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Human prenatal skin is populated by innate immune cells including macrophages, and whether they act solely in immunity or have additional functions in morphogenesis is unclear. We assembled the first comprehensive multi-omic reference atlas of prenatal human skin (7-16 post-conception weeks), combining single cell and spatial transcriptomic data, to characterise the skin’s microenvironmental cellular organisation. This revealed that crosstalk between non-immune and immune cells underpins formation of hair follicles, has implications for scarless wound healing, and is critical for skin angiogenesis. We benchmarked a skin organoid model, derived from human embryonic stem (ES) and induced pluripotent stem (iPS) cells, against prenatal and adult skin, demonstrating close recapitulation of the epidermal and dermal skin components during hair follicle development. Notably, the skin organoid lacked immune cells and had markedly diminished endothelial cell heterogeneity and quantity. From our in vivo skin cell atlas data, we found that macrophages and macrophage-derived growth factors play a key role in driving endothelial development prenatally. Indeed, vascular network formation was enhanced following transfer of autologous iPS-derived macrophages into both endothelial cell angiogenesis assays and skin organoid cultures. In summary, innate immune cells moonlight as key players in skin morphogenesis beyond their conventional immune roles, a function they achieve via extensive crosstalk with non-immune cells. Finally, we leveraged our human prenatal skin cell atlas to further our understanding of the pathogenesis of genetic hair and skin disorders.

After stroke, many people substantially reduce use of their impaired hand in daily life, even if they retain even a moderate level of functional hand ability. Here, we tested whether providing real-time, wearable feedback on the number of achieved hand movements, along with a daily goal, can help people increase hand use intensity. Twenty participants with chronic stroke wore the Manumeter, a novel magnetic wristwatch/ring system that counts finger and wrist movements. We randomized them to wear the device for three weeks with (feedback group) or without (control group) real-time hand count feedback and a daily goal. Participants in the control group used the device as a wristwatch, but it still counted hand movements. We found that the feedback group wore the Manumeter significantly longer (11.2 ± 1.3 h/day) compared to the control group (10.1 ± 1.1 h/day). The feedback group also significantly increased their hand counts over time (p = 0.012, slope = 9.0 hand counts/hour per day, which amounted to ~2000 additional counts per day by study end), while the control group did not (p-value = 0.059; slope = 4.87 hand counts/hour per day). There were no significant differences between groups in any clinical measures of hand movement ability that we measured before and after the feedback period, although several of these measures improved over time. Finally, we confirmed that the previously reported threshold relationship between hand functional capacity and daily use was stable over three weeks, even in the presence of feedback, and established the minimal detectable change for hand count intensity, which is about 30% of average daily intensity. These results suggest that disuse of the hand after stroke is temporarily modifiable with wearable feedback, but do not support that a 3-week intervention of wearable hand count feedback provides enduring therapeutic gains.

Adipose‐derived mesenchymal stem cell (ADSC)‐based regenerative therapies have shown potential for use in many chronic diseases. Aging diminishes stem cell regenerative potential, yet it is unknown whether stem cells from aged donors cause adverse effects in recipients. ADSCs can be obtained using minimally invasive approaches and possess low immunogenicity. Nevertheless, we found that transplanting ADSCs from old donors, but not those from young donors, induces physical dysfunction in older recipient mice. Using single‐cell transcriptomic analysis, we identified a naturally occurring senescent cell‐like population in ADSCs primarily from old donors that resembles in vitro‐generated senescent cells with regard to a number of key pathways. Our study reveals a previously unrecognized health concern due to ADSCs from old donors and lays the foundation for a new avenue of research to devise interventions to reduce harmful effects of ADSCs from old donors.

There are few wearable sensors suitable for daily monitoring of wrist and finger movements for hand-related healthcare applications. Here, we describe the development and validation of a novel algorithm for magnetically counting hand movements. We implemented the algorithm on a wristband that senses magnetic field changes produced by movement of a magnetic ring worn on the finger (the “Manumeter”). The “HAND” (Hand Activity estimated by Nonlinear Detection) algorithm assigns a “HAND count” by thresholding the real-time change in magnetic field created by wrist and/or finger movement. We optimized thresholds to achieve a HAND count accuracy of ~85% without requiring subject-specific calibration. Then, we validated the algorithm in a dexterity-impaired population by showing that HAND counts strongly correlate with clinical assessments of upper extremity (UE) function after stroke. Finally, we used HAND counts to test a recent hypothesis in stroke rehabilitation that real-world UE hand use increases only for stroke survivors who achieve a threshold level of UE functional capability. For 29 stroke survivors, HAND counts measured at home did not increase until the participants’ Box and Blocks Test scores exceeded ~50% normal. These results show that a threshold-based magnetometry approach can non-obtrusively quantify hand movements without calibration and also verify a key concept of real-world hand use after stroke.

IntroductionProgressive supranuclear palsy (PSP) is a devastating neurodegenerative disease characterised by cognitive, behavioural and motor problems. Motor symptoms are highly disabling, while cognitive and behavioural changes have a major impact on carer burden, quality of life and prognosis. Apathy and impulsivity are very common, often coexistent in PSP, and negatively predict survival. In preclinical models and other diseases, apathy and impulsivity are associated with noradrenergic deficits, which can be severe in PSP.Methods and analysisNoradrenaline for Progressive Supranuclear Palsy Syndromes trial is a randomised, double-blind, placebo-controlled, crossover design, Phase IIb clinical trial to evaluate the efficacy and safety of oral atomoxetine for the treatment of cognitive and behavioural changes in PSP. Participants receive atomoxetine 40 mg (10 mg/mL oral solution) once daily or a matched placebo solution, in random order, each for 8 weeks. An ‘informant’, who knows the patient with PSP well, is co-recruited to complete some of the trial outcome measures. Participants remain in the trial for 22 weeks after randomisation. The primary objectives are to assess (1) safety and tolerability and (2) efficacy versus placebo on challenging behaviours as reported in a subscale of the Cambridge Behavioural Inventory. Secondary and exploratory measures relate to cognition, the PSP Rating Scale, mood and potential baseline predictors of individual response to atomoxetine computed from imaging, genetic and cognitive measures at baseline.Ethics and disseminationThe trial was approved by the South Central-Oxford B Research Ethics Committee (REC) and the Medicines and Healthcare products Regulatory Agency (REC reference: 20/SC/0416). Dissemination will include publication in peer-reviewed journals, presentations at academic and public conferences and engagement with patients, the public, policymakers and practitioners.Trial registration numberISRCTN99462035; DOI: https://doi.org/10.1186/ISRCTN99462035; EudraCT (European Union Drug Regulating Authorities Clinical Trials Database)/CTIS (Clinical Trial Information System) number: 2019-004472-19; IRAS (Integrated Research Application System) number: 272063; Secondary identifying numbers: CPMS (Central Portfolio Management System) 44441.

Objectives. The study investigated executive function in adults with Down's syndrome. Design. Participants with Down's syndrome (N=26) were compared with non‐Down syndrome learning disabled participants (N=26). Method. The two group's performance on a range of tests of executive function were compared. Groups were matched on age and a measure of vocabulary. Results. The Down's syndrome group performed at a significantly lower level on a number of tests of executive function. Conclusion. It is suggested that impaired executive function in Down's syndrome is due to abnormal development of the prefrontal cortex in Down's syndrome. Tests of executive function may be sensitive to cognitive changes with the onset of dementia in people with Down's syndrome. Longitudinal studies examining changes in executive function in people with Down's syndrome are recommended.

Age-related changes in proprioception are known to affect postural stability, yet the extent to which such changes affect the finger joints is poorly understood despite the importance of finger proprioception in the control of skilled hand movement. We quantified age-related changes in finger proprioception in 37 healthy young, middle-aged, and older adults using two robot-based tasks wherein participants’ index and middle fingers were moved by an exoskeletal robot. The first task assessed finger position sense by asking participants to indicate when their index and middle fingers were directly overlapped during a passive crisscross movement; the second task assessed finger movement detection by asking participants to indicate the onset of passive finger movement. When these tasks were completed without vision, finger position sense errors were 48 % larger in older adults compared to young participants ( p  < 0.05); proprioceptive reaction time was 78 % longer in older adults compared to young adults ( p  < 0.01). When visual feedback was provided in addition to proprioception, these age-related differences were no longer apparent. No difference between dominant and non-dominant hand performance was found for either proprioception task. These findings demonstrate that finger proprioception is impaired in older adults, and visual feedback can be used to compensate for this deficit. The findings also support the feasibility and utility of the FINGER robot as a sensitive tool for detecting age-related decline in proprioception.

Many health authorities differentiate hospitalizations in patients infected with SARS-CoV-2 as being “for COVID-19” (due to direct manifestations of SARS-CoV-2 infection) versus being an “incidental” finding in someone admitted for an unrelated condition. We conducted a retrospective cohort study of all SARS-CoV-2 infected patients hospitalized via 47 Canadian emergency departments, March 2020-July 2022 to determine whether hospitalizations with “incidental” SARS-CoV-2 infection are less of a burden to patients and the healthcare system. Using a priori standardized definitions applied to hospital discharge diagnoses in 14,290 patients, we characterized COVID-19 as (i) the “Direct” cause for the hospitalization (70%), (ii) a potential “Contributing” factor for the hospitalization (4%), or (iii) an “Incidental” finding that did not influence the need for admission (26%). The proportion of incidental SARS-CoV-2 infections rose from 10% in Wave 1 to 41% during the Omicron wave. Patients with COVID-19 as the direct cause of hospitalization exhibited significantly longer LOS (mean 13.8 versus 12.1 days), were more likely to require critical care (22% versus 11%), receive COVID-19-specific therapies (55% versus 19%), and die (17% versus 9%) compared to patients with Incidental SARS-CoV-2 infections. However, patients hospitalized with incidental SARS-CoV-2 infection still exhibited substantial morbidity/mortality and hospital resource use.

Antibody responses elicited by current messenger RNA (mRNA) COVID-19 vaccines decline rapidly and require repeated boosting. To evaluate the immunogenicity and durability of heterologous and homologous prime-boost regimens involving the adenovirus vector vaccine Ad26.COV2.S and the mRNA vaccine BNT162b2. In this cohort study at a single clinical site in Boston, Massachusetts, 68 individuals who were vaccinated at least 6 months previously with 2 immunizations of BNT162b2 were boosted with either Ad26.COV2.S or BNT162b2. Enrollment of participants occurred from August 12, 2021, to October 25, 2021, and this study involved 4 months of follow-up. Data analysis was performed from November 2021 to February 2022. Participants who were previously vaccinated with BNT162b2 received a boost with either Ad26.COV2.S or BNT162b2. Humoral immune responses were assessed by neutralizing, binding, and functional antibody responses for 16 weeks following the boost. CD8+ and CD4+ T-cell responses were evaluated by intracellular cytokine staining assays. Among 68 participants who were originally vaccinated with BNT162b2 and boosted with Ad26.COV2.S (41 participants; median [range] age, 36 [23-84] years) or BNT162b2 (27 participants; median [range] age, 35 [23-76] years), 56 participants (82%) were female, 7 (10%) were Asian, 4 (6%) were Black, 4 (6%) were Hispanic or Latino, 3 (4%) were more than 1 race, and 53 (78%) were White. Both vaccines were found to be associated with increased humoral and cellular immune responses, including against SARS-CoV-2 variants of concern. BNT162b2 boosting was associated with a rapid increase of Omicron neutralizing antibodies that peaked at a median (IQR) titer of 1018 (699-1646) at week 2 and declined by 6.9-fold to a median (IQR) titer of 148 (95-266) by week 16. Ad26.COV2.S boosting was associated with increased Omicron neutralizing antibodies titers that peaked at a median (IQR) of 859 (467-1838) week 4 and declined by 2.1-fold to a median (IQR) of 403 (208-1130) by week 16. Heterologous Ad26.COV2.S boosting was associated with durable humoral and cellular immune responses in individuals who originally received the BNT162b2 vaccine. These data suggest potential benefits of heterologous prime-boost vaccine regimens for SARS-CoV-2.