Prolonged airway explant culture enables study of health, disease, and viral pathogenesis (preprint)

In vitro models play a major role in studying airway physiology and disease. However, the native lungs complex tissue architecture and non-epithelial cell lineages are not preserved in these models. Ex vivo tissue models could overcome in vitro limitations, but methods for long-term maintenance of ex vivo tissue has not been established. We describe methods to culture human large airway explants, small airway explants, and precision-cut lung slices for at least 14 days. Human airway explants recapitulate genotype-specific electrophysiology, characteristic epithelial, endothelial, stromal and immune cell populations, and model viral infection after 14 days in culture. These methods also maintain mouse, rabbit, and pig tracheal explants. Notably, intact airway tissue can be cryopreserved, thawed, and used to generate explants with recovery of function 14 days post-thaw. These studies highlight the broad applications of airway tissue explants and their use as translational intermediates between in vitro and in vivo studies.

The Accuracy of Wearable Photoplethysmography Sensors for Telehealth Monitoring: A Scoping Review.

Background and Objectives: Photoplethysmography (PPG) sensors have been increasingly used for remote patient monitoring, especially during the COVID-19 pandemic, for the management of chronic diseases and neurological disorders. There is an urgent need to evaluate the accuracy of these devices. This scoping review considers the latest applications of wearable PPG sensors with a focus on studies that used wearable PPG sensors to monitor various health parameters. The primary objective is to report the accuracy of the PPG sensors in both real-world and clinical settings. Methods: This scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Studies were identified by querying the Medline, Embase, IEEE, and CINAHL databases. The goal was to capture eligible studies that used PPG sensors to monitor various health parameters for populations with a minimum of 30 participants, with at least some of the population having relevant health issues. A total of 2,996 articles were screened and 28 are included in this review. Results: The health parameters and disorders identified and investigated in this study include heart rate and heart rate variability, atrial fibrillation, blood pressure (BP), obstructive sleep apnea, blood glucose, heart failure, and respiratory rate. An overview of the algorithms used, and their limitations is provided. Conclusion: Some of the barriers identified in evaluating the accuracy of multiple types of wearable devices include the absence of reporting standard accuracy metrics and a general paucity of studies with large subject size in real-world settings, especially for parameters such as BP.

Using Twitter to Understand COVID-19 Vaccine-Related Ageism during the Pandemic.

BACKGROUND AND OBJECTIVES: During the rollout of COVID-19 vaccines, older adults in high-income countries were often prioritized for inoculation in efforts to reduce COVID-19 related mortality. However, this prioritization may have contributed to intergenerational tensions and ageism, particularly with the limited supply of COVID-19 vaccines. This study examines Twitter discourse to understand vaccine-related ageism during the COVID-19 pandemic to inform future vaccination policies and practices to reduce ageism. RESEARCH DESIGN AND METHODS: We collected 1,369 relevant tweets on Twitter using the Twint application in Python from December 8, 2020 to December 31, 2021. Tweets were analyzed using thematic analysis, and steps were taken to ensure rigor. RESULTS: Our research identified four main themes including: i) blame and hostility: 'It's all their fault'; ii) incompetence and misinformation: 'clueless boomer'; iii) ageist political slander; and iv) combatting ageism: advocacy and accessibility. DISCUSSION AND IMPLICATIONS: Our findings exposed issues of victim-blaming, hate speech, pejorative content, and ageist political slander that is deepening the divide of intergenerational conflict. Although a subset of tweets countered negative outcomes and demonstrated intergenerational solidarity, our findings suggest that ageism may have contributed to COVID-19 vaccine hesitancy among older adults. Consequently, urgent action is needed to counter vaccine misinformation, prohibit aggressive messaging, and promote intergenerational unity during the COVID-19 pandemic and beyond.

Sizing Horizontal Geothermal Heat Exchangers for Community Greenhouses in Montreal

Community greenhouses are important for the production of local food and reduction of food supply insecurities within cities. As we've seen with Covid-19, pandemics highlight the criticality of local food access to underprivileged urban districts. Since almost 60 % of the energy used in greenhouses is spent in heating and cooling, ground heat exchangers (GHEs) can play a significant role in supplying temperature regulation, but geothermal heat pump systems tend to be expensive for community organizations. An efficient way to reduce GHEs installation costs is to dig trenches to install the system horizontally and cover a part of heating and cooling loads only. In order to ensure cost effectiveness and optimize operations, this type of system was studied for urban greenhouses where ground space can be limited. Sizing calculations were performed for GHEs of a 7.62 m x 15.24 m greenhouse located on the Island of Montreal where the annual, monthly, and hourly energy consumption were estimated from previous building simulations. Three scenarios were used to specify sizing of the system in terms of excavation dimensions and percentage of the greenhouse peak loads covered;(1) number and length of trenches required for a horizontal GHE (HGHE) covering 100% of cooling and heating loads;(2) number and length of trenches required for an HGHE to cover 100% of peak heating loads and 60% of peak cooling loads and;(3) the percentage of heating and cooling peak loads that can be covered by an HGHE located under the greenhouse with similar dimensions (around 116 m2). Estimated excavation dimensions for cases 1 and 2 are 51.8 m x 8 m (414.4 m2) and 40.8 m x 8 m (326.4 m2). Estimated percentage of peak loads covered for case 3 is 40% of heating peak loads and 30% of cooling peak loads. © 2022 Geothermal Resources Council. All rights reserved.

The Effect of COVID-19 on Spine Surgery.

STUDY DESIGN/SETTING: Retrospective cohort analysis. OBJECTIVES: To characterize the impact of COVID-19 on utilization of the ten most common spine procedures and percentages of outpatient procedures. METHODS: The PearlDiver national database was queried from January 2010 to April 2021 for short (<6 segments) and long segment posterior instrumented fusion (≥6 segments), posterior cervical fusion, anterior cervical decompression and fusion (ACDF), cervical laminectomy, laminoplasty, and disc arthroplasty, lumbar laminectomy, microdiscectomy, and interbody fusion. Annual procedure utilization between January 2010 through April 2021 was recorded and compared. Monthly trends were compared to January 2020. Outpatient trends were compared between 2010-2019 and 2019-2021 using segmented linear regression. RESULTS: Overall, all ten procedures decreased 4.3% in 2020 compared to 2019 and increased 6.3% in 2021 compared to 2019. March and April of 2020 had the largest decreases, with March 2020 decreasing 18.2% and April 2020 decreasing 51.6% compared to January 2020. Despite increasing COVID cases in January 2021, overall procedure utilization decreased only 1.8% compared to January 2020, and increased later in 2021 with April 2021 case volumes increasing by 138% compared to January 2020. Outpatient utilization of short segment posterior lumbar fusion and lumbar interbody fusion significantly increased during this time (P < .001). CONCLUSION: The greatest impact on spine surgery volume from the COVID-19 pandemic occurred in March and April 2020. Spine procedure utilization was otherwise similar or increased compared to January 2020. Additionally, the volume of outpatient short segment posterior fusion and lumbar interbody fusions increased during this time period.

Chemistry towards Biology-Instruct: Snapshot.

The knowledge of interactions between different molecules is undoubtedly the driving force of all contemporary biomedical and biological sciences. Chemical biology/biological chemistry has become an important multidisciplinary bridge connecting the perspectives of chemistry and biology to the study of small molecules/peptidomimetics and their interactions in biological systems. Advances in structural biology research, in particular linking atomic structure to molecular properties and cellular context, are essential for the sophisticated design of new medicines that exhibit a high degree of druggability and very importantly, druglikeness. The authors of this contribution are outstanding scientists in the field who provided a brief overview of their work, which is arranged from in silico investigation through the characterization of interactions of compounds with biomolecules to bioactive materials.

Posterior Glottic Injury Following Prolonged Intubation in COVID-19 Patients.

OBJECTIVE: The objective of this study was to characterize the risk factors for posterior glottic injury (PGI) in patients with coronavirus disease 2019 (COVID-19) who underwent prolonged intubation. STUDY DESIGN: This was a case-control study designed to assess the risk factors associated with development of PGI in COVID-19 patients who underwent prolonged intubation. SETTING: This single-center study was conducted at a tertiary care academic hospital in a metropolitan area. METHODS: We retrospectively reviewed patients who underwent prolonged intubation (≥7 days) for COVID-19 and compared those with PGI to those without. Patient demographics, comorbidities, and intubation characteristics were compared. Factors associated with PGI development among COVID-19 patients were assessed using multivariate regression. RESULTS: We identified 56 patients who presented with PGI following prolonged intubation for COVID-19 and 60 control patients who underwent prolonged intubation for COVID-19 but did not develop PGI. On univariate analyses, the number of reintubations due to failed extubation efforts was significantly associated with development of PGI (odds ratio [OR], 2.9; 95% CI, 1.4-6.2). On multivariate analyses, patients with cardiovascular disease (OR, 3.3; 95% CI, 1.2-9.0); non-COVID-19 respiratory illnesses, which included obstructive sleep apnea and asthma (OR, 5.9; 95% CI, 2.0-17.8); and diabetes mellitus (OR, 11.6; 95% CI, 3.7-36.6) were more likely to develop PGI. CONCLUSION: Our results represent the largest case-control study investigating risk factors for PGI in the setting of prolonged intubation specific to COVID-19. Our study suggests a significant role of comorbidities associated with poor wound healing with development of PGI.

SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction.

The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from hamster, which has an ACE2 sequence similar to human ACE2, angiotensin II evoked a small pericyte-mediated capillary constriction via AT1 receptors, but evoked a large constriction when the SARS-CoV-2 receptor binding domain (RBD, original Wuhan variant) was present. A mutated non-binding RBD did not potentiate constriction. A similar RBD-potentiated capillary constriction occurred in human cortical slices, and was evoked in hamster brain slices by pseudotyped virions expressing SARS-CoV-2 spike protein. This constriction reflects an RBD-induced decrease in the conversion of angiotensin II to angiotensin-(1-7) mediated by removal of ACE2 from the cell surface membrane, and was mimicked by blocking ACE2. The clinically-used drug losartan inhibited the RBD-potentiated constriction. Thus, AT1 receptor blockers could be protective in Covid-19 by preventing pericyte-mediated blood flow reductions in the brain, and perhaps the heart and kidney.

Stakeholder perspectives on the impact of Covid-19 on Oncology services: A qualitative study (preprint)

Background: As COVID-19 spread across the globe, cancer services were required to rapidly pivot to minimise risks without compromising outcomes for patients or staff. The aim of this study was to document changes to Oncology services as a result of COVID-19 from the perspectives of both providers and receivers of care during the initial phase of the pandemic. Methods: Participants were recruited between June and December 2020 through an email invitation via professional or consumer organisations, two hospital-based oncology services and snowballing. Semi-structured interviews focused on health service changes and their impacts, which were then analysed by thematic analysis. Results: Thirty-two patients, 16 carers and 29 health professionals were recruited.  Fifteen patients (n=47%) had localised disease and 19 (n=59%) were currently receiving treatment. Oncology staff included oncologists, palliative care physicians, nurses, allied health and psychosocial practitioners. Four themes arose from the data: safety, increased stress and burnout, communication challenges, and quality of cancer care. Conclusions: There is an ongoing need for cancer-specific information from a single, trusted source to inform medical practitioners and patients/carers. More data are required to inform evidence-based guidelines for cancer care during future pandemics. All stakeholders require ongoing support to avoid stress and burnout.

Thorectidiol A Isolated from the Marine Sponge Dactylospongia elegans Disrupts Interactions of the SARS-CoV-2 Spike Receptor Binding Domain with the Host ACE2 Receptor.

Thorectidiols isolated from the marine sponge Dactylospongia elegans (family Thorectidae, order Dictyoceratida) collected in Papua New Guinea are a family of symmetrical and unsymmetrical dimeric biphenyl meroterpenoid stereoisomers presumed to be products of oxidative phenol coupling of a co-occurring racemic monomer, thorectidol (3). One member of the family, thorectidiol A (1), has been isolated in its natural form, and its structure has been elucidated by analysis of NMR, MS, and ECD data. Acetylation of the sponge extract facilitated isolation of additional thorectidiol diacetate stereoisomers and the isolation of the racemic monomer thorectidol acetate (6). Racemic thorectidiol A (1) showed selective inhibition of the SARS-CoV-2 spike receptor binding domain (RBD) interaction with the host ACE2 receptor with an IC50 = 1.0 ± 0.7 µM.

Cardiac Surgery Outcomes During the COVID-19 Pandemic Worsened Across All Socioeconomic Statuses.

BACKGROUND: Increasing socioeconomic distress has been associated with worse cardiac surgery outcomes. The extent to which the pandemic affected cardiac surgical access and outcomes remains unknown. We sought to examine the relationship between the COVID-19 pandemic and outcomes after cardiac surgery by socioeconomic status. METHODS: All patients undergoing a Society of Thoracic Surgeons (STS) index operation in a regional collaborative, the Virginia Cardiac Services Quality Initiative (2011-2022), were analyzed. Patients were stratified by timing of surgery before vs during the COVID-19 pandemic (March 13, 2020). Hierarchic logistic regression assessed the relationship between the pandemic and operative mortality, major morbidity, and cost, adjusting for the Distressed Communities Index (DCI), STS predicted risk of mortality, intraoperative characteristics, and hospital random effect. RESULTS: A total of 37,769 patients across 17 centers were included. Of these, 7269 patients (19.7%) underwent surgery during the pandemic. On average, patients during the pandemic were less socioeconomically distressed (DCI 37.4 vs DCI 41.9; P < .001) and had a lower STS predicted risk of mortality (2.16% vs 2.53%, P < .001). After risk adjustment, the pandemic was significantly associated with increased mortality (odds ratio 1.398; 95% CI, 1.179-1.657; P < .001), cost (+$4823, P < .001), and STS failure to rescue (odds ratio 1.37; 95% CI, 1.10-1.70; P = .005). The negative impact of the pandemic on mortality and cost was similar regardless of DCI. CONCLUSIONS: Across all socioeconomic statuses, the pandemic is associated with higher cost and greater risk-adjusted mortality, perhaps related to a resource-constrained health care system. More patients during the pandemic were from less distressed communities, raising concern for access to care in distressed communities.

Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health crisis. The reduced efficacy of therapeutic monoclonal antibodies against emerging SARS-CoV-2 variants of concern (VOCs), such as omicron BA.5 subvariants, has underlined the need to explore a novel spectrum of antivirals that are effective against existing and evolving SARS-CoV-2 VOCs. To address the need for novel therapeutic options, we applied cell-based high-content screening to a library of natural products (NPs) obtained from plants, fungi, bacteria, and marine sponges, which represent a considerable diversity of chemical scaffolds. The antiviral effect of 373 NPs was evaluated using the mNeonGreen (mNG) reporter SARS-CoV-2 virus in a lung epithelial cell line (Calu-3). The screening identified 26 NPs with half-maximal effective concentrations (EC50) below 50 µM against mNG-SARS-CoV-2; 16 of these had EC50 values below 10 µM and three NPs (holyrine A, alotaketal C, and bafilomycin D) had EC50 values in the nanomolar range. We demonstrated the pan-SARS-CoV-2 activity of these three lead antivirals against SARS-CoV-2 highly transmissible Omicron subvariants (BA.5, BA.2 and BA.1) and highly pathogenic Delta VOCs in human Calu-3 lung cells. Notably, holyrine A, alotaketal C, and bafilomycin D, are potent nanomolar inhibitors of SARS-CoV-2 Omicron subvariants BA.5 and BA.2. The pan-SARS-CoV-2 activity of alotaketal C [protein kinase C (PKC) activator] and bafilomycin D (V-ATPase inhibitor) suggest that these two NPs are acting as host-directed antivirals (HDAs). Future research should explore whether PKC regulation impacts human susceptibility to and the severity of SARS-CoV-2 infection, and it should confirm the important role of human V-ATPase in the VOC lifecycle. Interestingly, we observed a synergistic action of bafilomycin D and N-0385 (a highly potent inhibitor of human TMPRSS2 protease) against Omicron subvariant BA.2 in human Calu-3 lung cells, which suggests that these two highly potent HDAs are targeting two different mechanisms of SARS-CoV-2 entry. Overall, our study provides insight into the potential of NPs with highly diverse chemical structures as valuable inspirational starting points for developing pan-SARS-CoV-2 therapeutics and for unravelling potential host factors and pathways regulating SARS-CoV-2 VOC infection including emerging omicron BA.5 subvariants.

Cerebral Venous Sinus Thrombosis in a Patient With a History of COVID-19 mRNA Vaccination

A 43-year-old woman with no significant medical history was admitted to our hospital's step down unit with a headache secondary to a cerebral venous sinus thrombosis (CVST), which had been discovered on computed tomography (CT) scan and confirmed with CT angiography. Copyright © 2022 Cliggott Publishing Co.. All rights reserved.

Delivering essential care services during COVID lockdowns: GP experiences and approaches

Background: While the UK's Royal College of General Practitioners developed guidance concerning the delivery of essential services during the COVID pandemic, no such guidance was available in Australia and little is known about the experiences or approaches taken by general practitioners (GPs) for the delivery of care in Australia. Aims/Objectives: To describe GPs' experiences and approaches to delivering essential clinical services (ECS) during COVID lockdowns. Method(s): A survey of GPs who had practiced during lockdowns in Melbourne and Sydney. Questions focused on changes made to care delivery including what services were continued: (1) regardless of outbreak scale, (2) if capacity allowed, or (3) postponed. Finding(s): Of 274 completed surveys, 95% of participants reported increased use of telehealth for diagnosis, investigation, and management of clinical conditions, and 97% for follow-up. Time-sensitive services such as provision of care for symptoms consistent with cancer or those with immediate health impact (e.g., immunisations, prolia injections) were generally continued even if requiring face-to face delivery. Consultations involving screening or health assessments or those necessitating face-to-face care but not clinically urgent (e.g., low risk cervical cancer screening and IUD insertions), were more likely to be postponed, as were visits to homebound and nursing home patients. Implications: The almost universal uptake of telehealth by GPs supported continuity of service provision during lockdown. Australian GPs acted autonomously to triage and provide ECS face to face through the lockdowns. To optimise future preparedness, local guidance for safe delivery of ECS must be developed considering contextual factors relevant to the Australian primary healthcare system.

The impact of the initial COVID-19 outbreak on young adults' mental health: a longitudinal study of risk and resilience factors.

Few studies assessing the effects of COVID-19 on mental health include prospective markers of risk and resilience necessary to understand and mitigate the combined impacts of the pandemic, lockdowns, and other societal responses. This population-based study of young adults includes individuals from the Neuroscience in Psychiatry Network (n = 2403) recruited from English primary care services and schools in 2012-2013 when aged 14-24. Participants were followed up three times thereafter, most recently during the initial outbreak of the COVID-19 outbreak when they were aged between 19 and 34. Repeated measures of psychological distress (K6) and mental wellbeing (SWEMWBS) were supplemented at the latest assessment by clinical measures of depression (PHQ-9) and anxiety (GAD-7). A total of 1000 participants, 42% of the original cohort, returned to take part in the COVID-19 follow-up; 737 completed all four assessments [mean age (SD), 25.6 (3.2) years; 65.4% female; 79.1% White]. Our findings show that the pandemic led to pronounced deviations from existing mental health-related trajectories compared to expected levels over approximately seven years. About three-in-ten young adults reported clinically significant depression (28.8%) or anxiety (27.6%) under current NHS guidelines; two-in-ten met clinical cut-offs for both. About 9% reported levels of psychological distress likely to be associated with serious functional impairments that substantially interfere with major life activities; an increase by 3% compared to pre-pandemic levels. Deviations from personal trajectories were not necessarily restricted to conventional risk factors; however, individuals with pre-existing health conditions suffered disproportionately during the initial outbreak of the COVID-19 pandemic. Resilience factors known to support mental health, particularly in response to adverse events, were at best mildly protective of individual psychological responses to the pandemic. Our findings underline the importance of monitoring the long-term effects of the ongoing pandemic on young adults' mental health, an age group at particular risk for the emergence of psychopathologies. Our findings further suggest that maintaining access to mental health care services during future waves, or potential new pandemics, is particularly crucial for those with pre-existing health conditions. Even though resilience factors known to support mental health were only mildly protective during the initial outbreak of the COVID-19 pandemic, it remains to be seen whether these factors facilitate mental health in the long term.

Antibacterial, Antibiofilm, and Antioxidant Activity of 15 Different Plant-Based Natural Compounds in Comparison with Ciprofloxacin and Gentamicin.

Plant-based natural compounds (PBCs) are comparatively explored in this study to identify the most effective and safe antibacterial agent/s against six World Health Organization concern pathogens. Based on a contained systematic review, 11 of the most potent PBCs as antibacterial agents are included in this study. The antibacterial and antibiofilm efficacy of the included PBCs are compared with each other as well as common antibiotics (ciprofloxacin and gentamicin). The whole plants of two different strains of Cannabis sativa are extracted to compare the results with sourced ultrapure components. Out of 15 PBCs, tetrahydrocannabinol, cannabidiol, cinnamaldehyde, and carvacrol show promising antibacterial and antibiofilm efficacy. The most common antibacterial mechanisms are explored, and all of our selected PBCs utilize the same pathway for their antibacterial effects. They mostly target the bacterial cell membrane in the initial step rather than the other mechanisms. Reactive oxygen species production and targeting [Fe-S] centres in the respiratory enzymes are not found to be significant, which could be part of the explanation as to why they are not toxic to eukaryotic cells. Toxicity and antioxidant tests show that they are not only nontoxic but also have antioxidant properties in Caenorhabditis elegans as an animal model.

The curve not taken: Effects of COVID-19 international comparison news.

International news can inform people not only about what is happening in other countries, but also about how their own country could benefit from policies that have proved successful elsewhere. Specifically, international policy comparison news, or news that compares the policies of two or more countries on the same issue, is a potentially important but underutilized and understudied form of news content. We use an experiment to test effects of exposure to news comparing the COVID-19 pandemic policies of the U.S. versus South Korea, and find that this increases knowledge of policy differences between the two countries, support for adopting similar policies in the U.S., presidential blame for the severity of the pandemic in the U.S., and trust in health experts. On most outcomes, these effects did not vary across political party lines, a particularly encouraging result given the polarized nature of policy debates on this issue.

Correlation between the binding affinity and the conformational entropy of nanobody SARS-CoV-2 spike protein complexes.

Camelid single-domain antibodies, also known as nanobodies, can be readily isolated from naïve libraries for specific targets but often bind too weakly to their targets to be immediately useful. Laboratory-based genetic engineering methods to enhance their affinity, termed maturation, can deliver useful reagents for different areas of biology and potentially medicine. Using the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and a naïve library, we generated closely related nanobodies with micromolar to nanomolar binding affinities. By analyzing the structure-activity relationship using X-ray crystallography, cryoelectron microscopy, and biophysical methods, we observed that higher conformational entropy losses in the formation of the spike protein-nanobody complex are associated with tighter binding. To investigate this, we generated structural ensembles of the different complexes from electron microscopy maps and correlated the conformational fluctuations with binding affinity. This insight guided the engineering of a nanobody with improved affinity for the spike protein.