Brighter nights and darker days predict higher mortality risk: A prospective analysis of personal light exposure in >88,000 individuals.

Light enhances or disrupts circadian rhythms, depending on the timing of exposure. Circadian disruption contributes to poor health outcomes that increase mortality risk. Whether personal light exposure predicts mortality risk has not been established. We therefore investigated whether personal day and night light, and light patterns that disrupt circadian rhythms, predicted mortality risk. UK Biobank participants (N = 88,905, 62.4 ± 7.8 y, 57% female) wore light sensors for 1 wk. Day and night light exposures were defined by factor analysis of 24-h light profiles. A computational model of the human circadian pacemaker was applied to model circadian amplitude and phase from light data. Cause-specific mortality was recorded in 3,750 participants across a mean (±SD) follow-up period of 8.0 ± 1.0 y. Individuals with brighter day light had incrementally lower all-cause mortality risk (adjusted-HR ranges: 0.84 to 0.90 [50 to 70th light exposure percentiles], 0.74 to 0.84 [70 to 90th], and 0.66 to 0.83 [90 to 100th]), and those with brighter night light had incrementally higher all-cause mortality risk (aHR ranges: 1.15 to 1.18 [70 to 90th], and 1.21 to 1.34 [90 to 100th]), compared to individuals in darker environments (0 to 50th percentiles). Individuals with lower circadian amplitude (aHR range: 0.90 to 0.96 per SD), earlier circadian phase (aHR range: 1.16 to 1.30), or later circadian phase (aHR range: 1.13 to 1.20) had higher all-cause mortality risks. Day light, night light, and circadian amplitude predicted cardiometabolic mortality, with larger hazard ratios than for mortality by other causes. Findings were robust to adjustment for age, sex, ethnicity, photoperiod, and sociodemographic and lifestyle factors. Minimizing night light, maximizing day light, and keeping regular light-dark patterns that enhance circadian rhythms may promote cardiometabolic health and longevity.

A new approach to Health Benefits Package design: an application of the Thanzi La Onse model in Malawi.

An efficient allocation of limited resources in low-income settings offers the opportunity to improve population-health outcomes given the available health system capacity. Efforts to achieve this are often framed through the lens of "health benefits packages" (HBPs), which seek to establish which services the public healthcare system should include in its provision. Analytic approaches widely used to weigh evidence in support of different interventions and inform the broader HBP deliberative process however have limitations. In this work, we propose the individual-based Thanzi La Onse (TLO) model as a uniquely-tailored tool to assist in the evaluation of Malawi-specific HBPs while addressing these limitations. By mechanistically modelling-and calibrating to extensive, country-specific data-the incidence of disease, health-seeking behaviour, and the capacity of the healthcare system to meet the demand for care under realistic constraints on human resources for health available, we were able to simulate the health gains achievable under a number of plausible HBP strategies for the country. We found that the HBP emerging from a linear constrained optimisation analysis (LCOA) achieved the largest health gain-∼8% reduction in disability adjusted life years (DALYs) between 2023 and 2042 compared to the benchmark scenario-by concentrating resources on high-impact treatments. This HBP however incurred a relative excess in DALYs in the first few years of its implementation. Other feasible approaches to prioritisation were assessed, including service prioritisation based on patient characteristics, rather than service type. Unlike the LCOA-based HBP, this approach achieved consistent health gains relative to the benchmark scenario on a year- to-year basis, and a 5% reduction in DALYs over the whole period, which suggests an approach based upon patient characteristics might prove beneficial in the future.

Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19.

BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

Hybrid Immunity and SARS-CoV-2 Antibodies: Results of the HEROES-RECOVER Prospective Cohort Study.

BACKGROUND: There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (infection with severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] or vaccination against coronavirus disease 2019 [COVID-19]). From a multi-site cohort of frontline workers, we examined the heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels. METHODS: Exposures included event count and event order, categorized into 7 permutations. Outcome was level of serum antibodies against receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein (total RBD-binding immunoglobulin). Means were examined up to 365 days after each of the first to seventh events. RESULTS: Analysis included 5793 participants measured from 7 August 2020 to 15 April 2023. Hybrid immunity from infection before 1 or 2 vaccine doses elicited modestly superior antibody responses after the second and third events (compared with infections or vaccine doses alone). This superiority was not repeated after additional events. Among adults infected before vaccination, adjusted geometric mean ratios (95% confidence interval [CI]) of anti-RBD early response (versus vaccinated only) were 1.23 (1.14-1.33), 1.09 (1.03-1.14), 0.87 (.81-.94), and 0.99 (.85-1.15) after the second to fifth events, respectively. Post-vaccination infections elicited superior responses; adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated only) were 0.93 (.75-1.17), 1.11 (1.06-1.16), 1.17 (1.11-1.24), and 1.20 (1.07-1.34) after the second to fifth events, respectively. CONCLUSIONS: Evidence of heterogeneity in antibody levels by permutations of infection and vaccination history could inform COVID-19 vaccination policy.

Long-term impact of immediate versus deferred antiretroviral therapy on kidney health in people with HIV.

People with human immunodeficiency virus (HIV) are at risk for chronic kidney disease (CKD) due to HIV and antiretroviral therapy (ART) nephrotoxicity. Immediate ART initiation reduces mortality and is now the standard of care, but the long-term impact of prolonged ART exposure on CKD is unknown. To evaluate this, the Strategic Timing of Antiretroviral Treatment (START) trial randomized 4,684 ART-naïve adults with CD4 cell count under 500 cells/mm3 to immediate versus deferred ART. We previously reported a small but statistically significantly greater decline in estimated glomerular filtration rate (eGFR) over a median of 2.1 years in participants randomized to deferred versus immediate ART. Here, we compare the incidence of CKD events and changes in eGFR and urine albumin/creatinine ratio (UACR) in participants randomized to immediate versus deferred ART during extended follow-up. Over a median of 9.3 years, eight participants experienced kidney failure or kidney-related death, three in the immediate and five in the deferred ART arms, respectively. Over a median of five years of more comprehensive follow-up, the annual rate of eGFR decline was 1.19 mL/min/1.73m2/year, with no significant difference between treatment arms (difference deferred - immediate arm 0.055; 95% confidence interval -0.106, 0.217 mL/min/1.73m2). Results were similar in models adjusted for baseline covariates associated with CKD, including UACR and APOL1 genotype. Similarly, there was no significant difference between treatment arms in incidence of confirmed UACR 30 mg/g or more (odds ratio 1.13; 95% confidence interval 0.85, 1.51). Thus, our findings provide the most definitive evidence to date in support of the long-term safety of early ART with respect to kidney health.

Prevention and Attenuation of Covid-19 with the BNT162b2 and mRNA-1273 Vaccines.

BACKGROUND: Information is limited regarding the effectiveness of the two-dose messenger RNA (mRNA) vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) in preventing infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in attenuating coronavirus disease 2019 (Covid-19) when administered in real-world conditions. METHODS: We conducted a prospective cohort study involving 3975 health care personnel, first responders, and other essential and frontline workers. From December 14, 2020, to April 10, 2021, the participants completed weekly SARS-CoV-2 testing by providing mid-turbinate nasal swabs for qualitative and quantitative reverse-transcriptase-polymerase-chain-reaction (RT-PCR) analysis. The formula for calculating vaccine effectiveness was 100% × (1 - hazard ratio for SARS-CoV-2 infection in vaccinated vs. unvaccinated participants), with adjustments for the propensity to be vaccinated, study site, occupation, and local viral circulation. RESULTS: SARS-CoV-2 was detected in 204 participants (5%), of whom 5 were fully vaccinated (≥14 days after dose 2), 11 partially vaccinated (≥14 days after dose 1 and <14 days after dose 2), and 156 unvaccinated; the 32 participants with indeterminate vaccination status (<14 days after dose 1) were excluded. Adjusted vaccine effectiveness was 91% (95% confidence interval [CI], 76 to 97) with full vaccination and 81% (95% CI, 64 to 90) with partial vaccination. Among participants with SARS-CoV-2 infection, the mean viral RNA load was 40% lower (95% CI, 16 to 57) in partially or fully vaccinated participants than in unvaccinated participants. In addition, the risk of febrile symptoms was 58% lower (relative risk, 0.42; 95% CI, 0.18 to 0.98) and the duration of illness was shorter, with 2.3 fewer days spent sick in bed (95% CI, 0.8 to 3.7). CONCLUSIONS: Authorized mRNA vaccines were highly effective among working-age adults in preventing SARS-CoV-2 infection when administered in real-world conditions, and the vaccines attenuated the viral RNA load, risk of febrile symptoms, and duration of illness among those who had breakthrough infection despite vaccination. (Funded by the National Center for Immunization and Respiratory Diseases and the Centers for Disease Control and Prevention.).

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.

BACKGROUND: LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19. METHODS: In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5. RESULTS: On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47). CONCLUSIONS: Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).

Stacked mutations in wheat homologues of rice SEMI-DWARF1 confer a novel semi-dwarf phenotype.

BACKGROUND: Semi-dwarfing alleles are used widely in cereals to confer improved lodging resistance and assimilate partitioning. The most widely deployed semi-dwarfing alleles in rice and barley encode the gibberellin (GA)-biosynthetic enzyme GA 20-OXIDASE2 (GA20OX2). The hexaploid wheat genome carries three homoeologous copies of GA20OX2, and because of functional redundancy, loss-of-function alleles of a single homoeologue would not be selected in wheat breeding programmes. Instead, approximately 70% of wheat cultivars carry gain-of-function mutations in REDUCED HEIGHT 1 (RHT1) genes that encode negative growth regulators and are degraded in response to GA. Semi-dwarf Rht-B1b or Rht-D1b alleles encode proteins that are insensitive to GA-mediated degradation. However, because RHT1 is expressed ubiquitously these alleles have pleiotropic effects that confer undesirable traits in some environments. RESULTS: We have applied reverse genetics to combine loss-of-function alleles in all three homoeologues of wheat GA20OX2 and its paralogue GA20OX1 and evaluated their performance in three years of field trials. ga20ox1 mutants exhibited a mild height reduction (approximately 3%) suggesting GA20OX1 plays a minor role in stem elongation in wheat. ga20ox2 mutants have reduced GA1 content and are 12-32% shorter than their wild-type segregants, comparable to the effect of the Rht-D1b 'Green Revolution' allele. The ga20ox2 mutants showed no significant negative effects on yield components in the spring wheat variety 'Cadenza'. CONCLUSIONS: Our study demonstrates that chemical mutagenesis can expand genetic variation in polyploid crops to uncover novel alleles despite the difficulty in identifying appropriate mutations for some target genes and the negative effects of background mutations. Field experiments demonstrate that mutations in GA20OX2 reduce height in wheat, but it will be necessary to evaluate the effect of these alleles in different genetic backgrounds and environments to determine their value in wheat breeding as alternative semi-dwarfing alleles.

From conceptualising to modelling structural determinants and interventions in HIV transmission dynamics models: a scoping review and methodological framework for evidence-based analyses.

BACKGROUND: Including structural determinants (e.g. criminalisation, stigma, inequitable gender norms) in dynamic HIV transmission models is important to help quantify their population-level impacts and guide implementation of effective interventions that reduce the burden of HIV and inequalities thereof. However, evidence-based modelling of structural determinants is challenging partly due to a limited understanding of their causal pathways and few empirical estimates of their effects on HIV acquisition and transmission. METHODS: We conducted a scoping review of dynamic HIV transmission modelling studies that evaluated the impacts of structural determinants, published up to August 28, 2023, using Ovid Embase and Medline online databases. We appraised studies on how models represented exposure to structural determinants and causal pathways. Building on this, we developed a new methodological framework and recommendations to support the incorporation of structural determinants in transmission dynamics models and their analyses. We discuss the data and analyses that could strengthen the evidence used to inform these models. RESULTS: We identified 17 HIV modelling studies that represented structural determinants and/or interventions, including incarceration of people who inject drugs (number of studies [n] = 5), violence against women (n = 3), HIV stigma (n = 1), and housing instability (n = 1), among others (n = 7). Most studies (n = 10) modelled exposures dynamically. Almost half (8/17 studies) represented multiple exposure histories (e.g. current, recent, non-recent exposure). Structural determinants were often assumed to influence HIV indirectly by influencing mediators such as contact patterns, condom use, and antiretroviral therapy use. However, causal pathways' assumptions were sometimes simple, with few mediators explicitly represented in the model, and largely based on cross-sectional associations. Although most studies calibrated models using HIV epidemiological data, less than half (7/17) also fitted or cross-validated to data on the prevalence, frequency, or effects of exposure to structural determinants. CONCLUSIONS: Mathematical models can play a crucial role in elucidating the population-level impacts of structural determinants and interventions on HIV. We recommend the next generation of models reflect exposure to structural determinants dynamically and mechanistically, and reproduce the key causal pathways, based on longitudinal evidence of links between structural determinants, mediators, and HIV. This would improve the validity and usefulness of predictions of the impacts of structural determinants and interventions.

Motoneuron-driven computational muscle modelling with motor unit resolution and subject-specific musculoskeletal anatomy.

The computational simulation of human voluntary muscle contraction is possible with EMG-driven Hill-type models of whole muscles. Despite impactful applications in numerous fields, the neuromechanical information and the physiological accuracy such models provide remain limited because of multiscale simplifications that limit comprehensive description of muscle internal dynamics during contraction. We addressed this limitation by developing a novel motoneuron-driven neuromuscular model, that describes the force-generating dynamics of a population of individual motor units, each of which was described with a Hill-type actuator and controlled by a dedicated experimentally derived motoneuronal control. In forward simulation of human voluntary muscle contraction, the model transforms a vector of motoneuron spike trains decoded from high-density EMG signals into a vector of motor unit forces that sum into the predicted whole muscle force. The motoneuronal control provides comprehensive and separate descriptions of the dynamics of motor unit recruitment and discharge and decodes the subject's intention. The neuromuscular model is subject-specific, muscle-specific, includes an advanced and physiological description of motor unit activation dynamics, and is validated against an experimental muscle force. Accurate force predictions were obtained when the vector of experimental neural controls was representative of the discharge activity of the complete motor unit pool. This was achieved with large and dense grids of EMG electrodes during medium-force contractions or with computational methods that physiologically estimate the discharge activity of the motor units that were not identified experimentally. This neuromuscular model advances the state-of-the-art of neuromuscular modelling, bringing together the fields of motor control and musculoskeletal modelling, and finding applications in neuromuscular control and human-machine interfacing research.

Greater sensitivity of the circadian system of women to bright light, but not dim-to-moderate light.

Women typically sleep and wake earlier than men and have been shown to have earlier circadian timing relative to the light/dark cycle that synchronizes the clock. A potential mechanism for earlier timing in women is an altered response of the circadian system to evening light. We characterized individual-level dose-response curves for light-induced melatonin suppression using a within-subjects protocol. Fifty-six participants (29 women, 27 men; aged 18-30 years) were exposed to a range of light illuminances (10, 30, 50, 100, 200, 400, and 2000 lux) using melatonin suppression relative to a dim control (<1 lux) as a marker of light sensitivity. Women were free from hormonal contraception. To examine the potential influence of sex hormones, estradiol and progesterone was examined in women and testosterone was examined in a subset of men. Menstrual phase was monitored using self-reports and estradiol and progesterone levels. Women exhibited significantly greater melatonin suppression than men under the 400-lux and 2000-lux conditions, but not under lower light conditions (10-200 lux). Light sensitivity did not differ by menstrual phase, nor was it associated with levels of estradiol, progesterone, or testosterone, suggesting the sex differences in light sensitivity were not acutely driven by circulating levels of sex hormones. These results suggest that sex differences in circadian timing are not due to differences in the response to dim/moderate light exposures typically experienced in the evening. The finding of increased bright light sensitivity in women suggests that sex differences in circadian timing could plausibly instead be driven by a greater sensitivity to phase-advancing effects of bright morning light.

A Protocol to Determine Circadian Phase by At-Home Salivary Dim Light Melatonin Onset Assessment.

Internal circadian phase assessment is increasingly acknowledged as a critical clinical tool for the diagnosis, monitoring, and treatment of circadian rhythm sleep-wake disorders and for investigating circadian timing in other medical disorders. The widespread use of in-laboratory circadian phase assessments in routine practice has been limited, most likely because circadian phase assessment is not required by formal diagnostic nosologies, and is not generally covered by insurance. At-home assessment of salivary dim light melatonin onset (DLMO, a validated circadian phase marker) is an increasingly accepted approach to assess circadian phase. This approach may help meet the increased demand for assessments and has the advantages of lower cost and greater patient convenience. We reviewed the literature describing at-home salivary DLMO assessment methods and identified factors deemed to be important to successful implementation. Here, we provide specific protocol recommendations for conducting at-home salivary DLMO assessments to facilitate a standardized approach for clinical and research purposes. Key factors include control of lighting, sampling rate, and timing, and measures of patient compliance. We include findings from implementation of an optimization algorithm to determine the most efficient number and timing of samples in patients with Delayed Sleep-Wake Phase Disorder. We also provide recommendations for assay methods and interpretation. Providing definitive criteria for each factor, along with detailed instructions for protocol implementation, will enable more widespread adoption of at-home circadian phase assessments as a standardized clinical diagnostic, monitoring, and treatment tool.

Health workforce needs in Malawi: analysis of the Thanzi La Onse integrated epidemiological model of care.

BACKGROUND: To make the best use of health resources, it is crucial to understand the healthcare needs of a population-including how needs will evolve and respond to changing epidemiological context and patient behaviour-and how this compares to the capabilities to deliver healthcare with the existing workforce. Existing approaches to planning either rely on using observed healthcare demand from a fixed historical period or using models to estimate healthcare needs within a narrow domain (e.g., a specific disease area or health programme). A new data-grounded modelling method is proposed by which healthcare needs and the capabilities of the healthcare workforce can be compared and analysed under a range of scenarios: in particular, when there is much greater propensity for healthcare seeking. METHODS: A model representation of the healthcare workforce, one that formalises how the time of the different cadres is drawn into the provision of units of healthcare, was integrated with an individual-based epidemiological model-the Thanzi La Onse model-that represents mechanistically the development of disease and ill-health and patients' healthcare seeking behaviour. The model was applied in Malawi using routinely available data and the estimates of the volume of health service delivered were tested against officially recorded data. Model estimates of the "time needed" and "time available" for each cadre were compared under different assumptions for whether vacant (or established) posts are filled and healthcare seeking behaviour. RESULTS: The model estimates of volume of each type of service delivered were in good agreement with the available data. The "time needed" for the healthcare workforce greatly exceeded the "time available" (overall by 1.82-fold), especially for pharmacists (6.37-fold) and clinicians (2.83-fold). This discrepancy would be largely mitigated if all vacant posts were filled, but the large discrepancy would remain for pharmacists (2.49-fold). However, if all of those becoming ill did seek care immediately, the "time needed" would increase dramatically and exceed "time supply" (2.11-fold for nurses and midwives, 5.60-fold for clinicians, 9.98-fold for pharmacists) even when there were no vacant positions. CONCLUSIONS: The results suggest that services are being delivered in less time on average than they should be, or that healthcare workers are working more time than contracted, or a combination of the two. Moreover, the analysis shows that the healthcare system could become overwhelmed if patients were more likely to seek care. It is not yet known what the health consequences of such changes would be but this new model provides-for the first time-a means to examine such questions.

Effects of the COVID-19 pandemic on the outcomes of HIV-exposed neonates: a Zimbabwean tertiary hospital experience.

INTRODUCTION: The COVID-19 pandemic has globally impacted health service access, delivery and resources. There are limited data regarding the impact on the prevention of mother to child transmission (PMTCT) service delivery in low-resource settings. Neotree ( www.neotree.org ) combines data collection, clinical decision support and education to improve care for neonates. Here we evaluate impacts of COVID-19 on care for HIV-exposed neonates. METHODS: Data on HIV-exposed neonates admitted to the neonatal unit (NNU) at Sally Mugabe Central Hospital, Zimbabwe, between 01/06/2019 and 31/12/2021 were analysed, with pandemic start defined as 21/03/2020 and periods of industrial action (doctors (September 2019-January 2020) and nurses (June 2020-September 2020)) included, resulting in modelling during six time periods: pre-doctors' strike (baseline); doctors' strike; post-doctors' strike and pre-COVID; COVID and pre-nurses' strike; nurses' strike; post nurses' strike. Interrupted time series models were used to explore changes in indicators over time. RESULTS: Of 8,333 neonates admitted to the NNU, 904 (11%) were HIV-exposed. Mothers of 706/765 (92%) HIV-exposed neonates reported receipt of antiretroviral therapy (ART) during pregnancy. Compared to the baseline period when average admissions were 78 per week (95% confidence interval (CI) 70-87), significantly fewer neonates were admitted during all subsequent periods until after the nurses' strike, with the lowest average number during the nurses' strike (28, 95% CI 23-34, p < 0.001). Across all time periods excluding the nurses strike, average mortality was 20% (95% CI 18-21), but rose to 34% (95% CI 25, 46) during the nurses' strike. There was no evidence for heterogeneity (p > 0.22) in numbers of admissions or mortality by HIV exposure status. Fewer HIV-exposed neonates received a PCR test during the pandemic (23%) compared to the pre-pandemic periods (40%) (RR 0.59, 95% CI 0.41-0.84, p < 0.001). The proportion of HIV-exposed neonates who received antiretroviral prophylaxis during admission was high throughout, averaging between 84% and 95% in each time-period. CONCLUSION: While antiretroviral prophylaxis for HIV-exposed neonates remained high throughout, concerning data on low admissions and increased mortality, similar in HIV-exposed and unexposed neonates, and reduced HIV testing, suggest some aspects of care may have been compromised due to indirect effects of the pandemic.

Isolated Medial Patellofemoral Ligament Reconstruction Results in Lower Failure and Complication Rates Than Isolated Trochleoplasty and Tibial Tubercle Osteotomy: A Systematic Review.

PURPOSE: To evaluate outcomes and complications of isolated medial patellofemoral ligament reconstruction (MPFLR), tibial tubercle osteotomy (TTO), and trochleoplasty for management of patellar instability. METHODS: A query of Scopus, PubMed, Google Scholar, Cochrane CENTRAL Register of Controlled Trials, and the Cochrane Database of Systematic Reviews was performed in accordance with 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Included studies reported clinical outcome data after isolated MPFLR, TTO, or trochleoplasty for patellar instability with a minimum 12-month follow-up. Meta-analysis and data aggregation was not performed. RESULTS: Thirty-six studies (5 trochleoplasty, 14 TTO, and 18 MPFLR) consisting of 1,389 patients (114 trochleoplasty, 374 TTO, and 1,001 MPFLR) were included. Risk of bias was assessed with the Methodological Index for Non-Randomized Studies score, which ranged from 11 to 12 in trochleoplasty, 10 to 18 in TTO, and 8 to 18 in MPFLR studies. Patient-reported outcome measures, including Lysholm score (trochleoplasty: 51.1-71 to 71-95; TTO: 57-63.3 to 84-98; MPFLR: 37.4-59.1 to 74-92.5), Kujala score (trochleoplasty: 56-71 to 78-92; TTO: 48.6-68 to 78-92; MPFLR: 53.3-60 to 81.5-92), visual analog scale for pain (trochleoplasty: 52-25; TTO: 54-76 to 14-27; MPFLR: 29 to 17, out of 100), and Tegner score (TTO: 3-4 to 3-4; MPFLR: 2.5-6 to 4.9-5), improved after all surgeries. Failure rates ranged from 0% to 33.3% after MPFLR, 0% to 30.8% after TTO, and 5.3% to 40% after trochleoplasty. Complication rates ranged from 0% to 14.7% after MPFLR, 1.6% to 58.3% after TTO, and 8% to 26.3% after trochleoplasty. CONCLUSIONS: Isolated MPFLR, TTO, or trochleoplasty may be effective treatment options for patellar stabilization. Although failure rates were highest after isolated trochleoplasty and complication rates were highest after TTO, these procedures are not interchangeable as each addresses a specific pathology. LEVEL OF EVIDENCE: Level IV, systematic review of Level II to IV studies.

Editorial Commentary: The Entry Point-Trochlear Groove Angle Measures Lateralization of the Proximal Trochlear Entry Point in Patients With Patellar Instability.

Patellar instability is a complex orthopaedic condition, occurring at an incidence of 23.2 per 100,000 person-years and resulting from a combination of osseous and soft-tissue factors. Osseous abnormalities associated with patellar instability include trochlear dysplasia and a lateralized tibial tubercle. Evaluation of these factors includes dysplasia evaluation using the Dejour classification and the tibial-tubercle-to-trochlear-groove distance (TT-TG) to evaluate relative lateralization of the tibial tubercle. Three-dimensional modeling has advanced the evaluation of complex trochlea geometry and patellar tracking. Evaluation of the TT-TG distance through flexion, dubbed the radial TT-TG distance, shows that radial TT-TG distances are notably larger than traditional TT-TG measurements, with increasing grade of dysplasia associated with a more pronounced difference between measurements. The entry point-trochlear groove angle may help more accurately describe the morphology of the proximal trochlea and aid in planning or assessing osseous correction with a trochleoplasty. The entry point-trochlear groove angle may also be of use as a variable to determine when an isolated medial patellofemoral ligament reconstruction may fail and require osseous correction. A lateralized proximal trochlea entry point is associated with recurrent patellar instability.

Effectiveness of Bivalent mRNA COVID-19 Vaccines in Preventing SARS-CoV-2 Infection in Children and Adolescents Aged 5 to 17 Years.

Importance: Bivalent mRNA COVID-19 vaccines were recommended in the US for children and adolescents aged 12 years or older on September 1, 2022, and for children aged 5 to 11 years on October 12, 2022; however, data demonstrating the effectiveness of bivalent COVID-19 vaccines are limited. Objective: To assess the effectiveness of bivalent COVID-19 vaccines against SARS-CoV-2 infection and symptomatic COVID-19 among children and adolescents. Design, Setting, and Participants: Data for the period September 4, 2022, to January 31, 2023, were combined from 3 prospective US cohort studies (6 sites total) and used to estimate COVID-19 vaccine effectiveness among children and adolescents aged 5 to 17 years. A total of 2959 participants completed periodic surveys (demographics, household characteristics, chronic medical conditions, and COVID-19 symptoms) and submitted weekly self-collected nasal swabs (irrespective of symptoms); participants submitted additional nasal swabs at the onset of any symptoms. Exposure: Vaccination status was captured from the periodic surveys and supplemented with data from state immunization information systems and electronic medical records. Main Outcome and Measures: Respiratory swabs were tested for the presence of the SARS-CoV-2 virus using reverse transcriptase-polymerase chain reaction. SARS-CoV-2 infection was defined as a positive test regardless of symptoms. Symptomatic COVID-19 was defined as a positive test and 2 or more COVID-19 symptoms within 7 days of specimen collection. Cox proportional hazards models were used to estimate hazard ratios for SARS-CoV-2 infection and symptomatic COVID-19 among participants who received a bivalent COVID-19 vaccine dose vs participants who received no vaccine or monovalent vaccine doses only. Models were adjusted for age, sex, race, ethnicity, underlying health conditions, prior SARS-CoV-2 infection status, geographic site, proportion of circulating variants by site, and local virus prevalence. Results: Of the 2959 participants (47.8% were female; median age, 10.6 years [IQR, 8.0-13.2 years]; 64.6% were non-Hispanic White) included in this analysis, 25.4% received a bivalent COVID-19 vaccine dose. During the study period, 426 participants (14.4%) had laboratory-confirmed SARS-CoV-2 infection. Among these 426 participants, 184 (43.2%) had symptomatic COVID-19, 383 (89.9%) were not vaccinated or had received only monovalent COVID-19 vaccine doses (1.38 SARS-CoV-2 infections per 1000 person-days), and 43 (10.1%) had received a bivalent COVID-19 vaccine dose (0.84 SARS-CoV-2 infections per 1000 person-days). Bivalent vaccine effectiveness against SARS-CoV-2 infection was 54.0% (95% CI, 36.6%-69.1%) and vaccine effectiveness against symptomatic COVID-19 was 49.4% (95% CI, 22.2%-70.7%). The median observation time after vaccination was 276 days (IQR, 142-350 days) for participants who received only monovalent COVID-19 vaccine doses vs 50 days (IQR, 27-74 days) for those who received a bivalent COVID-19 vaccine dose. Conclusion and Relevance: The bivalent COVID-19 vaccines protected children and adolescents against SARS-CoV-2 infection and symptomatic COVID-19. These data demonstrate the benefit of COVID-19 vaccine in children and adolescents. All eligible children and adolescents should remain up to date with recommended COVID-19 vaccinations.

Severe Acute Respiratory Syndrome Coronavirus 2 Infection History and Antibody Response to 3 Coronavirus Disease 2019 Messenger RNA Vaccine Doses.

BACKGROUND: Data on antibody kinetics are limited among individuals previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). From a cohort of healthcare personnel and other frontline workers in 6 US states, we assessed antibody waning after messenger RNA (mRNA) dose 2 and response to dose 3 according to SARS-CoV-2 infection history. METHODS: Participants submitted sera every 3 months, after SARS-CoV-2 infection, and after each mRNA vaccine dose. Sera were tested for antibodies and reported as area under the serial dilution curve (AUC). Changes in AUC values over time were compared using a linear mixed model. RESULTS: Analysis included 388 participants who received dose 3 by November 2021. There were 3 comparison groups: vaccine only with no known prior SARS-CoV-2 infection (n = 224); infection prior to dose 1 (n = 123); and infection after dose 2 and before dose 3 (n = 41). The interval from dose 2 and dose 3 was approximately 8 months. After dose 3, antibody levels rose 2.5-fold (95% confidence interval [CI] = 2.2-3.0) in group 2 and 2.9-fold (95% CI = 2.6-3.3) in group 1. Those infected within 90 days before dose 3 (and median 233 days [interquartile range, 213-246] after dose 2) did not increase significantly after dose 3. CONCLUSIONS: A third dose of mRNA vaccine typically elicited a robust humoral immune response among those with primary vaccination regardless of SARS-CoV-2 infection >3 months prior to boosting. Those with infection <3 months prior to boosting did not have a significant increase in antibody concentrations in response to a booster.

Risk Factors for Reinfection with SARS-CoV-2 Omicron Variant among Previously Infected Frontline Workers.

In a cohort of essential workers in the United States previously infected with SARS-CoV-2, risk factors for reinfection included being unvaccinated, infrequent mask use, time since first infection, and being non-Hispanic Black. Protecting workers from reinfection requires a multipronged approach including up-to-date vaccination, mask use as recommended, and reduction in underlying health disparities.