Inverse folding of protein complexes with a structure-informed language model enables unsupervised antibody evolution (preprint)

Large language models trained on sequence information alone are capable of learning high level principles of protein design. However, beyond sequence, the three-dimensional structures of proteins determine their specific function, activity, and evolvability. Here we show that a general protein language model augmented with protein structure backbone coordinates and trained on the inverse folding problem can guide evolution for diverse proteins without needing to explicitly model individual functional tasks. We demonstrate inverse folding to be an effective unsupervised, structure-based sequence optimization strategy that also generalizes to multimeric complexes by implicitly learning features of binding and amino acid epistasis. Using this approach, we screened [~]30 variants of two therapeutic clinical antibodies used to treat SARS- CoV-2 infection and achieved up to 26-fold improvement in neutralization and 37-fold improvement in affinity against antibody-escaped viral variants-of-concern BQ.1.1 and XBB.1.5, respectively. In addition to substantial overall improvements in protein function, we find inverse folding performs with leading experimental success rates among other reported machine learning-guided directed evolution methods, without requiring any task-specific training data.

Spatial and Temporal Patterns of SARS-CoV-2 transmission in uMgungundlovu, Kwa-Zulu Natal, South Africa (preprint)

Background. Investigating the spatial distribution of SARS-CoV-2 at a local level and describing the pattern of disease occurrence can be used as the basis for efficient prevention and control measures. This research project aims to utilize geospatial analysis to understand the distribution patterns of SARS-CoV-2 and its relationship with certain co-existing factors. Methods. Spatial characteristics of SARS-CoV-2 were investigated over the first four waves of transmission using ESRI ArcGISPro v2.0, including Local Indicators of Spatial Association (LISA) with Morans "I" as the measure of spatial autocorrelation; and Kernel Density Estimation (KDE). In implementing temporal analysis, time series analysis using the Python Seaborn library was used, with separate modelling carried out for each wave. Results. Statistically significant SARS-CoV-2 incidences were noted across age groups with p-values consistently < 0.001. The central region of the district experienced a higher level of clusters indicated by the LISA (Morans I: Wave 1 - 0.22, Wave 2 - 0.2, Wave 3 - 0.11, Wave 4 - 0.13) and the KDE (Highest density of cases: wave 1: 25.1-50, wave 2: 101-150, wave 3: 101-150, wave 4: 50.1-100). Temporal analysis showed more fluctuation at the beginning of each wave with less fluctuation in identified cases within the middle to end of each wave. Conclusion. A Geospatial approach of analysing infectious disease transmission is proposed to guide control efforts (e.g., testing/tracing and vaccine rollout) for populations at higher vulnerability. Additionally, the nature and configuration of the social and built environment may be associated with increased transmission. However, locally specific empirical research is required to assess other relevant factors associated with increased transmission.

Decreased efficacy of a COVID-19 vaccine due to mutations present in early SARS-CoV-2 variants of concern (preprint)

With the SARS-CoV-2 virus still circulating and evolving, there remains an outstanding question if variant-specific vaccines represent the optimal path forward, or if other strategies might be more efficacious towards providing broad protection against emerging variants. Here, we examine the efficacy of strain-specific variants of our previously reported, pan-sarbecovirus vaccine candidate, DCFHP-alum, a ferritin nanoparticle functionalized with an engineered form of the SARS-CoV-2 spike protein. In non-human primates, DCFHP-alum elicits neutralizing antibodies against all known VOCs that have emerged to date and SARS-CoV-1. During development of the DCFHP antigen, we investigated the incorporation of strain-specific mutations from the major VOCs that had emerged to date: D614G, Epsilon, Alpha, Beta, and Gamma. Here, we report the biochemical and immunological characterizations that led us to choose the ancestral Wuhan-1 sequence as the basis for the final DCFHP antigen design. Specifically, we show by size exclusion chromatography and differential scanning fluorimetry that mutations in the VOCs adversely alter the antigen\'s structure and stability. More importantly, we determined that DCFHP without strain-specific mutations elicits the most robust, cross-reactive response in both pseudovirus and live virus neutralization assays. Our data suggest potential limitations to the variant-chasing approach in the development of protein nanoparticle vaccines, but also have implications for other approaches including mRNA-based vaccines.

Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure in elderly patients: A sub-analysis of the STRONG-HF randomized clinical trial.

AIMS: STRONG-HF examined a high-intensity care (HIC) strategy of rapid up-titration of guideline-directed medical therapy (GDMT) and close follow-up after acute heart failure (AHF) admission. We assess the role of age on efficacy and safety of HIC. METHODS AND RESULTS: Hospitalized AHF patients, not treated with optimal GDMT were randomized to HIC or usual care. The primary endpoint of 180-day death or HF readmission occurred equally in older (>65 years, n = 493, 74 ± 5 years) and younger patients (53 ± 11 years, adjusted hazard ratio [aHR] 1.02, 95% confidence interval [CI] 0.73-1.43, p = 0.89). Older patients received slightly lower GDMT to day 21, but same doses at day 90 and 180. The effect of HIC on the primary endpoint was numerically higher in younger (aHR 0.51, 95% CI 0.32-0.82) than older patients (aHR 0.73, 95% CI 0.46-1.15, adjusted interaction p = 0.30), partially related to COVID-19 deaths. After exclusion of COVID-19 deaths, the effect of HIC was similar in younger (aHR 0.51, 95% CI 0.32-0.82) and older patients (aHR 0.63, 95% CI 0.32-1.02, adjusted interaction p = 0.56), with no treatment-by-age interaction (interaction p = 0.57). HIC induced larger improvements in quality of life to day 90 in younger (EQ-VAS adjusted-mean difference 5.51, 95% CI 3.20-7.82) than in older patients (1.77, 95% CI -0.75 to 4.29, interaction p = 0.032). HIC was associated with similar rates of adverse events in older and younger patients. CONCLUSION: High-intensity care after AHF was safe and resulted in a significant reduction of all-cause death or HF readmission at 180 days across the study age spectrum. Older patients have smaller benefits in terms of quality of life.

An investigation of the correlation of vitamin D status and management outcomes in patients with severe COVID-19 at a South African tertiary hospital.

Background: Severe COVID-19 has a poor prognosis, and biomarkers may predict disease severity. This study aimed to assess the effect of baseline Vitamin D (VitD) inadequacy on outcome of patients with severe COVID-19 admitted to intensive care unit (ICU) in a tertiary hospital in South Africa. Methods: Patients with confirmed SARS-CoV-2 were recruited during wave II of the pandemic in Cape Town. Eighty-six patients were included in the study. They were categorized into three groups "VitD deficient, VitD insufficient and VitD sufficient". We combined the VitD deficient with insufficient group to form "VitD inadequate'' group. Cox regression analysis was done to assess the association between VitD status and mortality. Factors with p< 0.05 in adjusted multivariable cox regression were considered statistically significant. Results: The proportion of VitD inadequacy was 64% (55/86), with significantly higher proportion of hypertension (66%; p 0.012). Kaplan Meir curve showed no significant difference in the probability of survival among the COVID-19 patients admitted in the ICU with or without VitD inadequacy. However, patients with elevated serum creatinine were significantly more at risk of dying (Adjusted Hazard Ratio 1.008 (1.002 - 1.030, p<0.017). Conclusion: Our study found a high prevalence of VitD inadequacy (combined deficiency and insufficiency) in COVID-19 patients admitted to the ICU. This may indicate a possible risk of severe disease. Whilst there was no statistically significant relationship between VitD status and mortality in this cohort, baseline VitD may be an important prognostic biomarker in COVID-19 patients admitted to the ICU, particularly in those with comorbidities that predispose to VitD deficiency.

Barriers and facilitators to anti-retroviral therapy adherence among adolescents aged 10 to 19 years living with HIV in sub-Saharan Africa: A mixed-methods systematic review and meta-analysis.

BACKGROUND: Human Immunodeficiency Virus (HIV) significantly affects adolescents globally, with the sub-Saharan Africa (SSA) reporting a high burden of the disease. HIV testing, treatment, and retention to care are low among adolescents. We conducted a mixed-method systematic review to assess anti-retroviral therapy (ART) adherence; barriers and facilitators to ART adherence and ART outcomes among adolescents living with HIV and on ART in sub-Saharan Africa. METHODS: We conducted searches in four scientific databases for studies conducted between 2010 and March 2022 to identify relevant primary studies. Studies were screened against inclusion criteria and assessed for quality, and data was extracted. Meta-analysis of rates and odd ratios was used to plot the quantitative studies and meta-synthesis summarized the evidence from qualitative studies. RESULTS: A total of 10 431 studies were identified and screened against the inclusion/ exclusion criteria. Sixty-six studies met the inclusion criteria (41 quantitative, 16 qualitative, and 9 mixed-methods study designs). Fifty-three thousand two hundred and seventeen (53 217) adolescents (52 319 in quantitative studies and 899 in qualitative studies) were included in the review. Thirteen support focused interventions for improved ART adherence were identified from quantitative studies. The plotted results from the meta-analysis found an ART adherence rate of 65% (95%CI 56-74), viral load suppression was 55% (95%CI 46-64), un-suppressed viral load rate of 41% (95%CI 32-50), and loss to follow up of 17% (95%CI 10-24) among adolescents. Meta-synthesis found six themes of barriers to ART (social, patient-based, economic, health system-based, therapy-based, and cultural barriers) in both the qualitative and quantitative studies, and three themes of facilitators to ART were also identified (social support, counselling, and ART education and secrecy or confidentiality) from qualitative studies. CONCLUSION: ART adherence remains low among adolescents in SSA despite multiple interventions implemented to improve ART adherence. The low adherence rate may hinder the attainment of the UNAIDS 2030 targets. Additionally, various barriers to ART adherence due to lack of support have been reported among this age group. However, interventions aimed at improving social support, educating, and counselling adolescents may improve and sustain ART adherence. TRIAL REGISTRATION: Systematic review registration: PROSPERO CRD42021284891.

2020 Keywords Symposium

2020 (Introduction) Jennifer C. Nash and Samantha Pinto 125 Abolish Marisol LeBrón 128 Asynchronous Monica L. Miller 134 COVID Silver Linings Ann Cvetkovich 139 Essential Worker Julie Livingston 144 Food-in-Place (Shelter-in-Place) Psyche Williams-Forson 148 Mask Ruha Benjamin 151 Mutual Aid Christina Hanhardt 152 PPE Harris Solomon, Neelima Navuluri, Charles W. Hargett, Peter S. Kussin 158 Risk Factor Noémi Tousignant 163 Social Distancing Joshua Chambers-Letson 169 Stay at Home Tiana Reid 175 Supply Chain Management Miriam Posner 178 Synchronous Racquel Gates 181 Wave/Forest Fire Sari Altschuler 187 Zoom Gayle Wald 192 Zoonosis (Virus) Banu Subramaniam 196 2020 Jennifer C. Nash and Samantha Pinto Academic projects are often born from desire. Essential workers—disproportionately Black and Brown—were ordered to continue working, while others began "panic baking" and "panic shopping" (the disappearance of flour, yeast, and toilet paper from grocery stores marked the first quarter of the year).1 While some buried their dead in anguish and isolation,2 others purchased real estate, thanks to record-low interest rates and new demands for more space as houses were transformed into offices and schools.3 In some ways, this is a quintessentially American story—the variety of ways that crisis is experienced and inhabited, with the starkest and most deathly outcomes reserved for those most precarious as the capitalist machine keeps rolling along. Bleeding into 2021, crisis and critique have merged into a lexicon that is repeated, rehearsed, rehashed, remade.5 These terms have become part of a collective vocabulary, a shared index for describing the relentless conditions of the present, even as that present is experienced and endured differently. Media has obsessively reported that this is a crisis that mostly women are bearing, but universities have done far too little to recognize these facts on the ground for caretakers, including the return to in-campus teaching when vaccines are not available for children under twelve.6 We name this as two senior scholars, keenly aware of how "home-schooling" disproportionately affects junior women scholars and primary caretaker colleagues navigating the dual demands of tenure and caregiving. [...]the same is true of race, as institutions have begun diversity trainings, hired diversity coordinators, promised diversity cluster hires, and launched university-wide reckonings with race and "DEI."

Single Ventricle Reconstruction III: Brain Connectome and Neurodevelopmental Outcomes: Design, Recruitment, and Technical Challenges of a Multicenter, Observational Neuroimaging Study.

Patients with hypoplastic left heart syndrome who have been palliated with the Fontan procedure are at risk for adverse neurodevelopmental outcomes, lower quality of life, and reduced employability. We describe the methods (including quality assurance and quality control protocols) and challenges of a multi-center observational ancillary study, SVRIII (Single Ventricle Reconstruction Trial) Brain Connectome. Our original goal was to obtain advanced neuroimaging (Diffusion Tensor Imaging and Resting-BOLD) in 140 SVR III participants and 100 healthy controls for brain connectome analyses. Linear regression and mediation statistical methods will be used to analyze associations of brain connectome measures with neurocognitive measures and clinical risk factors. Initial recruitment challenges occurred that were related to difficulties with: (1) coordinating brain MRI for participants already undergoing extensive testing in the parent study, and (2) recruiting healthy control subjects. The COVID-19 pandemic negatively affected enrollment late in the study. Enrollment challenges were addressed by: (1) adding additional study sites, (2) increasing the frequency of meetings with site coordinators, and (3) developing additional healthy control recruitment strategies, including using research registries and advertising the study to community-based groups. Technical challenges that emerged early in the study were related to the acquisition, harmonization, and transfer of neuroimages. These hurdles were successfully overcome with protocol modifications and frequent site visits that involved human and synthetic phantoms.

A ferritin-based COVID-19 nanoparticle vaccine that elicits robust, durable, broad-spectrum neutralizing antisera in non-human primates.

While the rapid development of COVID-19 vaccines has been a scientific triumph, the need remains for a globally available vaccine that provides longer-lasting immunity against present and future SARS-CoV-2 variants of concern (VOCs). Here, we describe DCFHP, a ferritin-based, protein-nanoparticle vaccine candidate that, when formulated with aluminum hydroxide as the sole adjuvant (DCFHP-alum), elicits potent and durable neutralizing antisera in non-human primates against known VOCs, including Omicron BQ.1, as well as against SARS-CoV-1. Following a booster ~one year after the initial immunization, DCFHP-alum elicits a robust anamnestic response. To enable global accessibility, we generated a cell line that can enable production of thousands of vaccine doses per liter of cell culture and show that DCFHP-alum maintains potency for at least 14 days at temperatures exceeding standard room temperature. DCFHP-alum has potential as a once-yearly (or less frequent) booster vaccine, and as a primary vaccine for pediatric use including in infants.

Efficient evolution of human antibodies from general protein language models.

Natural evolution must explore a vast landscape of possible sequences for desirable yet rare mutations, suggesting that learning from natural evolutionary strategies could guide artificial evolution. Here we report that general protein language models can efficiently evolve human antibodies by suggesting mutations that are evolutionarily plausible, despite providing the model with no information about the target antigen, binding specificity or protein structure. We performed language-model-guided affinity maturation of seven antibodies, screening 20 or fewer variants of each antibody across only two rounds of laboratory evolution, and improved the binding affinities of four clinically relevant, highly mature antibodies up to sevenfold and three unmatured antibodies up to 160-fold, with many designs also demonstrating favorable thermostability and viral neutralization activity against Ebola and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudoviruses. The same models that improve antibody binding also guide efficient evolution across diverse protein families and selection pressures, including antibiotic resistance and enzyme activity, suggesting that these results generalize to many settings.

Multi-faceted intervention to improve management of antibiotics for children presenting to primary care with acute cough and respiratory tract infection (CHICO): efficient cluster randomised controlled trial.

OBJECTIVE: To assess whether an easy-to-use multifaceted intervention for children presenting to primary care with respiratory tract infections would reduce antibiotic dispensing, without increasing hospital admissions for respiratory tract infection. DESIGN: Two arm randomised controlled trial clustered by general practice, using routine outcome data, with qualitative and economic evaluations. SETTING: English primary care practices using the EMIS electronic medical record system. PARTICIPANTS: Children aged 0-9 years presenting with respiratory tract infection at 294 general practices, before and during the covid-19 pandemic. INTERVENTION: Elicitation of parental concerns during consultation; a clinician focused prognostic algorithm to identify children at very low, normal, or elevated 30 day risk of hospital admission accompanied by antibiotic prescribing guidance; and a leaflet for carers including safety netting advice. MAIN OUTCOME MEASURES: Rate of dispensed amoxicillin and macrolide antibiotics (superiority comparison) and hospital admissions for respiratory tract infection (non-inferiority comparison) for children aged 0-9 years over 12 months (same age practice list size as denominator). RESULTS: Of 310 practices needed, 294 (95%) were randomised (144 intervention and 150 controls) representing 5% of all registered 0-9 year olds in England. Of these, 12 (4%) subsequently withdrew (six owing to the pandemic). Median intervention use per practice was 70 (by a median of 9 clinicians). No evidence was found that antibiotic dispensing differed between intervention practices (155 (95% confidence interval 138 to 174) items/year/1000 children) and control practices (157 (140 to 176) items/year/1000 children) (rate ratio 1.011, 95% confidence interval 0.992 to 1.029; P=0.25). Pre-specified subgroup analyses suggested reduced dispensing in intervention practices with fewer prescribing nurses, in single site (compared with multisite) practices, and in practices located in areas of lower socioeconomic deprivation, which may warrant future investigation. Pre-specified sensitivity analysis suggested reduced dispensing among older children in the intervention arm (P=0.03). A post hoc sensitivity analysis suggested less dispensing in intervention practices before the pandemic (rate ratio 0.967, 0.946 to 0.989; P=0.003). The rate of hospital admission for respiratory tract infections in the intervention practices (13 (95% confidence interval 10 to 18) admissions/1000 children) was non-inferior compared with control practices (15 (12 to 20) admissions/1000 children) (rate ratio 0.952, 0.905 to 1.003). CONCLUSIONS: This multifaceted antibiotic stewardship intervention for children with respiratory tract infections did not reduce overall antibiotic dispensing or increase respiratory tract infection related hospital admissions. Evidence suggested that in some subgroups and situations (for example, under non-pandemic conditions) the intervention slightly reduced prescribing rates but not in a clinically relevant way. TRIAL REGISTRATION: ISRCTN11405239ISRCTN registry ISRCTN11405239.

Effects of sleep disturbance on dyspnoea and impaired lung function following hospital admission due to COVID-19 in the UK: a prospective multicentre cohort study.

BACKGROUND: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. METHODS: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2-7 months after hospital discharge and a later time point 10-14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). FINDINGS: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4-6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5-8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (-19%; 95% CI -20 to -16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18-39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27-41% of this effect. INTERPRETATION: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. FUNDING: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council.

Impact of the COVID-19 pandemic on colorectal cancer screening in New York City.

BACKGROUND: The COVID-19 pandemic significantly impacted the delivery of cancer screening. The resulting decrease in outpatient visits and cancellations of non-urgent procedures have negatively affected colorectal cancer (CRC) screening. We aimed to determine the effect of the pandemic on CRC screening at a safety-net hospital and a private health system based in New York City. METHODS: We identified individuals eligible for CRC screening aged 50 to 75 years presenting for outpatient care at a safety-net public hospital and private health system in April through September of 2019 and 2020. The primary outcome was the proportion of screening-eligible patients seen in primary care who underwent CRC screening. RESULTS: The safety-net hospital had 516 (6.1% of screening-eligible individuals) and 269 (4.3%) screening tests completed in 2019 and 2020, respectively (p < 0.01). Fecal immunochemical tests (FIT) accounted for 69.6% of screening in 2019 and 88.1% in 2020. Colonoscopy accounted for 20.3% of screening in 2019 and 11.9% in 2020. The private health system had 39 (0.7%) and 21 (0.6%) screening tests completed in 2019 and 2020, respectively (p = 0.48). FIT accounted for 61.9% of screening in 2019 and 57.1% in 2020. Colonoscopy accounted for 38.1% of screening in 2019 and 42.9% in 2020. CONCLUSION: Absolute numbers of screening tests decreased for both institutions during the COVID-19 pandemic. We observed a decrease in screening uptake and increase in proportional FIT use in the safety-net hospital but no change in the private health system.

Persistent SARS-CoV-2-specific immune defects in kidney transplant recipients following third mRNA vaccine dose.

Kidney transplant recipients (KTRs) show poorer response to SARS-CoV-2 mRNA vaccination, yet response patterns and mechanistic drivers following third doses are ill-defined. We administered third monovalent mRNA vaccines to n = 81 KTRs with negative or low-titer anti-receptor binding domain (RBD) antibody (n = 39 anti-RBDNEG; n = 42 anti-RBDLO), compared with healthy controls (HCs, n = 19), measuring anti-RBD, Omicron neutralization, spike-specific CD8+%, and SARS-CoV-2-reactive T cell receptor (TCR) repertoires. By day 30, 44% anti-RBDNEG remained seronegative; 5% KTRs developed BA.5 neutralization (vs 68% HCs, P < .001). Day 30 spike-specific CD8+% was negative in 91% KTRs (vs 20% HCs; P = .07), without correlation to anti-RBD (rs = 0.17). Day 30 SARS-CoV-2-reactive TCR repertoires were detected in 52% KTRs vs 74% HCs (P = .11). Spike-specific CD4+ TCR expansion was similar between KTRs and HCs, yet KTR CD8+ TCR depth was 7.6-fold lower (P = .001). Global negative response was seen in 7% KTRs, associated with high-dose MMF (P = .037); 44% showed global positive response. Of the KTRs, 16% experienced breakthrough infections, with 2 hospitalizations; prebreakthrough variant neutralization was poor. Absent neutralizing and CD8+ responses in KTRs indicate vulnerability to COVID-19 despite 3-dose mRNA vaccination. Lack of neutralization despite CD4+ expansion suggests B cell dysfunction and/or ineffective T cell help. Development of more effective KTR vaccine strategies is critical. (NCT04969263).

Feasibility and first results of the 'Trials-within-Cohorts' (TwiCs) design in patients undergoing radiotherapy for lung cancer.

Background: 'Trials-within-Cohorts' (TwiCs), previously known as 'cohort multiple randomized controlled trials' is a pragmatic trial design, supporting an efficient and representative recruitment of patients for (future) trials. To our knowledge, the 'COhort for Lung cancer Outcome Reporting and trial inclusion' (COLOR) is the first TwiCs in lung cancer patients. In this study we aimed to assess the feasibility and first year results of COLOR.Material and Methods: All patients diagnosed with lung cancer referred to the Radiotherapy department were eligible to participate in the ongoing prospective COLOR study. At inclusion, written informed consent was requested for use of patient data, participation in patient-reported outcomes (PROs), and willingness to participate in (future) trials. Feasibility was studied by assessing participation and comparing baseline PROs to EORTC reference values. First-year results of PROs at baseline and 3 months after inclusion were evaluated separately for stereotactic body radiotherapy (SBRT) and conventional radiotherapy patients.Results: Of the 338 eligible patients between July 2020 and July 2021, 169 (50%) participated. Among these, 127 (75%) gave informed consent to PROs participation and 110 (65%) were willing to participate in (future) trials. The inclusion percentage dropped from 77% to 33% when the information procedure was switched from in-person to by phone (due to COVID-19 pandemic measures). Baseline PROs for physical and cognitive functioning were comparable in COLOR patients compared to the EORTC reference values. No significant changes in PROs were observed 3 months after inclusion, except for a slight increase in pain scores in the SBRT group (n = 97).Conclusions: The TwiCs-design appears feasible in lung cancer patients with fair participation rates (although negatively impacted by the COVID-19 pandemic). With a planned expansion to other centers, the COLOR-study is expected to enable multiple (randomized) evaluations of experimental interventions with important advantages for recruitment, generalizability, and long-term outcome data collection.

Distressed Work: Chronic Imperatives and Distress in Covid-19 Critical Care.

This ethnographic study introduces the term "distressed work" to describe the emergence of chronic frictions between moral imperatives for health care workers to keep working and the dramatic increase in distress during the Covid-19 pandemic. Interviews and observant participation conducted in a hospital intensive care unit during the Covid-19 pandemic reveal how health care workers connected job duties with extraordinary emotional, physical, and moral burdens. We explore tensions between perceived obligations of health care professionals and the structural contexts of work. Key findings cluster around the moral imperatives of health care work and the distress that work engendered as work spaces, senses of vocation, patient and family interactions, and end-of-life care shifted. While the danger of working beyond limits has long been an ordinary feature of health care work, it has now become a chronic crisis. Assessing this problem in terms of distressed work and its structural contexts can better address effective, worker-informed responses to current health care labor dilemmas.

The clinical and epidemiological characteristics of a series of patients living with HIV admitted for COVID-19 in a district hospital.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to evolve. Globally, COVID-19 continues to strain even the most resilient healthcare systems, with Omicron being the latest variant. We made a thorough search for literature describing the effects of the COVID-19 in a high human immunodeficiency virus (HIV)/tuberculosis (TB) burden district-level hospital setting. We found scanty literature. METHODS: A retrospective observational study was conducted at Khayelitsha District Hospital in Cape Town, South Africa (SA) over the period March 2020-December 2021. We included confirmed COVID-19 cases with HIV infection aged from 18 years and above. Analysis was performed to identify predictors of mortality or hospital discharge among people living with HIV (PLWH). Predictors investigated include CD4 count, antiretroviral therapy (ART), TB, non-communicable diseases, haematological, and biochemical parameters. FINDINGS: This cohort of PLWH with SARS-CoV-2 infection had a median (IQR) age of 46 (37-54) years, male sex distribution of 29.1%, and a median (IQR) CD4 count of 267 (141-457) cells/mm3. Of 255 patients, 195 (76%) patients were discharged, 60 (24%) patients died. One hundred and sixty-nine patients (88%) were on ART with 73(28%) patients having acquired immunodeficiency syndrome (AIDS). After multivariable analysis, smoking (risk ratio [RR]: 2.86 (1.75-4.69)), neutrophilia [RR]: 1.024 (1.01-1.03), and glycated haemoglobin A1 (HbA1c) [RR]: 1.01 (1.007-1.01) were associated with mortality. CONCLUSION: The district hospital had a high COVID-19 mortality rate among PLWH. Easy-to-access biomarkers such as CRP, neutrophilia, and HbA1c may play a significant role in informing clinical management to prevent high mortality due to COVID-19 in PLWH at the district-level hospitals.

Rapid triage and transition to telehealth for heart transplant patients in the COVID-19 pandemic setting.

BACKGROUND: In the setting of the COVID-19 pandemic, a rapid uptake of telehealth services was instituted with the aim of reducing the spread of disease to vulnerable patient populations including heart transplant recipients. METHODS: Single-center, cohort study of all heart transplant patients seen by our institution's transplant program during the first 6 weeks of transition from in-person consultation to telehealth (23 March - 5 June 2020). RESULTS: Face-to-face consultation allocation strongly favored patients in the early post-operative period (34 vs. 242 weeks post-transplant; p < 0.001). Telehealth consultation dramatically reduced patient travel and wait times (80 min per visit saved in telehealth patients). No apparent excess re-hospitalization or mortality was seen in telehealth patients. CONCLUSIONS: With appropriate triage, telehealth was feasible in heart transplant recipients, with videoconferencing being the preferred modality. Patients seen face-to-face were those triaged to be higher acuity based on time since transplant and overall clinical status. These patients have the expected higher rates of hospital re-admission, and therefore should continue to be seen in person.

Evolution of a System to Monitor Infant Neuromotor Development in the Home: Lessons from COVID-19.

In the nine months leading up to COVID-19, our biomedical engineering research group was in the very early stages of development and in-home testing of HUGS, the Hand Use and Grasp Sensor (HUGS) system. HUGS was conceived as a tool to allay parents' anxiety by empowering them to monitor their infants' neuromotor development at home. System focus was on the evolving patterns of hand grasp and general upper extremity movement, over time, in the naturalistic environment of the home, through analysis of data captured from force-sensor-embedded toys and 3D video as the baby played. By the end of March, 2020, as the COVID-19 pandemic accelerated and global lockdown ensued, home visits were no longer possible and HUGS system testing ground to an abrupt halt. In the spring of 2021, still under lockdown, we were able to resume recruitment and in-home testing with HUGS-2, a system whose key requirement was that it be contactless. Participating families managed the set up and use of HUGS-2, supported by a detailed library of video materials and virtual interaction with the HUGS team for training and troubleshooting over Zoom. Like the positive/negative poles of experience reported by new parents under the isolation mandated to combat the pandemic, HUGS research was both impeded and accelerated by having to rely solely on distance interactions to support parents, troubleshoot equipment, and securely transmit data. The objective of this current report is to chronicle the evolution of HUGS. We describe a system whose design and development straddle the pre- and post-pandemic worlds of family-centered health technology design. We identify and classify the clinical approaches to infant screening that predominated in the pre-COVID-19 milieu and describe how these procedural frameworks relate to the family-centered conceptualization of HUGS. We describe how working exclusively through the proxy of parents revealed the family's priorities and goals for child interaction and surfaced HUGS design shortcomings that were not evident in researcher-managed, in-home testing prior to the pandemic.

The association between acid-base status and clinical outcome in critically ill COVID-19 patients admitted to intensive care unit with an emphasis on high anion gap metabolic acidosis.

OBJECTIVE: The aim of this study was to identify arterial blood gas (ABG) abnormalities, with a focus on a high anion gap (AG) metabolic acidosis and evaluate outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the ICU. METHODS: A retrospective, observational study was conducted in a tertiary hospital in Cape Town during the first and second COVID-19 waves. Age, gender, sodium (Na), potassium (K), chloride (Cl), bicarbonate (HCO3std), pH, partial pressure of carbon dioxide (pCO2), creatinine, estimated glomerular filtration rate (eGFR), lactate levels and ABG results were obtained. The Pearson χ2 test or Fisher exact test and the Wilcoxon rank-sum test were used to compare mortality and survival. To identify factors associated with non-survival, a multivariable model was developed. RESULTS: This study included 465 patients, 226 (48%) of whom were female. The sample population's median (IQR) age was 54.2 (46.1-61.3) years, and 63% of the patients died. ABG analyses found that 283 (61%) of the 465 patients had alkalosis (pH ≥ 7.45), 65 (14%) had acidosis (pH ≤ 7.35) and 117 (25%) had normal pH (7.35-7.45). In the group with alkalosis, 199 (70.3%) had a metabolic alkalosis and in the group with acidosis, 42 (64%) had a metabolic acidosis with an increased AG of more than 17. Non-survivors were older than survivors (56.4 years versus 50.3 years, p < .001). CONCLUSION: Most of the COVID-19 patients admitted to the ICU had an alkalosis, and those with acidosis had a much worse prognosis. Higher AG metabolic acidosis was not associated with patients' characteristics.