Plasma proteomic evidence for increased Alzheimer's disease-related brain pathology after SARS-CoV-2 infection (preprint)

Viral infections have been linked to an increased risk for dementia. We investigated whether SARS-CoV-2 infection increases preclinical brain pathology associated with Alzheimer's disease (AD) by comparing changes in plasma biomarkers in UK Biobank participants with and without prior SARS-CoV-2 infection. We discovered an association between SARS-CoV-2 infection and reduced plasma A{beta}42:A{beta}40 concentration ratio. In older participants, SARS-CoV-2 infection was associated with both lower plasma A{beta}42 and higher plasma pTau-181. These biomarker changes, which have been associated with beta-amyloid accumulation and prodromal AD, were associated with increased brain imaging signatures of AD, poorer cognitive scores, and worse assessments of overall health and appeared to be greater in participants who had been hospitalised with COVID-19. Protein biomarker risk scores for other diseases were also raised among individuals who had past SARS-CoV-2 infections. Our data provide support for the hypothesis that viral infections can accelerate prodromal AD pathology and highlight biomarker profiles indicative of an increased risk of dementia and systemic diseases after SARS-CoV-2 infection, particularly in older people.

Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19 (preprint)

The most common cause of death due to COVID-19 remains respiratory failure. Yet, our understanding of the precise cellular and molecular changes underlying lung alveolar damage is limited. Here, we integrate single cell transcriptomic data of COVID-19 donor lungs with spatial transcriptomic data stratifying histopathological stages of diffuse alveolar damage (DAD). We identify changes in cellular composition across progressive DAD, including waves of molecularly distinct macrophages and depleted epithelial and endothelial populations throughout different types of tissue damage. Predicted markers of pathological states identify immunoregulatory signatures, including IFN-alpha and metallothionein signatures in early DAD, and fibrosis-related collagens in organised DAD. Furthermore, we predict a fibrinolytic shutdown via endothelial upregulation of SERPINE1/PAI-1. Cell-cell interaction analysis revealed macrophage-derived SPP1/osteopontin signalling as a key regulator during early DAD. These results provide the first comprehensive, spatially resolved atlas of DAD stages, highlighting the cellular mechanisms underlying pro-inflammatory and pro-fibrotic pathways across alveolar damage progression.

Durable immunity to SARS-CoV-2 in both lower and upper airways achieved with a gorilla adenovirus (GRAd) S-2P vaccine in non-human primates (preprint)

SARS-CoV-2 continues to pose a global threat, and current vaccines, while effective against severe illness, fall short in preventing transmission. To address this challenge, theres a need for vaccines that induce mucosal immunity and can rapidly control the virus. In this study, we demonstrate that a single immunization with a novel gorilla adenovirus-based vaccine (GRAd) carrying the pre-fusion stabilized Spike protein (S-2P) in non-human primates provided protective immunity for over one year against the BA.5 variant of SARS-CoV-2. A prime-boost regimen using GRAd followed by adjuvanted S-2P (GRAd+S-2P) accelerated viral clearance in both the lower and upper airways. GRAd delivered via aerosol (GRAd(AE)+S-2P) modestly improved protection compared to its matched intramuscular regimen, but showed dramatically superior boosting by mRNA and, importantly, total virus clearance in the upper airway by day 4 post infection. GrAd vaccination regimens elicited robust and durable systemic and mucosal antibody responses to multiple SARS-CoV-2 variants, but only GRAd(AE)+S-2P generated long-lasting T cell responses in the lung. This research underscores the flexibility of the GRAd vaccine platform to provide durable immunity against SARS-CoV-2 in both the lower and upper airways.

Mucosal Adenoviral-vectored Vaccine Boosting Durably Prevents XBB.1.16 Infection in Nonhuman Primates (preprint)

Waning immunity and continued virus evolution have limited the durability of protection from symptomatic infection mediated by intramuscularly (IM)-delivered mRNA vaccines against COVID-19 although protection from severe disease remains high. Mucosal vaccination has been proposed as a strategy to increase protection at the site of SARS-CoV-2 infection by enhancing airway immunity, potentially reducing rates of infection and transmission. Here, we compared protection against XBB.1.16 virus challenge 5 months following IM or mucosal boosting in non-human primates (NHP) that had previously received a two-dose mRNA-1273 primary vaccine regimen. The mucosal boost was composed of a bivalent chimpanzee adenoviral-vectored vaccine encoding for both SARS-CoV-2 WA1 and BA.5 spike proteins (ChAd-SARS-CoV-2-S) and delivered either by an intranasal mist or an inhaled aerosol. An additional group of animals was boosted by the IM route with bivalent WA1/BA.5 spike-matched mRNA (mRNA-1273.222) as a benchmark control. NHP were challenged in the upper and lower airways 18 weeks after boosting with XBB.1.16, a heterologous Omicron lineage strain. Cohorts boosted with ChAd-SARS-CoV-2-S by an aerosolized or intranasal route had low to undetectable virus replication as assessed by levels of subgenomic SARS-CoV-2 RNA in the lungs and nose, respectively. In contrast, animals that received the mRNA-1273.222 boost by the IM route showed minimal protection against virus replication in the upper airway but substantial reduction of virus RNA levels in the lower airway. Immune analysis showed that the mucosal vaccines elicited more durable antibody and T cell responses than the IM vaccine. Protection elicited by the aerosolized vaccine was associated with mucosal IgG and IgA responses, whereas protection elicited by intranasal delivery was mediated primarily by mucosal IgA. Thus, durable immunity and effective protection against a highly transmissible heterologous variant in both the upper and lower airways can be achieved by mucosal delivery of a virus-vectored vaccine. Our study provides a template for the development of mucosal vaccines that limit infection and transmission against respiratory pathogens. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/565765v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@d49b9dorg.highwire.dtl.DTLVardef@347455org.highwire.dtl.DTLVardef@1c1a196org.highwire.dtl.DTLVardef@1579130_HPS_FORMAT_FIGEXP M_FIG C_FIG

Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial.

Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 h from injury were randomized to receive either riluzole, at an oral dose of 100 mg twice per day (BID) for the first 24 h followed by 50 mg BID for the following 13 days, or placebo. The primary efficacy end-point was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the riluzole-treated patients compared with placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor scores (CI: -6.79-12.52). No drug-related serious adverse events were associated with the use of riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, riluzole was associated with significant improvement in total motor scores (estimate: standard error [SE] 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the Spinal Cord Independence Measure score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the Short Form 36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received riluzole had a higher average gain in neurological levels at 6 months compared with placebo (mean 0.50 levels gained vs. 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.

SARS-CoV-2 seroprevalence among blood donors in Uganda: 2019-2022.

BACKGROUND: The true burden of COVID-19 in low- and middle-income countries remains poorly characterized, especially in Africa. Even prior to the availability of SARS-CoV-2 vaccines, countries in Africa had lower numbers of reported COVID-19 related hospitalizations and deaths than other regions globally. METHODS: Ugandan blood donors were evaluated between October 2019 and April 2022 for IgG antibodies to SARS-CoV-2 nucleocapsid (N), spike (S), and five variants of the S protein using multiplexed electrochemiluminescence immunoassays (MesoScale Diagnostics, Rockville, MD). Seropositivity for N and S was assigned using manufacturer-provided cutoffs and trends in seroprevalence were estimated by quarter. Statistically significant associations between N and S antibody seropositivity and donor characteristics in November-December 2021 were assessed by chi-square tests. RESULTS: A total of 5393 blood unit samples from donors were evaluated. N and S seropositivity increased throughout the pandemic to 82.6% in January-April 2022. Among seropositive individuals, N and S antibody levels increased ≥9-fold over the study period. In November-December 2021, seropositivity to N and S antibody was higher among repeat donors (61.3%) compared with new donors (55.1%; p = .043) and among donors from Kampala (capital city of Uganda) compared with rural regions (p = .007). Seropositivity to S antibody was significantly lower among HIV-seropositive individuals (58.8% vs. 84.9%; p = .009). CONCLUSIONS: Despite previously reported low numbers of COVID-19 cases and related deaths in Uganda, high SARS-CoV-2 seroprevalence and increasing antibody levels among blood donors indicated that the country experienced high levels of infection over the course of the pandemic.

RBD-based high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways (preprint)

SARS-CoV-2 has the capacity to evolve mutations to escape vaccine-and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool. Here, we challenged rhesus macaques with SARS-CoV-2 Delta and simultaneously treated them with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment gave equivalent protection in upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 did not block the development of memory responses to Delta and did not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome

Human immunodeficiency virus (HIV)-1, the virus that causes HIV infection and acquired immunodeficiency syndrome (AIDS), has caused cases of infection recognized in the United States since the late 1970s. As scientists seek a cure for HIV, much has been learned about the interaction of the virus and the immune system. Recent advances in therapies used as tools for HIV treatment and prevention have resulted in a worldwide decrease in new infections, and public health campaigns are aimed at reducing new cases to a level signaling the end of the HIV epidemic. While organs and tissue systems may be damaged not only by HIV but also by the treatment of HIV with antiretroviral medications, people living with HIV can live a normal life span with appropriate medical management. The new epidemic affecting humankind, the novel coronavirus disease that emerged in 2019 (COVID-19) caused by the severe acute respiratory syndrome (SARS) coronavirus-2 (CoV-2), is disrupting HIV treatment and prevention programs worldwide and has laid bare health and healthcare disparities and inequalities existing in rich and poor countries alike. The effects of the COVID-19 pandemic on the HIV epidemic have yet to be realized. © 2023 Elsevier Ltd. All rights reserved.

The Great Contrast Shortage of 2022-Lessons learnt in Australia.

INTRODUCTION: Computed tomography (CT) imaging is one of the most commonly used diagnostic tools. Iodine-based contrast media (IBCM) are frequently administered intravenously to improve soft tissue contrast in a wide range of CT scans. Supply chain disruptions triggered by the SARS-CoV-19 pandemic led to a global shortage of IBCM in mid-2022. The purpose of this study was to explore the impact of this shortage on the delivery of healthcare in Western Australia. METHODS: We performed a single-centre retrospective analysis of the provision of CT studies, comparing historical patterns to the shortage period. We focussed our attention on the total number of CT scans (noncontrast CT [NCCT] and contrast-enhanced CT [CECT]) and also specifically CT pulmonary angiogram (CTPA) and CT neck angiogram with or without inclusion of circle of Willis (CTNA) examinations. We also examined whether a decrease was compensated by increasing frequency of alternate examinations such as ventilation/perfusion (V/Q) scans, carotid Doppler ultrasound studies and Magnetic Resonance Angiograms (MRAs). RESULTS: Since 2012, there has been an approximate linear increase in the frequency of CT examinations. During the period of contrast shortage, there was an abrupt drop-off by approximately 50% in the CECT, CTPA and CTNA groups compared with the preceding 6 weeks (49%, 55% and 44%, respectively, with P < 0.001 in all cases). During the contrast shortage, the frequency of V/Q scans increased fivefold (from 13 to 65; P < 0.001). However, the provision of carotid Doppler ultrasound studies and MRAs remained approximately stable in frequency across recent time intervals. CONCLUSION: Our findings demonstrate that the IBCM shortage crisis had a very significant impact on the delivery of healthcare. While V/Q scans could (partially) substitute for CTPA studies in suspected pulmonary emboli, there appeared to be no valid alternative for CTNA studies in stroke calls. The unexpected and critical shortage of IBCM forced healthcare professionals to conserve resources, prioritise indications, triage patients based on risk, explore alternate imaging strategies and prepare for similar events recurring in the future.

Late-presenting Plasmodium falciparum Malaria in a Non-Endemic Setting During COVID-19 Travel Restrictions.

We report a case of febrile Plasmodium falciparum malaria in a 36-year-old male patient occurring 14 years after immigration from and more than 12 months since a return visit to the endemic area. The critical need for awareness regarding late presentations of P. falciparum is discussed.

Substance Use Among Physician Assistant Students: A National Study on the Prevalence of Alcohol, Tobacco, Illicit Substances, and Medication Use.

INTRODUCTION: The purpose of this study was to discover the substance use prevalence among physician assistant students (PA-S) compared with the age-relevant general US population and to examine the frequency of stress, burnout, anxiety, and depression during the didactic and clinical phases, while accounting for the impact of the COVID-19 pandemic. METHODS: A 20-item survey instrument was created. Self-reported data included demographics, anxiety, burnout, tobacco, illicit substances, and prescription medication use. Outcome-based inventories included a modified Perceived Stress Scale, Patient Health Questionnaire-2 (PHQ-2), and Alcohol Use Disorder Identification Test-Concise. The survey was emailed to all US programs (∼270 programs; ∼25,000 students), with 54 programs approving dissemination to their students (n∼4,760). RESULTS: Of the 1432 responses (30% response rate, 96% completion rate), the final validated sample was 1378 students (56.1% didactic, 43.8% clinical). When compared with the national population, PA-S prevalence for tobacco (5.2%) and illicit substance use (9.9%) were notably lower; alcohol (53.5%) was comparable; and prescription medication (7.0%) is only reported for PA students due to the lack of a national comparison. A higher frequency of substance use was observed during the didactic (52.5%) vs clinical (47.5%) phases. Stress was the dominant factor in both phases (93.5% didactic, 86.1% clinical). Respondents reported that the COVID-19 pandemic had minimal impact on reported rates, other than alcohol. DISCUSSION: Although PA-S substance use prevalence is at or below the national population, PA programs are encouraged to review their policies and provide conversations and resources for students who may have one or more risk factors and experience a negative effect from current substance use.

Clinically stable covid-19 patients presenting to acute unscheduled episodic care venues have increased risk of hospitalization: secondary analysis of a randomized control trial.

BACKGROUND: Assessment for risks associated with acute stable COVID-19 is important to optimize clinical trial enrollment and target patients for scarce therapeutics. To assess whether healthcare system engagement location is an independent predictor of outcomes we performed a secondary analysis of the ACTIV-4B Outpatient Thrombosis Prevention trial. METHODS: A secondary analysis of the ACTIV-4B trial that was conducted at 52 US sites between September 2020 and August 2021. Participants were enrolled through acute unscheduled episodic care (AUEC) enrollment location (emergency department, or urgent care clinic visit) compared to minimal contact (MC) enrollment (electronic contact from test center lists of positive patients).We report the primary composite outcome of cardiopulmonary hospitalizations, symptomatic venous thromboembolism, myocardial infarction, stroke, transient ischemic attack, systemic arterial thromboembolism, or death among stable outpatients stratified by enrollment setting, AUEC versus MC. A propensity score for AUEC enrollment was created, and Cox proportional hazards regression with inverse probability weighting (IPW) was used to compare the primary outcome by enrollment location. RESULTS: Among the 657 ACTIV-4B patients randomized, 533 (81.1%) with known enrollment setting data were included in this analysis, 227 from AUEC settings and 306 from MC settings. In a multivariate logistic regression model, time from COVID test, age, Black race, Hispanic ethnicity, and body mass index were associated with AUEC enrollment. Irrespective of trial treatment allocation, patients enrolled at an AUEC setting were 10-times more likely to suffer from the adjudicated primary outcome, 7.9% vs. 0.7%; p < 0.001, compared with patients enrolled at a MC setting. Upon Cox regression analysis adjustment patients enrolled at an AUEC setting remained at significant risk of the primary composite outcome, HR 3.40 (95% CI 1.46, 7.94). CONCLUSIONS: Patients with clinically stable COVID-19 presenting to an AUEC enrollment setting represent a population at increased risk of arterial and venous thrombosis complications, hospitalization for cardiopulmonary events, or death, when adjusted for other risk factors, compared with patients enrolled at a MC setting. Future outpatient therapeutic trials and clinical therapeutic delivery programs of clinically stable COVID-19 patients may focus on inclusion of higher-risk patient populations from AUEC engagement locations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498273.

Scotland's "Incentivised Laparoscopy Practice" programme: Engaging trainees with take-home laparoscopy simulation.

BACKGROUND: The transfer validity of portable laparoscopy simulation is well established. However, attempts to integrate take-home simulation into surgical training have met with inconsistent engagement worldwide, as for example in our 2014-15 study of an Incentivised Laparoscopy Practice programme (ILPv1). Drawing on learning from our subsequent multi-centre study examining barriers and facilitators, we revised the programme for 2018 onwards. We now report on engagement with the 2018-2022 versions of this home-based simulation programme (ILP v2.1-2.3). METHODS: In ILP v2.1-2.3, three consecutive year-groups of new-start Core Surgical Trainees (n = 48, 46 and 53) were loaned portable simulators. The 6-month education programme included induction, technical support, and intermittent feedback. Six tasks were prescribed, with video instruction and charting of metric scores. Video uploads were required and scored by faculty. A pass resulted in an eCertificate, expected at Annual Review (but not mandatory for progression). ILP was set within a wider reform, "Improving Surgical Training". RESULTS: ILP v2.1-2.3 saw pass rates of 94%, 76% and 70% respectively (45/48, 35/46 and 37/53 trainees), compared with only 26% (7/27) in ILP v1, despite now including some trainees not intending careers in laparoscopic specialties. The ILP v2.2 group all reported their engagement with the whole simulation strategy was hampered by the COVID19 pandemic. CONCLUSIONS: Simply providing take-home simulators, no matter how good, is not enough. To achieve trainee engagement, a whole programme is required, with motivated learners, individual and group practice, intermittent feedback, and clear goals and assessments. ILP is a complex intervention, best understood as a "reform within a reform, within a context."

Relation of Incident Type 1 Diabetes to Recent COVID-19 Infection: Cohort Study Using e-Health Record Linkage in Scotland.

OBJECTIVE: Studies using claims databases reported that SARS-CoV-2 infection >30 days earlier was associated with an increase in the incidence of type 1 diabetes. Using exact dates of diabetes diagnosis from the national register in Scotland linked to virology laboratory data, we sought to replicate this finding. RESEARCH DESIGN AND METHODS: A cohort of 1,849,411 individuals aged <35 years without diabetes, including all those in Scotland who subsequently tested positive for SARS-CoV-2, was followed from 1 March 2020 to 22 November 2021. Incident type 1 diabetes was ascertained from the national registry. Using Cox regression, we tested the association of time-updated infection with incident diabetes. Trends in incidence of type 1 diabetes in the population from 2015 through 2021 were also estimated in a generalized additive model. RESULTS: There were 365,080 individuals who had at least one detected SARS-CoV-2 infection during follow-up and 1074 who developed type 1 diabetes. The rate ratio for incident type 1 diabetes associated with first positive test for SARS-CoV-2 (reference category: no previous infection) was 0.86 (95% CI 0.62, 1.21) for infection >30 days earlier and 2.62 (95% CI 1.81, 3.78) for infection in the previous 30 days. However, negative and positive SARS-CoV-2 tests were more frequent in the days surrounding diabetes presentation. In those aged 0-14 years, incidence of type 1 diabetes during 2020-2021 was 20% higher than the 7-year average. CONCLUSIONS: Type 1 diabetes incidence in children increased during the pandemic. However, the cohort analysis suggests that SARS-CoV-2 infection itself was not the cause of this increase.

Sparse spatially clustered coefficient model via adaptive regularization.

Large spatial datasets with many spatial covariates have become ubiquitous in many fields in recent years. A question of interest is to identify which covariates are likely to influence a spatial response, and whether and how the effects of these covariates vary across space, including potential abrupt changes from region to region. To solve this question, a new efficient regularized spatially clustered coefficient (RSCC) regression approach is proposed, which could achieve variable selection and identify latent spatially heterogeneous covariate effects with clustered patterns simultaneously. By carefully designing the regularization term of RSCC as a chain graph guided fusion penalty plus a group lasso penalty, the RSCC model is computationally efficient for large spatial datasets while still achieving the theoretical guarantees for estimation. RSCC also adopts the idea of adaptive learning to allow for adaptive weights and adaptive graphs in its regularization terms and further improves the estimation performance. RSCC is applied to study the acceptance of COVID-19 vaccines using county-level data in the United States and discover the determinants of vaccination acceptance with varying effects across counties, revealing important within-state and across-state spatially clustered patterns of covariates effects.

Risk factors of postoperative intensive care unit admission during the COVID-19 pandemic: A multicentre retrospective cohort study.

Background: During the Coronavirus disease 2019 (COVID-19) pandemic, intensive care unit (ICU) capacity was scarce. Since surgical patients also require ICU admission, determining which factors lead to an increased risk of postoperative ICU admission is essential. This study aims to determine which factors led to an increased risk of unplanned postoperative ICU admission during the COVID-19 pandemic. Methods: This multicentre retrospective cohort study investigated all patients who underwent surgery between 9 March 2020 and 30 June 2020. The primary endpoint was the number of surgical patients requiring postoperative ICU admission. The secondary endpoint was to determine factors leading to an increased risk of unplanned postoperative ICU admission, calculated by multivariate analysis with odds ratios (OR's) and 95% confidence (CI) intervals. Results: One hundred eighty-five (4.6%) of the 4051 included patients required unplanned postoperative ICU admission. COVID-19 positive patients were at an increased risk of being admitted to the ICU compared to COVID-19 negative (OR 3.14; 95% CI 1.06-9.33; p = 0.040) and untested patients (OR 0.48; 95% CI 0.32-0.70; p = 0.001). Other predictors were male gender (OR 1.36; 95% CI 1.02-1.82; p = 0.046), body mass index (BMI) (OR 1.05; 95% CI 1.02-1.08; p = 0.001), surgical urgency and surgical discipline. Conclusion: A confirmed COVID-19 infection, male gender, elevated BMI, surgical urgency, and surgical discipline were independent factors for an increased risk of unplanned postoperative ICU admission. In the event of similar pandemics, postponing surgery in patients with an increased risk of postoperative ICU admission may be considered.

The human E3 ligase RNF185 is a regulator of the SARS-CoV-2 envelope protein.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks multiple human proteins during infection and viral replication. To examine whether any viral proteins employ human E3 ubiquitin ligases, we evaluated the stability of SARS-CoV-2 proteins with inhibition of the ubiquitin proteasome pathway. Using genetic screens to dissect the molecular machinery involved in the degradation of candidate viral proteins, we identified human E3 ligase RNF185 as a regulator of protein stability for the SARS-CoV-2 envelope protein. We found that RNF185 and the SARS-CoV-2 envelope co-localize to the endoplasmic reticulum (ER). Finally, we demonstrate that the depletion of RNF185 significantly increases SARS-CoV-2 viral titer in a cellular model. Modulation of this interaction could provide opportunities for novel antiviral therapies.

Technegas, A Universal Technique for Lung Imaging in Nuclear Medicine: Technology, Physicochemical Properties, and Clinical Applications.

Technegas was developed in Australia as an imaging radioaerosol in the late 1980s and is now commercialized by Cyclomedica, Pty Ltd. for diagnosing pulmonary embolism (PE). Technegas is produced by heating technetium-99m in a carbon crucible for a few seconds at high temperatures (2750 °C) to generate technetium-carbon nanoparticles with a gas-like behaviour. The submicron particulates formed allow easy diffusion to the lung periphery when inhaled. Technegas has been used for diagnosis in over 4.4 m patients across 60 countries and now offers exciting opportunities in areas outside of PE, including asthma and chronic obstructive pulmonary disease (COPD). The Technegas generation process and the physicochemical attributes of the aerosol have been studied over the past 30 years in parallel with the advancement in different analytical methodologies. Thus, it is now well established that the Technegas aerosol has a radioactivity aerodynamic diameter of <500 nm and is composed of agglomerated nanoparticles. With a plethora of literature studying different aspects of Technegas, this review focuses on a historical evaluation of the different methodologies' findings over the years that provides insight into a scientific consensus of this technology. Also, we briefly discuss recent clinical innovations using Technegas and a brief history of Technegas patents.

Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils.

The self-assembly of the Nucleocapsid protein (NCAP) of SARS-CoV-2 is crucial for its function. Computational analysis of the amino acid sequence of NCAP reveals low-complexity domains (LCDs) akin to LCDs in other proteins known to self-assemble as phase separation droplets and amyloid fibrils. Previous reports have described NCAP's propensity to phase-separate. Here we show that the central LCD of NCAP is capable of both, phase separation and amyloid formation. Within this central LCD we identified three adhesive segments and determined the atomic structure of the fibrils formed by each. Those structures guided the design of G12, a peptide that interferes with the self-assembly of NCAP and demonstrates antiviral activity in SARS-CoV-2 infected cells. Our work, therefore, demonstrates the amyloid form of the central LCD of NCAP and suggests that amyloidogenic segments of NCAP could be targeted for drug development.

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome.

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2-41.2) vs. 32.1 (26.8-38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated. In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.