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For unknow reasons, the melanocyte stem cell (McSC) system fails earlier than other adult stem cell populations1, which leads to hair greying in most humans and mice2,3. Current dogma states that McSCs are reserved in an undifferentiated state in the hair follicle niche, physically segregated from differentiated progeny that migrate away following cues of regenerative stimuli4–8. Here we show that most McSCs toggle between transit-amplifying and stem cell states for both self-renewal and generation of mature progeny, a mechanism fundamentally distinct from those of other self-renewing systems. Live imaging and single-cell RNA sequencing revealed that McSCs are mobile, translocating between hair follicle stem cell and transit-amplifying compartments where they reversibly enter distinct differentiation states governed by local microenvironmental cues (for example, WNT). Long-term lineage tracing demonstrated that the McSC system is maintained by reverted McSCs rather than by reserved stem cells inherently exempt from reversible changes. During ageing, there is accumulation of stranded McSCs that do not contribute to the regeneration of melanocyte progeny. These results identify a new model whereby dedifferentiation is integral to homeostatic stem cell maintenance and suggest that modulating McSC mobility may represent a new approach for the prevention of hair greying.

To describe sleep characteristics in the third trimester of pregnancy for women who had a prior pregnancy loss compared to women with no history of loss.Descriptive comparison of baseline data prior to randomization for a clinical trial.Participants' homes.Eligible women recruited from childbirth education classes during third trimester were over 18 years old, in partnered relationships, spoke English, did not work nightshift or have a diagnosed sleep disorder, and had no current complications or prior pregnancy loss (n = 140). Women with prior miscarriage or stillbirth were offered enrollment in an ancillary study (n = 20).Sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI) and wrist actigraphy. Other measures included relationship satisfaction, perceived stress, and depressive symptoms. For this analysis, only third trimester data prior to randomization were compared.Both groups had similar actigraphy-recorded sleep duration (7.1 ± 1.1 hours) and sleep efficiency (83.7 ± 7.9%). However, the pregnancy loss group had significantly (p = .050) worse PSQI scores (7.8 ± 2.6) than controls (6.7 ± 3.1), resulting primarily from the sleep disturbance component (p = .003), specifically bad dreams (p = .030) and legs twitching/jerking (p = .071). Controlling for demographic and health factors in multivariate analyses, prior pregnancy loss was significant for sleep disturbance (p = .047), bad dreams (p = .018), and partner-reported leg twitching/jerking (p = .048).Long after the acute grief of a pregnancy loss, perceived sleep quality can be problematic during the next pregnancy. Whether poor sleep quality is present prior to the pregnancy loss or reflects long-term maternal sleep characteristics require further research.

Tenofovir diphosphate (TFVdp; an active metabolite of oral HIV pre-exposure prophylaxis [PrEP]) is measured in dried blood spots (DBS) to estimate adherence. However, TFVdp's long half-life in whole blood may lead to misclassification following a recent change in adherence. PrEP's other metabolite, emtricitabine triphosphate (FTCtp), has a shorter half-life in whole blood but adherence thresholds are undefined. We characterized DBS TFVdp and FTCtp concentrations across many dosing scenarios. Population PK models were fit to TFVdp and FTCtp DBS concentrations from a directly observed therapy study (NCT03218592). Concentrations were simulated for 90 days of daily dosing followed by 90 days of 1 to 7 doses/week and for event-driven PrEP (edPrEP) scenarios. Thresholds of 1000 and 200 fmol/punch, for TFVdp and FTCtp, respectively, were reflective of taking 4 doses/week (a minimum target for effective PrEP in men). TFVdp was1000 fmol/punch for 17 days after initiating daily PrEP and1000 fmol/punch for 62 days after decreasing to 3 doses/week. Respectively, FTCtp was200 fmol/punch for 4 days and200 fmol/punch for 6 days. Accuracy of edPrEP adherence classification depended on duration between last sex act and DBS sampling for both measures with misclassification ranging from 9-100%. These data demonstrate adherence misclassification by DBS TFVdp for 2 months following a decline in adherence, elucidating the need for FTCtp to estimate recent adherence. We provide proof of principle that individualized interpretation is needed to support edPrEP adherence monitoring. Our collective approach facilitates clinicians' ability to interpret DBS results and administer patient-centric interventions.

BackgroundNVX-CoV2373, an adjuvanted, recombinant SARS-CoV-2 spike (rS) protein vaccine, consistently demonstrated protective efficacy against COVID-19 in clinical trials and has received regulatory authorizations or approvals worldwide.MethodsPREVENT-19 (NCT04611802) is a phase 3, randomized, observer-blinded, placebo-controlled trial evaluating safety, immunogenicity, and efficacy of NVX-CoV2373 in ≈30 000 participants ≥18 years in the United States and Mexico. Vaccine humoral immune response (ie, serum immunoglobulin [IgG] antibodies, hACE2 receptor binding inhibition antibodies, and neutralizing antibodies to SARS-CoV-2) (ancestral strain) was assessed in 1200 participants randomly selected and equally divided between participants 18–64 and ≥65 years.ResultsIn the per protocol analysis, NVX-CoV2373 induced vigorous serum antibody responses among the 1063 analyzed participants who were SARS-CoV-2 seronegative at baseline, received both doses of study treatment, and had serology results available 2 weeks after dose 2. Geometric mean (GM) responses in both younger and older adults were higher among recipients of vaccine versus placebo for IgG (64 259 vs 121 and 37 750 vs 133 ELISA units, respectively), hACE2 receptor binding inhibition GM titers (GMTs) (222 vs 5 and 136 vs 5, respectively), and neutralizing antibody GMTs (1303 vs 11 and 900 vs 11, respectively). Humoral responses were 30–40% lower in participants ≥65 years or HIV-positive; however, seroconversion rates were high and comparable between the age cohorts, regardless of HIV serostatus.ConclusionsNVX-CoV2373 elicited robust humoral immune responses against ancestral SARS-CoV-2 virus 2 weeks following the second vaccination in adult PREVENT-19 participants, consistent with previously reported high vaccine efficacy.PREVENT-19ClinicalTrials.govnumber,NCT04611802

Introduction: Little is known about the stability of occupational physical activity (PA) and documented compensation effects over time. Study objectives were to (a) determine the stability of accelerometer estimates of occupational and nonoccupational PA over 6 months and 1 year in adults who do not change jobs, (b) examine PA stability in office workers relative to employees with nonoffice jobs who may be more susceptible to seasonal perturbations in work tasks, and (c) examine the stability data for compensation effects seen at baseline in this sample. Methods: City/county government workers from a variety of labor sectors wore an accelerometer at initial data collection, and at 6 (n = 98) and 12 months (n = 38) following initial data collection. Intraclass correlation coefficients (ICCs) were calculated for accelerometer counts and minutes by intensity, domain, and office worker status. Partial correlation coefficients were examined for compensation effects. Results: ICCs ranged from .19 to .91 for occupational and nonwork activity variables. ICCs were similar by office worker status. In both counts and minutes, greater occupational PA correlated with lower total nonwork PA. However, as minutes of occupational moderate to vigorous physical activity increased, nonoccupational moderate to vigorous physical activity did not decrease. Conclusions: There was moderate to high stability in occupational and nonoccupational PA over 6- and 12-month data collection. Occupational PA stability was greater in nonoffice workers, suggesting that those employees’ PA may be less prone to potential cyclical factors at the workplace. Confirmation of the compensation effect further supports the need for workplace intervention studies to examine changes in all intensities of activity during and outside of work time.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality worldwide. As SARS-CoV-2 moves into endemic status, vaccination remains a key element in protecting the health of individuals, societies, and economies worldwide. NVX-CoV2373 (Novavax, Gaithersburg, MD) is a recombinant protein vaccine composed of SARS-CoV-2 spike trimer nanoparticles formulated with saponin-based Matrix-M™ adjuvant (Novavax, Gaithersburg, MD). NVX-CoV2373 is authorized for emergency use in adults and adolescents aged ≥12 years in the United States and numerous other countries. In clinical trials, NVX-CoV2373 showed tolerable reactogenicity and favorable safety profiles characterized by mostly mild-to-moderate adverse events of short duration and by low rates of severe and serious adverse events comparable to those seen with placebo. The two-dose primary vaccination series resulted in robust increases in anti-spike protein immunoglobulin G, neutralizing antibody titers, and cellular immune responses. NVX-CoV2373 vaccination was associated with complete protection against severe disease and a high (90%) rate of protection against symptomatic disease in adults, including symptomatic disease caused by SARS-CoV-2 variants. Additionally, the NVX-CoV2373 adjuvanted recombinant protein platform offers a means to address issues of COVID-19 vaccination hesitancy and global vaccine equity.

Background Novavax COVID-19 Vaccine, Adjuvanted (5 µg recombinant spike protein/50 µg Matrix-MTM adjuvant; NVX-CoV2373) has received regulatory authorizations for use in adults ≥ 18 years globally. Methods Participants from PREVENT-19 (NCT04611802), a phase 3, randomized, observer-blinded, placebo-controlled trial that evaluated the efficacy, safety, and immunogenicity of a primary series of 2 doses of NVX-CoV2373 given 21 days apart, in adults ≥ 18 years in the United States and Mexico, were eligible to receive a booster dose at least 6 months after the initial vaccination series. Short-term safety and immunogenicity of the booster dose was assessed in an ad hoc analysis of 298 participants. Results There was an incremental increase compared to the initial vaccination series in local and systemic reactogenicity, which was transient and mostly mild-to-moderate in intensity. Most unsolicited adverse events were also mild-to-moderate in severity; there were no deaths or treatment-related SAEs and 2/298 booster recipients in this analysis reported unrelated SAEs. Neutralizing, anti-S IgG, and hACE2 receptor binding inhibiting antibodies against the ancestral (Wuhan) strain 28 days after booster were higher than those 14 days after primary vaccination (Table). Overall, humoral responses were high regardless of interval between priming and booster vaccination, but a longer interval yielded stronger responses. Higher immune responses against the Omicron BA.1, BA.2, and BA.5 variants were also observed after the booster dose than after the primary series in a subset of 14-18 participants tested. Overall, humoral responses were high and broad regardless of age after any vaccination, but higher responses were observed in adults < 65 years after initial and booster vaccinations. A booster dose induced more robust antibody responses compared with the primary series in adults ≥ 65 years. Conclusion A single booster dose of NVX-CoV2373 demonstrated a satisfactory safety profile, and high levels of neutralizing, anti-S IgG, and hACE2 inhibition antibody responses against the SARS-CoV-2 prototype Wuhan as well as against the Omicron variant including recently emerged sub-variants. Disclosures Germán Áñez, MD, Novavax Inc.: employer|Novavax Inc.: Stocks/Bonds Lisa M. Dunkle, MD, Novavax, Inc: Employee|Novavax, Inc: Stocks/Bonds Nita Patel, MS, CRP, Novavax, Inc.: employer|Novavax, Inc.: Stocks/Bonds Joyce S. Plested, PhD, Novavax Inc.: employer|Novavax Inc.: Stocks/Bonds|Novavax Inc.: Stocks/Bonds Alice McGarry, MPH, Novavax: Employee|Novavax: Stocks/Bonds Wayne Woo, MS, Novavax: Employee|Novavax: Stocks/Bonds Rongman Cai, PhD, Novavax Inc.: employer|Novavax Inc.: Stocks/Bonds Iksung Cho, MS, Novavax, Inc.: employer|Novavax, Inc.: Stocks/Bonds.

Background Long-acting injectable antiretroviral therapy (LAI) is an exciting alternative to daily oral ART. Less frequent dosing afforded by LAI may be especially pertinent for persons who inject drugs (PWID), who experience more HIV-related mortality largely driven by inadequate ART adherence. We used the Consolidated Framework on Implementation Research (CFIR) to characterize determinants of LAI implementation, focusing on use among PWID, in Hanoi, Vietnam. Methods We conducted in-depth interviews with HIV-infected PWID, ART providers, and policymakers using purposive sampling, recruiting respondents with diverse ART experience from public HIV/ART clinics and national regulatory agencies. Participants were briefed regarding LAI ART, including administration, effectiveness, side effects, and dosing frequency. Data were coded and analyzed using thematic analysis. Results We interviewed 19 PWID, 14 providers, and five policymakers (February-November, 2021). We identified recurrent themes in CFIR domains. Intervention: All informants were excited about LAI, citing convenience and discrete dosing as major facilitators. Surprisingly, provider concerns, including more frequent clinic visits and injection reactions, were rarely voiced by PWID who described monthly injections as similar to current visit frequency and cited “high pain tolerance.” Outer: Providers and policymakers were eager to offer patients ART choice but were divided as to if LAI distribution should proceed with sub-population prioritization. Inner: Providers described personnel and clinic logistic concerns but were confident these could be addressed. Individual: Providers were motivated and confident in their ability to deliver LAI. Process: Transitions to new ART and provision of COVID-19 vaccines were frequently invoked by providers and policymakers as interventions informing LAI implementation. FigureDeterminants of LAI ART implementation in Vietnam using the domains of the Consolidated Framework on Implementation Research Conclusion Using CFIR, we identified multiple determinants of LAI implementation in Vietnam. Stakeholders agreed that LAI was feasible and acceptable. Medication tolerance and efficacy concerns highlight the importance of patient and provider education. Areas where stakeholders diverge should be considered in designing LAI implementation strategies. Disclosures Joseph J. Eron, MD, Adagio Therapeutics: data safety monitoring committee|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Glaxo Smith Kline: Advisor/Consultant|Merck: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support.

Background Family Integrated Care (FICare) benefits preterm infants compared with Family-Centered Care (FCC), but research is lacking in United States (US) Neonatal Intensive Care Units (NICUs). The outcomes for infants of implementing FICare in the US are unknown given differences in parental leave benefits and health care delivery between the US and other countries where FICare is used. We compared preterm weight and discharge outcomes between FCC and mobile-enhanced FICare (mFICare) in the US. Methods In this quasi-experimental study, we enrolled preterm infant (≤ 33 weeks)/parent dyads from 3 NICUs into sequential cohorts: FCC or mFICare. Our primary outcome was 21-day change in weight z-scores. Our secondary outcomes were nosocomial infection, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), and human milk feeding (HMF) at discharge. We used intention-to-treat analyses to examine the effect of the FCC and mFICare models overall and per protocol analyses to examine the effects of the mFICare intervention components. Findings 253 infant/parent dyads participated (141 FCC; 112 mFICare). There were no parent-related adverse events in either group. In intention-to-treat analyses, we found no group differences in weight, ROP, BPD or HMF. The FCC cohort had 2.6-times (95% CI: 1.0, 6.7) higher odds of nosocomial infection than the mFICare cohort. In per-protocol analyses, we found that infants whose parents did not receive parent mentoring or participate in rounds lost more weight relative to age-based norms (group-difference=-0.128, CI: -0.227, -0.030; group-difference=-0.084, CI: -0.154, -0.015, respectively). Infants whose parents did not participate in rounds or group education had 2.9-times (CI: 1.0, 9.1) and 3.8-times (CI: 1.2, 14.3) higher odds of nosocomial infection, respectively. Conclusion We found indications that mFICare may have direct benefits on infant outcomes such as weight gain and nosocomial infection. Future studies using implementation science designs are needed to optimize intervention delivery and determine acute and long-term infant and family outcomes. Clinical Trial Registration NCT03418870 01/02/2018.

BACKGROUND: Social support is associated with decreased symptoms of postpartum mood and anxiety disorders (PMAD) in mothers of healthy infants, but few studies have investigated the relationship between social support and PMAD symptoms in mothers with preterm infants. The purpose of this study was to examine the relationship between social support and symptoms of PMADs reported by mothers in the months following hospital discharge of their preterm infant. METHODS: Mothers of infants less than 33 weeks gestational age were enrolled from neonatal intensive care units (NICU) at 6 sites. Mothers were invited to complete PMAD measures of depression, anxiety and post-traumatic stress approximately three months following the infant’s discharge. Multivariable regression was used to evaluate relationships between social support and PMAD measures. RESULTS: Of 129 participating mothers, 1 in 5 mothers reported clinically significant PMAD symptoms of: depression (24%), anxiety (19%), and post-traumatic stress (20%). Social support was strongly inversely associated with all three PMADs. Social support explained between 21 – 26% of the variance in depression, anxiety and post-traumatic stress symptoms, after accounting for relevant infant and parent characteristics. CONCLUSION: Increased social support may buffer against PMAD symptoms in mothers of preterm infants after discharge. Research is needed to determine effective screening and interventions aimed at promoting social support for parents during and following their infant’s hospitalisation.