies/mL, and 65 to 85% of samples with 50,000-500,000 copies/mL. At viral load <50,000 copies/mL, antigen tests showed better sensitivity in detecting pre-Delta compared to Omicron variants. LumiraDx was more sensitive than ACON at low viral load. CONCLUSIONS: Antigen tests had decreased sensitivity for detecting presumed Omicron compared to pre-Delta variants at low viral load.

BRIEF OF DEFENDANT-APPELLEE, UNITED STATES

Whether the U.S. Court of Federal Claims ("Court of Federal Claims" or "lower court") has subject matter jurisdiction over appellant's claim for a right to cost reimbursement under a United States Agency for International Development ("USAID") grant award that did not contain a money-mandating provision and consideration. 2. [...]the Court of Federal Claims erroneously analogized the grant award to a traditional procurement contract. Because of this errant comparison, the lower court's analysis is flawed, and so, DW's claim falls outside the narrow grant of jurisdiction at the Court of Federal Claims. [...]this court should reverse the lower court's holding and dismiss DW's claim in its entirety. [...]because of the fixed-price nature of the grant, DW assumed the risk of incurring costs not included in its budget.

Trajectories of participation in daily life among individuals newly diagnosed with cancer: A 5-month longitudinal study.

PURPOSE: To determine how participation in daily life is impacted during the first six months following a new cancer diagnosis and to identify risk factors for participation restrictions. Patient-reported outcomes (PROs) were used to suggest referrals to rehabilitation services. METHODS: Participants (n = 123) were adults (> 18 years) with the newly diagnosed primary brain, breast, colorectal, or lung cancer. PROs were collected at baseline (within 30 days of diagnosis/treatment initiation), two and five months post baseline. Daily life participation was assessed through the community participation indicators (CPI) (score range: 0-1) and patient-reported outcome measurement information system (PROMIS) ability to participate, (score range: 20-80; mean: 50, SD: 10). PROMIS-43 profile was also completed. Linear mixed-effect models with random intercept evaluated change in participation over time. RESULTS: The baseline total sample mean CPI score was 0.56; patients reported mildly impaired participation based on PROMIS scores (baseline: 46.19, 2-month follow-up: 44.81, 5 months: 44.84). However, no statistically significant changes in participation were observed over the study period. Risk factors for lower participation included receiving chemotherapy, lower physical function, higher anxiety and fatigue, and reduction in employment, p < 0.05. PROs indicated that roughly half of the participants may benefit from physical or occupational therapy or mental health support, but only 20-36% were referred by their medical team. CONCLUSION: People newly diagnosed with cancer experience impaired participation, but they are infrequently referred to supportive services such as rehabilitation. The use of PROs to assess participation, physical function, and mental health can promote access to supportive care services by identifying patients who may benefit from rehabilitation beyond those identified through routine clinical care.

Nirmatrelvir-ritonivir, COVID-19, and possible adverse cutaneous reactions.

Nirmatrelvir-ritonivir (Paxlovid) recently received emergency use authorization for the treatment of coronavirus disease 2019 (COVID-19). Literature has linked numerous cutaneous adverse effects to nirmatrelvir and ritonavir, the copackaged tablets within Paxlovid. A review and comparison of these adverse effects to the common cutaneous manifestations of COVID-19 is provided. Numerous drug-to-drug interactions exist between nirmatrelvir-ritonivir and commonly-used medications within dermatology.

Residential clustering of COVID-19 cases and efficiency of building-wide compulsory testing notices as a transmission control measure in Hong Kong.

We described the frequency of residential case clusters and the efficiency of compulsory testing in identifying cases using buildings targeted in compulsory testing and locally infected COVID-19 cases matched by residence in Hong Kong. Most of the buildings (4246/7688, 55.2%) with COVID-19 cases identified had only one reported case and 13% of the daily reported cases were detected through compulsory testing. Compulsory testing notices could be essential in attempting to eliminate infections ('zero covid') and impactful early in an epidemic but appears to be relatively inefficient in response to sustained community transmission.

Telehealth for Pediatric Disorders of Gut-Brain Interaction During the COVID-19 Pandemic.

A retrospective chart review was completed to examine psychological treatment duration and response among pediatric patients with a disorder of gut-brain interaction including functional abdominal pain and irritable bowel syndrome. Cognitive behavioral therapy (CBT) was delivered via telehealth with a licensed psychologist or supervised psychology trainee embedded in a pediatric gastroenterology clinic. Participants were 22 youth (mean age = 14.36 years) who received CBT via telehealth between February and September of 2021, after completing an initial evaluation between February and July of 2021. Patients completed reliable and valid self-report measures of functional disability and pain during treatment. A unique CBT model was employed with an initial focus on psychoeducation and function regardless of level of severity of functional impairment. Consistent with study hypotheses, nonparametric statistical analyses demonstrated statistically significant reductions in functional disability and pain following implementation of the CBT model via telehealth. Contrary to predictions, there was no relation found between severity of functional impairment and duration of treatment.

Investigating the impact of music therapy on two in-patient psychiatric wards for people living with dementia: retrospective observational study.

BACKGROUND: Music therapy can lift mood and reduce agitation for people living with dementia (PwD) in community and residential care settings, potentially reducing the prevalence of distress behaviours. However, less is known about the impact of music therapy on in-patient psychiatric wards for PwD. AIMS: To investigate the impact of music therapy on two in-patient psychiatric wards for PwD. METHOD: A mixed-methods design was used. Statistical analysis was conducted on incidents involving behaviours reported as 'disruptive and aggressive' in 2020, when music therapy delivery varied because of the COVID-19 pandemic. Semi-structured interviews conducted online with three music therapists and eight ward-based staff were analysed using reflexive thematic analysis. RESULTS: Quantitative findings showed a significant reduction in the frequency of behaviours reported as disruptive and aggressive on days with in-person music therapy (every 14 days) than on the same weekday with no or online music therapy (every 3.3 or 3.1 days, respectively). Qualitative findings support this, with music therapy reported by music therapists and staff members to be accessible and meaningful, lifting mood and reducing agitation, with benefits potentially lasting throughout the day and affecting the ward environment. CONCLUSIONS: We identified a significant reduction in the occurrence of distress behaviours on days with in-person music therapy when compared with no music therapy. Music therapy was reported to be a valuable intervention, supporting patient mood and reducing agitation. Interventional studies are needed to investigate the impact of music therapy and its optimum mode of delivery.

A multi-organoid platform identifies CIART as a key factor for SARS-CoV-2 infection.

COVID-19 is a systemic disease involving multiple organs. We previously established a platform to derive organoids and cells from human pluripotent stem cells to model SARS-CoV-2 infection and perform drug screens1,2. This provided insight into cellular tropism and the host response, yet the molecular mechanisms regulating SARS-CoV-2 infection remain poorly defined. Here we systematically examined changes in transcript profiles caused by SARS-CoV-2 infection at different multiplicities of infection for lung airway organoids, lung alveolar organoids and cardiomyocytes, and identified several genes that are generally implicated in controlling SARS-CoV-2 infection, including CIART, the circadian-associated repressor of transcription. Lung airway organoids, lung alveolar organoids and cardiomyocytes derived from isogenic CIART-/- human pluripotent stem cells were significantly resistant to SARS-CoV-2 infection, independently of viral entry. Single-cell RNA-sequencing analysis further validated the decreased levels of SARS-CoV-2 infection in ciliated-like cells of lung airway organoids. CUT&RUN, ATAC-seq and RNA-sequencing analyses showed that CIART controls SARS-CoV-2 infection at least in part through the regulation of NR4A1, a gene also identified from the multi-organoid analysis. Finally, transcriptional profiling and pharmacological inhibition led to the discovery that the Retinoid X Receptor pathway regulates SARS-CoV-2 infection downstream of CIART and NR4A1. The multi-organoid platform identified the role of circadian-clock regulation in SARS-CoV-2 infection, which provides potential therapeutic targets for protection against COVID-19 across organ systems.

The impact of influenza vaccination on surgical outcomes in COVID-19 positive patients: An analysis of 43,580 patients.

BACKGROUND: Multiple recent studies suggest a possible protective effect of the influenza vaccine against severe acute respiratory coronavirus 2 (SARS-CoV-2). This effect has yet to be evaluated in surgical patients. This study utilizes a continuously updated federated electronic medical record (EMR) network (TriNetX, Cambridge, MA) to analyze the influence of the influenza vaccine against post-operative complications in SARS-CoV-2-positive patients. METHODS: The de-identified records of 73,341,020 patients globally were retrospectively screened. Two balanced cohorts totaling 43,580 surgical patients were assessed from January 2020-January 2021. Cohort One received the influenza vaccine six months-two weeks prior to SARS-CoV-2-positive diagnosis, while Cohort Two did not. Post-operative complications within 30, 60, 90, and 120 days of undergoing surgery were analyzed using common procedural terminology(CPT) codes. Outcomes were propensity score matched for characteristics including age, race, gender, diabetes, obesity, and smoking. RESULTS: SARS-CoV-2-positive patients receiving the influenza vaccine experienced significantly decreased risks of sepsis, deep vein thrombosis, dehiscence, acute myocardial infarction, surgical site infections, and death across multiple time points(p<0.05, Bonferroni Correction p = 0.0011). Number needed to vaccinate (NNV) was calculated for all significant and nominally significant findings. CONCLUSION: Our analysis examines the potential protective effect of influenza vaccination in SARS-CoV-2-positive surgical patients. Limitations include this study's retrospective nature and reliance on accuracy of medical coding. Future prospective studies are warranted to confirm our findings.

Transcriptional reprogramming of infiltrating neutrophils drives lung disease in severe COVID-19 despite low viral load.

Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths confined to Black/African American (AA) patients in some areas. Nevertheless, targeted studies within this vulnerable population are scant. Here, we applied multi-omics single-cell analyses of immune profiles from matching airways and blood samples of Black/AA patients during acute SARS-CoV-2 infection. Transcriptional reprogramming of infiltrating IFITM2+/S100A12+ mature neutrophils, likely recruited via the IL-8/CXCR2 axis, led to a persistent and self-sustaining pulmonary neutrophilia with advanced features of acute respiratory distress syndrome (ARDS) despite low viral load in the airways. In addition, exacerbated neutrophil production of IL-8, IL-1ß, IL-6, and CCL3/4, along with elevated levels of neutrophil elastase and myeloperoxidase, were the hallmarks of a transcriptionally active and pathogenic airway neutrophilia. Although our analysis was limited to Black/AA patients and was not designed as a comparative study across different ethnicities, we present an unprecedented in-depth analysis of the immunopathology that leads to ARDS in a well-defined patient population disproportionally affected by severe COVID-19.

Trends in Incident Pediatric Diabetes and the COVID-19 Pandemic

Objectives To identify trends in presentation and incidence of pediatric new-onset type 1 diabetes (T1D) and type 2 diabetes (T2D) during the COVID-19 pandemic. Methods Demographics, anthropometrics, and initial labs from patients ages 0-21 who presented with new-onset diabetes to a pediatric tertiary care center were recorded over a three-year time period from April 1, 2018 until March 31, 2021. Time periods were separated as follows: April 1, 2018- March 31, 2019, April 1, 2019- March 31, 2020, and April 1, 2020- March 31, 2021. The final time period represents the COVID-19 pandemic. Microsoft Excel (2016) was used to calculate descriptive statistics (eg. Mean, standard deviations) and perform statistical analysis of continuous variables (eg. ANOVA). Statistical analysis of categorical variables (eg. sex, race, ethnicity) was performed by Chi-squared test or Fisher's exact test using R studio version 3.5.2. Cochran Armitage tests were performed to assess for trends in severity of diabetic patients from 2018 to 2020 and to determine if COVID-19 impacted diabetes severity using R (version 1.4.1106) and the DescTools package. Results In total, 207 patients were diagnosed with incident diabetes from April 2018 through March 2021, 108 with T1D and 86 with T2D. During the pandemic incident cases of pediatric T1D increased from 31 in each of the prior two years to 46;an increase of 48%. The number of patients with T1D presenting with mild diabetic ketoacidosis (DKA) significantly increased from 6% to 23% (p-value = 0.027). Incident cases of pediatric T2D increased by 231% from 2019 to 2020. The rate of patients with T2D presenting in DKA increased overall from 12% (n=2) in 2018 and 6% (n=1) in 2019, to 23% in 2020 (n=12), an increase of 91.7% from 2018 to 2020 . Furthermore, patients with T2D presenting with mild DKA increased by 116%. Prior to the pandemic, incident cases of T2D accounted for 35% of all newly diagnosed pediatric diabetes cases. During the pandemic, for the first time, incident cases of T2D accounted for more than half of the all newly diagnosed pediatric diabetes cases (53%). Conclusions There were more incident pediatric T1D and T2D cases as well as an increase in DKA at presentation during the COVID-19 pandemic. More importantly, incident T2D cases were higher than the incident T1D during the pandemic. This clearly suggests a disruption and change in the childhood diabetes trends with profound individual and community health consequences.

Transcriptional reprogramming of infiltrating neutrophils drives lung disease in severe COVID-19 despite low viral load

Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths confined to Black/African American (AA) patients in some areas. Nevertheless, targeted studies within this vulnerable population are scant. Here, we applied multi-omics single-cell analyses of immune profiles from matching airways and blood samples of Black/AA patients during acute SARS-CoV-2 infection. Transcriptional reprogramming of infiltrating IFITM2+/S100A12+ mature neutrophils, likely recruited via the IL-8/CXCR2 axis, led to a persistent and self-sustaining pulmonary neutrophilia with advanced features of acute respiratory distress syndrome (ARDS) despite low viral load in the airways. In addition, exacerbated neutrophil production of IL-8, IL-1β, IL-6, and CCL3/4, along with elevated levels of neutrophil elastase and myeloperoxidase, were the hallmarks of a transcriptionally active and pathogenic airway neutrophilia. Although our analysis was limited to Black/AA patients and was not designed as a comparative study across different ethnicities, we present an unprecedented in-depth analysis of the immunopathology that leads to ARDS in a well-defined patient population disproportionally affected by severe COVID-19.

An Increase in Same-day Discharge After Total Joint Arthroplasty During the COVID-19 Pandemic Does Not Influence Patient Outcomes: A Retrospective Cohort Analysis.

Background: The coronavirus disease 2019 (COVID-19) pandemic caused major transitions in total joint arthroplasty (TJA), notably with the increased utilization of same-day discharge (SDD) pathways. This study assessed the effect of accelerated discharge pathways following the resumption of elective cases during the COVID-19 pandemic on SDD rates, adverse events, and characteristics associated with successful SDD following total hip and total knee arthroplasty. Methods: This retrospective study split patients into cohorts: TJA prior to COVID-19 (pre-COVID, July 2019-December 2019) and TJA following the resumption of elective surgeries (post-COVID, July 2020-December 2020). Patient characteristics such as age, sex, body mass index, American Society of Anesthesiologists score, and pertinent comorbidities were analyzed, and length of stay, 30-day emergency department (ED) visit rates, readmissions, and reoperations were compared. Results: A total of 1333 patients met inclusion criteria that were divided into pre-COVID (692) and post-COVID (641) cohorts. The pre-COVID group had a median age of 69 years (interquartile range 63-76), and the post-COVID group had a median age of 68 years (interquartile range 61-75) (P = .024). SDD increased from 0.1% to 28.9% (P < .001), and length of stay decreased from 1.3 days to 0.89 days (P < .001). There was no change in 30-day ED visits, readmissions, or reoperations (P = .817, P = .470, and P = .643, respectively). There was no difference in ED visits, readmissions, or reoperations in SDD patients. The odds of SDD were associated with age (P < .001, odds ratio [OR] = 0.94), body mass index (P = .006, OR = 0.95), male sex (P < .001, OR = 1.83), and history of tobacco use (P < .001, OR = 1.87). Conclusions: At our institution, the COVID-19 pandemic accelerated the utilization of SDD pathways without increasing ED visits, readmissions, or reoperations.