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Abstract Background Attention Deficit Hyperactivity Disorder (ADHD) is the most prevalent childhood psychiatric condition with profound public health, personal, and family consequences. ADHD requires comprehensive treatment; however, lack of communication and integration across multiple points of care is a substantial barrier to progress. Given the chronic and pervasive challenges associated with ADHD, innovative approaches are crucial. We developed the digital health intervention (DHI)—CoolTaCo [Cool Technology Assisting Co-regulation] to address these critical barriers. CoolTaCo uses Patient-Centered Digital Healthcare Technologies (PC-DHT) to promote co-regulation (child/parent), capture patient data, support efficient healthcare delivery, enhance patient engagement, and facilitate shared decision-making, thereby improving access to timely and targeted mental health intervention for children at significant risk for poor outcomes. The present paper will describe our planned protocol to evaluate the efficacy of CoolTaCo via randomized control trial (RCT). Methods/design We will recruit 60 children (ages 8–12) with ADHD who will be randomized to either immediate (n = 30) or delayed (n = 30) treatment (i.e., a waitlist control group). Among those randomized to immediate treatment, half will be assigned to DHI (delivered via a smartwatch and smartphone application), the other half to an active control treatment as usual (TAU). Unlike the DHI group, the TAU group will receive the smartwatch with no assigned activities, applications, or interventions on the devices. The intervention period will last 16 weeks; after a participant has been in the delayed treatment group for 16 weeks and has completed the post-waiting period assessment, they will be randomly assigned to either the intervention or active control group. Thus, 30 participants will complete the intervention, and 30 will complete the active control, with half of the total sample completing a waitlist period. Discussion Individuals with ADHD have complex needs. Despite improvement in outcomes following cognitive behavioral therapies (CBT) and pharmaceutical treatment, long-term maintenance is a challenge often not addressed by traditional medical approaches, and, as we described, ineffective approaches to information sharing across points of care create further barriers to progress. Our research will fill a significant gap in translating early treatment investments and gains into long-term, sustainable outcomes. This study was registered as a clinic trial at ClinicalTrials.gov (Digital Health Intervention for Children With ADHD, ID# NCT06456372) on 06/13/2024.

The Incredible Years Teacher Classroom Management (TCM) programme is an evidence-based training with documented positive effects on teachers' classroom management strategies and pupil mental health. However, programme effectiveness alone does not ensure sustainability. This study explored teachers' views on the sustainability of the TCM programme. One year after attending the TCM training, 25 UK primary schoolteachers participated in three focus groups and ten individual interviews. Data were thematically analysed using the Framework Method. One year after the training, teachers were still using TCM strategies, adapting their use to their new cohort of pupils and still reported positive effects on children, teacher-parent relationships, and themselves. However, some school-level and educational policy changes hindered their intended use of TCM strategies. Teachers had shared the TCM strategies with their colleagues, with mixed responses from the latter. To ensure the sustainability of the programme, teachers endorsed refresher sessions and a whole-school training approach.

Abstract Background Cytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- and loss-of-function mechanisms of disease. To study gain-of-function, TDP-43 overexpression has been used to generate in vitro and in vivo model systems. Methods We analyzed RNA-seq datasets from mouse and human neurons overexpressing TDP-43 to explore species specific splicing patterns. We explored the dynamics between TDP-43 levels and exon repression in vitro. Furthermore we analyzed human brain samples and publicly available RNA datasets to explore the relationship between exon repression and disease. Results Our study shows that excessive levels of nuclear TDP-43 protein lead to constitutive exon skipping that is largely species-specific. Furthermore, while aberrant exon skipping is detected in some human brains, it is not correlated with disease, unlike the incorporation of cryptic exons that occurs after loss of TDP-43. Conclusions Our findings emphasize the need for caution in interpreting TDP-43 overexpression data and stress the importance of controlling for exon skipping when generating models of TDP-43 proteinopathy.

Summary: TDP-43 nuclear clearance and cytoplasmic aggregation are hallmarks of TDP-43 proteinopathies. We recently demonstrated that binding to endogenous nuclear GU-rich RNAs sequesters TDP-43 in the nucleus by restricting its passive nuclear export. Here, we tested the feasibility of synthetic RNA oligonucleotide-mediated augmentation of TDP-43 nuclear localization. Using biochemical assays, we compared the ability of GU-rich oligonucleotides to engage in multivalent, RRM-dependent binding with TDP-43. When transfected into cells, (GU)16 attenuated TDP-43 mislocalization induced by transcriptional blockade or RanGAP1 ablation. Clip34nt and (GU)16 accelerated TDP-43 nuclear re-import after cytoplasmic mislocalization. RNA pulldowns confirmed that multivalent GU-oligonucleotides induced high molecular weight RNP complexes, incorporating TDP-43 and possibly other GU-binding proteins. Transfected GU-repeat oligos disrupted TDP-43 cryptic exon repression, likely by diverting TDP-43 from endogenous RNAs, except for Clip34nt that contains interspersed A and C. Thus, exogenous multivalent GU-RNAs can promote TDP-43 nuclear localization, though pure GU-repeat motifs impair TDP-43 function.

Introduction: Leakage of orogastric secretions past the cuff of a tracheal tube is a contributory factor in ventilator-associated pneumonia. Current bench test methods specified in the International Standard for Anaesthetic and Respiratory Equipment (EN ISO 5361:2023) to test cuff leakage involve using a glass or plastic rigid cylinder model of the trachea. There is a need for more realistic models to inform cuff leakage. Methods: We used human computerised tomography data and additive manufacturing (3D printing), combined with casting techniques to fabricate a bio-inspired synthetic tracheal model with analogous tissue characteristics. We conducted cuff leakage tests according to EN ISO 5361:2023 and compared results for high-volume low-pressure polyvinyl chloride and polyurethane cuffs between the rigid cylinder trachea with our bio-inspired model. Results: The tracheal model demonstrated close agreement with published tracheal tissue hardness for cartilaginous and membranous soft tissues. For high-volume low-pressure polyvinyl chloride cuffs the leakage rate was >50% lower in the bio-inspired tracheal model compared with the rigid cylinder model (151 [8] vs 261 [11] ml h−1). For high-volume low-pressure polyurethane cuffs, much lower leakage rates were observed than polyvinyl chloride cuffs in both models with leakage rates higher for the bio-inspired trachea model (0.1 [0.2] vs 0 [0] ml h−1). Conclusion: A reproducible tracheal model that incorporates the mechanical properties of the human trachea can be manufactured from segmented CT images and additive manufactured moulds, providing a useful tool to inform future cuff development, leakage testing for industrial applications, and clinical decision-making. There are differences between cuff leakage rates between the bio-inspired model and the rigid cylinder recommended in EN ISO 5361:2023. The bio-inspired model could lead to more accurate and realistic cuff leakage rate testing which would support manufacturers in refining their designs. Clinicians would then be able to choose better tracheal tubes based on the outcomes of this testing.

Abstract With concurrent global epidemics of chronic pain and opioid use disorders, there is a critical need to identify, target and manipulate specific cell populations expressing the mu-opioid receptor (MOR). However, available tools and transgenic models for gaining long-term genetic access to MOR+ neural cell types and circuits involved in modulating pain, analgesia and addiction across species are limited. To address this, we developed a catalog of MOR promoter (MORp) based constructs packaged into adeno-associated viral vectors that drive transgene expression in MOR+ cells. MORp constructs designed from promoter regions upstream of the mouse Oprm1 gene (mMORp) were validated for transduction efficiency and selectivity in endogenous MOR+ neurons in the brain, spinal cord, and periphery of mice, with additional studies revealing robust expression in rats, shrews, and human induced pluripotent stem cell (iPSC)-derived nociceptors. The use of mMORp for in vivo fiber photometry, behavioral chemogenetics, and intersectional genetic strategies is also demonstrated. Lastly, a human designed MORp (hMORp) efficiently transduced macaque cortical OPRM1+ cells. Together, our MORp toolkit provides researchers cell type specific genetic access to target and functionally manipulate mu-opioidergic neurons across a range of vertebrate species and translational models for pain, addiction, and neuropsychiatric disorders.

Abstract Background More than half of cancers could be prevented by employing evidence-based interventions (EBIs), including prevention interventions targeting nutrition, physical activity, and tobacco. Federally qualified health centers (FQHCs) are the primary source of patient care for over 30 million Americans — making them an optimal setting for ensuring evidence-based prevention that advances health equity. The aims of this study are to (1) determine the degree to which primary cancer prevention EBIs are being implemented within Massachusetts FQHCs and (2) describe how these EBIs are implemented internally and via community partnerships. Methods We used an explanatory sequential mixed methods design to assess the implementation of cancer prevention EBIs. First, we collected 34 quantitative surveys from staff at 16 FQHCs across Massachusetts to determine the frequency of EBI implementation. We followed up with 12 qualitative one-on-one interviews among a sample of staff to understand how the EBIs selected on the survey were implemented. Exploration of contextual influences on implementation and use of partnerships was guided by the Consolidated Framework for Implementation Research (CFIR). Quantitative data were summarized descriptively, and qualitative analyses used reflexive, thematic approaches, beginning deductively with codes from CFIR, then inductively coding additional categories. Results All FQHCs indicated they offered clinic-based tobacco interventions, such as clinician-delivered screening practices and prescription of tobacco cessation medications. Quitline interventions and some diet/physical activity EBIs were available at all FQHCs, but staff perceptions of penetration were low. Only 38% of FQHCs offered group tobacco cessation counseling and 63% referred patients to mobile phone-based cessation interventions. We found multilevel factors influenced implementation across intervention types — including the complexity of intervention trainings, available time and staffing, motivation of clinicians, funding, and external policies and incentives. While partnerships were described as valuable, only one FQHC reported using clinical-community linkages for primary cancer prevention EBIs. Conclusions Adoption of primary prevention EBIs in Massachusetts FQHCs is relatively high, but stable staffing and funding are required to successfully reach all eligible patients. FQHC staff are enthusiastic about the potential of community partnerships to foster improved implementation—providing training and support to build these relationships will be key to fulfilling that promise.

Abstract Mechanisms underlying long-term sustained weight loss and glycemic normalization after obesity surgery include changes in gut hormone levels, including glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). We demonstrate that two peptide biased agonists (GEP44 and GEP12) of the GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors (GLP-1R, Y1-R, and Y2-R, respectively) elicit Y1-R antagonist-controlled, GLP-1R-dependent stimulation of insulin secretion in both rat and human pancreatic islets, thus revealing the counteracting effects of Y1-R and GLP-1R agonism. These agonists also promote insulin-independent Y1-R-mediated glucose uptake in muscle tissue ex vivo and more profound reductions in food intake and body weight than liraglutide when administered to diet-induced obese rats. Our findings support a role for Y1-R signaling in glucoregulation and highlight the therapeutic potential of simultaneous receptor targeting to achieve long-term benefits for millions of patients.

TDP-43 is an essential RNA-binding protein strongly implicated in the pathogenesis of neurodegenerative disorders characterized by cytoplasmic aggregates and loss of nuclear TDP-43. The protein shuttles between nucleus and cytoplasm, yet maintaining predominantly nuclear TDP-43 localization is important for TDP-43 function and for inhibiting cytoplasmic aggregation. We previously demonstrated that specific RNA binding mediates TDP-43 self-assembly and biomolecular condensation, requiring multivalent interactions via N- and C-terminal domains. Here, we show that these complexes play a key role in TDP-43 nuclear retention. TDP-43 forms macromolecular complexes with a wide range of size distribution in cells and we find that defects in RNA binding or inter-domain interactions, including phase separation, impair the assembly of the largest species. Our findings suggest that recruitment into these macromolecular complexes prevents cytoplasmic egress of TDP-43 in a size-dependent manner. Our observations uncover fundamental mechanisms controlling TDP-43 cellular homeostasis, whereby regulation of RNA-mediated self-assembly modulates TDP-43 nucleocytoplasmic distribution. Moreover, these findings highlight pathways that may be implicated in TDP-43 proteinopathies and identify potential therapeutic targets.

Despite improvements in early detection and therapeutic interventions, the mortality rate for Black breast cancer patients is still significantly higher than that of White breast cancer patients. This study seeks to understand differences in the patient experience that lead to this disparity. Semi-structured interviews were conducted to understand the breast cancer treatment process and patient experiences. This study collected health services and timeline data from medical records. Based on these two data sources, the patient's journey in breast cancer treatment was mapped and a thematic analysis was conducted to identify challenges and barriers in the process. The cancer care continuum consists of four stages-diagnosis, surgery, chemotherapy/radiation, and follow-up care. The themes contributing to patient experiences and challenges were identified and compared in each stage for both Black and White patients. Both Black and White participants faced challenges related to financial constraints, treatment changes, lack of autonomy, and insufficient emotional support. However, Black participants additionally faced significant barriers in terms of cultural concordance, effective patient-provider communication, and delay in diagnosis. This study highlights the importance of incorporating effective provider-patient communication, navigation, and emotional support, especially for Black breast cancer patients throughout the cancer care continuum to address healthcare disparities.

Objective: The dorsal vagal complex (DVC) of the hindbrain is a major point of integration for central and peripheral signals that regulate a wide variety of metabolic functions to maintain energy balance. The REV-ERB nuclear receptors are important modulators of molecular metabolism, but their role in the DVC has yet to be established. Methods: Male REV-ERBα/β floxed mice received stereotaxic injections of a Cre expressing virus to the DVC to create the DVC REV-ERBα/β double knockout (DVC RDKO). Control littermates received stereotaxic injections to the DVC of a green fluorescent protein expressing virus. Animals were maintained on a normal chow diet or a 60% high-fat diet to observe the metabolic phenotype arising from DVC RDKO under healthy and metabolically stressed conditions. Results: DVC RDKO animals on high-fat diet exhibited increased weight gain compared to control animals maintained on the same diet. Increased weight gain in DVC RDKO animals was associated with decreased basal metabolic rate and dampened signature of brown adipose tissue activity. RDKO decreased gene expression of calcitonin receptor in the DVC and tyrosine hydroxylase in the brown adipose tissue. Conclusions: These results suggest a previously unappreciated role of REV-ERB nuclear receptors in the DVC for maintaining energy balance and metabolic rate potentially through indirect sympathetic outflow to the brown adipose tissue.

Objective: Many Black breast cancer patients experience chemotherapy-induced peripheral neuropathy (CIPN). Our study assessed Black breast cancer patients’ questions about a biomarker test that can predict likelihood of CIPN. Methods: Nineteen Black women who were previous/current breast cancer patients participated in focus groups. Researchers briefly explained CIPN and the biomarker test, and then participants were asked what questions they would have about the test and its use in treatment decisions. These participant-voiced questions composed the data for this study and were analyzed using thematic analysis. Results: Participants’ questions centered on six themes: reasons for the test, effect on timeline of breast cancer treatment, testing procedure, limits of test (including accuracy), research done to develop this test (including research participants), and concerns about personal information connected to the test (including DNA). Conclusion: This study provides an exploratory look at questions that Black breast cancer patients may have about toxicity biomarker testing use in breast cancer treatment decisions. Innovation: These findings provide a starting point for developing patient-centered approaches for integrating this precision medicine tool into clinical care. The methodological choice to generate participants’ questions (rather than answers to a question) led to robust, actionable data.

Food intake is determined by learned appetitive responses and physiological “appetition” signals after eating begins. Here, authors show melanin-concentrating hormone (MCH)-producing neurons integrate these processes to promote caloric intake.

Wavelet ridge analysis was applied to the data of drifters caught in the Cyprus Gyre in the eastern Mediterranean Sea to study surface currents at low (rotating circulation) and high (near-inertial motion) frequencies. Drifter observations indicate that the orbital speed is highest at about 30 km from the gyre center (reaching ~45 cm/s) and that the Rossby number in the gyre can be as high as 0.25. Drifters also show that strong near-inertial currents with speed of 35-40 cm/s can exceed the gyre rotation speed and that the background vorticity inside the gyre generally shifts the effective inertial frequency to values smaller than the local inertial frequency. As a result, the near-inertial currents are subinertial and are trapped in the mesoscale vortex. For example, the near-inertial motions in the Cyprus Gyre in June 2017 reached 40 cm/s in its inner core with a red shift of ~0.1 cpd, while on its edge they were limited to 10-20 cm/s, under similar wind forcing. This difference is due to trapping of the near-inertial energy inside the gyre. The observed inertial currents are largely driven by the local wind, especially when the effective inertial frequency becomes diurnal and resonance with wind diurnal variability occurs. A damped slab model of the inertial currents in the mixed layer is only partially successful in simulating the observations.

Abstract Background Four large community-randomized trials examining universal testing and treatment (UTT) to reduce HIV transmission were conducted between 2012–2018 in Botswana, Kenya, Uganda, Zambia and South Africa. In 2014, the UNAIDS 90–90-90 targets were adopted as a useful metric to monitor coverage. We systematically review the approaches used by the trials to measure intervention delivery, and estimate coverage against the 90–90-90 targets. We aim to provide in-depth understanding of the background contexts and complexities that affect estimation of population-level coverage related to the 90–90-90 targets. Methods Estimates were based predominantly on “process” data obtained during delivery of the interventions which included a combination of home-based and community-based services. Cascade coverage data included routine electronic health records, self-reported data, survey data, and active ascertainment of HIV viral load measurements in the field. Results The estimated total adult populations of trial intervention communities included in this study ranged from 4,290 (TasP) to 142,250 (Zambian PopART Arm-B). The estimated total numbers of PLHIV ranged from 1,283 (TasP) to 20,541 (Zambian PopART Arm-B). By the end of intervention delivery, the first-90 target (knowledge of HIV status among all PLHIV) was met by all the trials (89.2%-94.0%). Three of the four trials also achieved the second- and third-90 targets, and viral suppression in BCPP and SEARCH exceeded the UNAIDS target of 73%, while viral suppression in the Zambian PopART Arm-A and B communities was within a small margin (~ 3%) of the target. Conclusions All four UTT trials aimed to implement wide-scale testing and treatment for HIV prevention at population level and showed substantial increases in testing and treatment for HIV in the intervention communities. This study has not uncovered any one estimation approach which is superior, rather that several approaches are available and researchers or policy makers seeking to measure coverage should reflect on background contexts and complexities that affect estimation of population-level coverage in their specific settings. All four trials surpassed UNAIDS targets for universal testing in their intervention communities ahead of the 2020 milestone. All but one of the trials also achieved the 90–90 targets for treatment and viral suppression. UTT is a realistic option to achieve 95–95-95 by 2030 and fast-track the end of the HIV epidemic.

Abstract Opioid exposure is known to cause transcriptomic changes in the nucleus accumbens (NAc). However, no studies to date have investigated cell type-specific transcriptomic changes associated with volitional opioid taking. Here, we use single nucleus RNA sequencing (snRNAseq) to comprehensively characterize cell type-specific alterations of the NAc transcriptome in rats self-administering morphine. One cohort of male Brown Norway rats was injected with acute morphine (10 mg/kg, i.p.) or saline. A second cohort of rats was allowed to self-administer intravenous morphine (1.0 mg/kg/infusion) for 10 consecutive days. Each morphine-experienced rat was paired with a yoked saline control rat. snRNAseq libraries were generated from NAc punches and used to identify cell type-specific gene expression changes associated with volitional morphine taking. We identified 1106 differentially expressed genes (DEGs) in the acute morphine group, compared to 2453 DEGs in the morphine self-administration group, across 27 distinct cell clusters. Importantly, we identified 1329 DEGs that were specific to morphine self-administration. DEGs were identified in novel clusters of astrocytes, oligodendrocytes, and D1R- and D2R-expressing medium spiny neurons in the NAc. Cell type-specific DEGs included Rgs9, Celf5, Oprm1, and Pde10a. Upregulation of Rgs9 and Celf5 in D2R-expressing neurons was validated by RNAscope. Approximately 85% of all oligodendrocyte DEGs, nearly all of which were associated with morphine taking, were identified in two subtypes. Bioinformatic analyses identified cell type-specific upstream regulatory mechanisms of the observed transcriptome alterations and downstream signaling pathways, including both novel and previously identified molecular pathways. These findings show that volitional morphine taking is associated with distinct cell type-specific transcriptomic changes in the rat NAc and highlight specific striatal cell populations and novel molecular substrates that could be targeted to reduce compulsive opioid taking.

Objective: Nausea and vomiting remain life-threatening obstacles to successful treatment of chronic diseases, despite a cadre of available antiemetic medications. Our inability to effectively control chemotherapy-induced nausea and vomiting (CINV) highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that block CINV. Methods: Behavioral pharmacology assays of nausea and emesis in 3 different mammalian species were combined with histological and unbiased transcriptomic analyses to investigate the beneficial effects of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism on CINV. Results: Single-nuclei transcriptomics and histological approaches in rats revealed a topographical, molecularly distinct, GABA-ergic neuronal population in the dorsal vagal complex (DVC) that is modulated by chemotherapy but rescued by GIPR agonism. Activation of DVCGIPR neurons substantially decreased behaviors indicative of malaise in cisplatin-treated rats. Strikingly, GIPR agonism blocks cisplatin-induced emesis in both ferrets and shrews. Conclusion: Our multispecies study defines a peptidergic system that represents a novel therapeutic target for the management of CINV, and potentially other drivers of nausea/emesis.

The “two-process model” is a promising technique for interpreting stellar chemical abundance data from large-scale surveys (e.g., the Sloan Digital Sky Survey IV/V and the Galactic Archeology with HERMES survey), enabling more quantitative empirical studies of differences in chemical enrichment history between galaxies without relying on detailed yield and evolution models. In this work, we fit two-process model parameters to (1) a luminous giant Milky Way (MW) sample and (2) stars comprising the Sagittarius dwarf galaxy (Sgr). We then use these two sets of model parameters to predict the abundances of 14 elements of stars belonging to the MW and in five of its massive satellite galaxies, analyzing the residuals between the predicted and observed abundances. We find that the model fit to (1) results in large residuals (0.1–0.3 dex) for most metallicity-dependent elements in the metal-rich ([Mg/H] > −0.8) stars of the satellite galaxies. However, the model fit to (2) results in small or no residuals for all elements across all satellite galaxies. Therefore, despite the wide variation in [X/Mg]–[Mg/H] abundance patterns of the satellite galaxies, the two-process framework provides an accurate characterization of their abundance patterns across many elements, but these multielement patterns are systematically different between the dwarf galaxy satellites and the MW disks. We consider a variety of scenarios for the origin of this difference, highlighting the possibility that a large inflow of pristine gas to the MW disk diluted the metallicity of star-forming gas without changing abundance ratios.

With high equilibrium temperatures and tidally locked rotation, ultra-hot Jupiters (UHJs) are unique laboratories within which to probe extreme atmospheric physics and chemistry. In this paper, we present high-resolution dayside spectroscopy of the UHJ WASP-189 b obtained with the new Gemini High-resolution Optical SpecTrograph (GHOST) at the Gemini South Observatory. The observations, which cover 3 hr of post-eclipse orbital phases, were obtained during the instrument’s System Verification run. We detect the planet’s atmosphere via the Doppler cross-correlation technique, and recover a detection of neutral iron in the planet’s dayside atmosphere at a significance of 7.5 σ in the red arm of the data, verifying the presence of a thermal inversion. We also investigate the presence of other species in the atmosphere and discuss the implications of model injection/recovery tests. These results represent the first atmospheric characterization of an exoplanet with GHOST’s high-resolution mode, and demonstrate the potential of this new instrument in detecting and studying ultra-hot exoplanet atmospheres.

Stellar abundance measurements are subject to systematic errors that induce extra scatter and artificial correlations in elemental abundance patterns. We derive empirical calibration offsets to remove systematic trends with surface gravity $\mathrm{log}(g)$ in 17 elemental abundances of 288,789 evolved stars from the SDSS APOGEE survey. We fit these corrected abundances as the sum of a prompt process tracing core-collapse supernovae and a delayed process tracing Type Ia supernovae, thus recasting each star’s measurements into the amplitudes A _cc and A _Ia and the element-by-element residuals from this two-parameter fit. As a first application of this catalog, which is 8× larger than that of previous analyses that used a restricted $\mathrm{log}(g)$ range, we examine the median residual abundances of 14 open clusters, nine globular clusters, and four dwarf satellite galaxies. Relative to field Milky Way disk stars, the open clusters younger than 2 Gyr show ≈0.1−0.2 dex enhancements of the neutron-capture element Ce, and the two clusters younger than 0.5 Gyr also show elevated levels of C+N, Na, S, and Cu. Globular clusters show elevated median abundances of C+N, Na, Al, and Ce, and correlated abundance residuals that follow previously known trends. The four dwarf satellites show similar residual abundance patterns despite their different star formation histories, with ≈0.2–0.3 dex depletions in C+N, Na, and Al and ≈0.1 dex depletions in Ni, V, Mn, and Co. We provide our catalog of corrected APOGEE abundances, two-process amplitudes, and residual abundances, which will be valuable for future studies of abundance patterns in different stellar populations and of additional enrichment processes that affect galactic chemical evolution.

This study probes the chemical abundances of the neutron-capture elements cerium and neodymium in the inner Milky Way from an analysis of a sample of ∼2000 stars in the Galactic bulge bar spatially contained within ∣ X _Gal ∣ < 5 kpc, ∣ Y _Gal ∣ < 3.5 kpc, and ∣ Z _Gal ∣ < 1 kpc, and spanning metallicities between −2.0 ≲ [Fe/H] ≲ +0.5. We classify the sample stars into low- or high-[Mg/Fe] populations and find that, in general, values of [Ce/Fe] and [Nd/Fe] increase as the metallicity decreases for the low- and high-[Mg/Fe] populations. Ce abundances show a more complex variation across the metallicity range of our bulge-bar sample when compared to Nd, with the r -process dominating the production of neutron-capture elements in the high-[Mg/Fe] population ([Ce/Nd] < 0.0). We find a spatial chemical dependence of Ce and Nd abundances for our sample of bulge-bar stars, with low- and high-[Mg/Fe] populations displaying a distinct abundance distribution. In the region close to the center of the MW, the low-[Mg/Fe] population is dominated by stars with low [Ce/Fe], [Ce/Mg], [Nd/Mg], [Nd/Fe], and [Ce/Nd] ratios. The low [Ce/Nd] ratio indicates a significant contribution in this central region from r -process yields for the low-[Mg/Fe] population. The chemical pattern of the most metal-poor stars in our sample suggests an early chemical enrichment of the bulge dominated by yields from core-collapse supernovae and r -process astrophysical sites, such as magnetorotational supernovae.

We present the discovery of Ursa Major III/UNIONS 1, the least luminous known satellite of the Milky Way, which is estimated to have an absolute V -band magnitude of $+{2.2}_{-0.3}^{+0.4}$ mag, equivalent to a total stellar mass of ${16}_{-5}^{+6}$ M _⊙ . Ursa Major III/UNIONS 1 was uncovered in the deep, wide-field Ultraviolet Near Infrared Optical Northern Survey (UNIONS) and is consistent with an old ( τ > 11 Gyr), metal-poor ([Fe/H] ∼ −2.2) stellar population at a heliocentric distance of ∼10 kpc. Despite its being compact ( r _h = 3 ± 1 pc) and composed of few stars, we confirm the reality of Ursa Major III/UNIONS 1 with Keck II/DEIMOS follow-up spectroscopy and identify 11 radial velocity members, eight of which have full astrometric data from Gaia and are co-moving based on their proper motions. Based on these 11 radial velocity members, we derive an intrinsic velocity dispersion of ${3.7}_{-1.0}^{+1.4}$ km s ^−1 but some caveats preclude this value from being interpreted as a direct indicator of the underlying gravitational potential at this time. Primarily, the exclusion of the largest velocity outlier from the member list drops the velocity dispersion to ${1.9}_{-1.1}^{+1.4}$ km s ^−1 , and the subsequent removal of an additional outlier star produces an unresolved velocity dispersion. While the presence of binary stars may be inflating the measurement, the possibility of a significant velocity dispersion makes Ursa Major III/UNIONS 1 a high-priority candidate for multi-epoch spectroscopic follow-ups to deduce the true nature of this incredibly faint satellite.

Heart rate is an extremely important physiological parameter to measure in critically unwell infants, as it is the main physiological marker that changes in response to a change in infant condition. Heart rate is routinely measured peripherally on a limb with a pulse oximeter. However, when infants are critically unwell, the blood supply to these peripheries is reduced in preference for central perfusion of vital organs such as the brain and heart. Measurement of heart rate with a reflection mode photoplethysmogram (PPG) sensor on the forehead could help minimise this problem and make it easier for other important medical equipment, such as cannulas, to be placed on the limbs. This study compares heart rates measured with a forehead-based PPG sensor against a wrist-based PPG sensor in 19 critically unwell infants in neonatal intensive care collecting 198 h of data. The two heart rates were compared using positive percentage agreement, Spearman’s correlation coefficient and Bland-Altman analysis. The forehead PPG sensor showed good agreement with the wrist-based PPG sensor with limits of agreement of 8.44 bpm, bias of −0.22 bpm; positive percentage agreement of 98.87%; and Spearman’s correlation coefficient of 0.9816. The analysis demonstrates that the forehead is a reliable alternative location for measuring vital signs using the PPG.

Background: We nested a seroprevalence survey within the TREATS (Tuberculosis Reduction through Expanded Antiretroviral Treatment and Screening) project. We aimed to measure the seroprevalence of SARS-CoV-2 infection and investigate associated risk factors in one community (population ∼27,000) with high prevalence of TB/HIV in Zambia. Methods: The study design was cross-sectional. A random sample of 3592 individuals aged ≥15 years enrolled in the TREATS TB-prevalence survey were selected for antibody testing. Randomly selected blocks of residence were visited between October 2020 and March 2021. Antibodies against SARS-CoV-2 were detected using Abbott- ARCHITECT SARS-CoV-2 IgG assay. Results: A total of 3035/3526 (86.1%) individuals had a blood sample taken. Antibody testing results were available for 2917/3035 (96.1%) participants. Overall, 401/2977 (13.5%) individuals tested positive for IgG antibodies. Seroprevalence was similar by sex (12.7% men vs 14.0% women) and was lowest in the youngest age group 15–19 years (9.7%) and similar in ages 20 years and older (∼15%). We found no evidence of an association between seroprevalence and HIV-status or TB. There was strong evidence (p

Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β cell destruction. Coxsackievirus B3 (CVB3) infection and melanoma differentiation-associated protein 5–dependent (MDA5-dependent) antiviral responses are linked with T1D development. Mutations within IFIH1, coding for MDA5, are correlated with T1D susceptibility, but how these mutations contribute to T1D remains unclear. Utilizing nonobese diabetic (NOD) mice lacking Ifih1 expression (KO) or containing an in-frame deletion within the ATPase site of the helicase 1 domain of MDA5 (ΔHel1), we tested the hypothesis that partial or complete loss-of-function mutations in MDA5 would delay T1D by impairing proinflammatory pancreatic macrophage and T cell responses. Spontaneous T1D developed in female NOD and KO mice similarly, but was significantly delayed in ΔHel1 mice, which may be partly due to a concomitant increase in myeloid-derived suppressor cells. Interestingly, KO male mice had increased spontaneous T1D compared with NOD mice. Whereas NOD and KO mice developed CVB3-accelerated T1D, ΔHel1 mice were protected partly due to decreased type I IFNs, pancreatic infiltrating TNF+ macrophages, IFN-γ+CD4+ T cells, and perforin+CD8+ T cells. Furthermore, ΔHel1 MDA5 protein had reduced ATP hydrolysis compared with wild-type MDA5. Our results suggest that dampened MDA5 function delays T1D, yet loss of MDA5 promotes T1D.

Abstract Background Identifying successful strategies to improve participant retention in longitudinal studies remains a challenge. In this study we evaluated whether non-traditional fieldworker shifts (after hours during the week and weekends) enhanced participant retention when compared to retention during traditional weekday shifts in the HPTN 071 (PopART) population cohort (PC). Methods HPTN 071 (PopART) PC participants were recruited and followed up in their homes on an annual basis by research fieldworkers over a 3-4 year period. The average number of successful follow-up visits, where a PC participant was found and retained in the study, was calculated for each of 3 visit schedules (early weekday shift, late weekday shift, and Saturday shift), and standardized to account for variation in fieldwork shift duration. We used one-way univariate analysis of variance (ANOVA) to describe differences in mean-successful visits and 95% confidence intervals between the shift types. Results Data on 16 651 successful visits were included. Successful visit rates were higher when conducting Saturday visits (14.0; 95% CI: 11.3-16.6) compared to both regular (4.5; 95% CI: 3.7-5.3) and late weekday shifts (5.3; 95% CI: 4.7-5.8) overall and in all subgroup analyses (P

Introduction Ethnic disparities in treatment with clozapine, the antipsychotic recommended for treatment-resistant schizophrenia (TRS), have been reported. However, these investigations frequently suffer from potential residual confounding. For example, few studies have restricted the analyses to TRS samples and none has controlled for benign ethnic neutropenia. Objectives This study investigated if service-users’ ethnicity influenced clozapine prescription in a cohort of people with TRS. Methods Information from the clinical records of South London and Maudsley NHS Trust was used to identify a cohort of service-users with TRS between 2007 and 2017. In this cohort, we used logistic regression to investigate any association between ethnicity and clozapine prescription while adjusting for potential confounding variables, including sociodemographic factors, psychiatric multimorbidity, substance use, benign ethnic neutropenia, and inpatient and outpatient care received. Results We identified 2239 cases that met the criteria for TRS. Results show that after adjusting for confounding variables, people with Black African ethnicity had half the odds of being treated with clozapine and people with Black Caribbean or Other Black background had about two-thirds the odds of being treated with clozapine compared White British service-users. No disparities were observed regarding other ethnic groups, namely Other White background, South Asian, Other Asian, or any other ethnicity. Conclusions There was evidence of inequities in care among Black ethnic groups with TRS. Interventions targeting barriers in access to healthcare are recommended. Disclosure During the conduction of the study, DFdF, GKS, and RH received funds from the NIHR Maudsley Biomedical Research Centre. For other activities outside the submitted work, DFdF received research funding from the UK Department of Health and Social Care, Janss

Introduction Studies have shown ethnic inequalities in health, with a higher incidence of illnesses among people of some minoritised ethnic groups. Furthermore, it has been observed that people with severe mental illnesses have a higher risk for multimorbidity. However, no study has investigated ethnic disparities in comorbidity in people with a schizophrenia spectrum disorder. Objectives This study investigates potential ethnic disparities in physical health comorbidity in a cohort of people with psychosis. Methods Using a cross-sectional design, we identified service-users of the South London and Maudsley NHS Trust who were diagnosed with a schizophrenia spectrum disorder between 2007 and 2020. We assessed the prevalence of asthma, bronchitis, diabetes, hypertension, low blood pressure, overweight or obesity, and rheumatoid arthritis. Latent class analyses were used to investigate distinct profiles of comorbidity. Multinomial regression was then used to investigate ethnic disparities in these profiles. The regression model was adjusted for gender, age, neighbourhood deprivation, smoking and duration of care. Results On a sample of 23,418 service-users with psychosis, we identified two classes of comorbidity: low comorbidity and multiple comorbidities. Compared to the White British ethnicity, a higher risk for multiple comorbidities was observed for people with any Black background, Indian, Pakistani, Asian British, and mixed-race ethnicities. Furthermore, Black African women had a significantly higher risk for multiple comorbidities than their male counterparts. Conclusions Ethnic disparities are observed in multiple comorbidities among people with psychosis. Further research is needed to understand the impact of these disparities, especially in relation to mortality. Disclosure No significant relationships.

Introduction There is emerging evidence of heterogeneity within treatment-resistance schizophrenia (TRS), with some people not responding to antipsychotic treatment from illness onset and a smaller group becoming treatment-resistant after an initial response period. It has been suggested that these groups have different aetiologies. Few studies have investigated socio-demographic and clinical differences between early and late onset of TRS. Objectives This study aims to investigate socio-demographic and clinical correlates of late-onset of TRS. Methods Using data from the electronic health records of the South London and Maudsley, we identified a cohort of people with TRS. Regression analyses were conducted to identify correlates of the length of treatment to TRS. Analysed predictors include gender, age, ethnicity, positive symptoms severity, problems with activities of daily living, psychiatric comorbidities, involuntary hospitalisation and treatment with long-acting injectable antipsychotics. Results We observed a continuum of the length of treatment until TRS presentation. Having severe hallucinations and delusions at treatment start was associated shorter duration of treatment until the presentation of TRS. Conclusions Our findings do not support a clear cut categorisation between early and late TRS, based on length of treatment until treatment resistance onset. More severe positive symptoms predict earlier onset of treatment resistance. Disclosure DFdF, GKS, EF and IR have received research funding from Janssen and H. Lundbeck A/S. RDH and HS have received research funding from Roche, Pfizer, Janssen and Lundbeck. SES is employed on a grant held by Cardiff University from Takeda Pharmaceutical Comp

PurposeTo examine the time course of recovery for gait and neuromuscular function immediately after and 24-h post interval training. In addition, this study compared the impact of different statistical approaches on detecting changes.MethodsTwenty (10F, 10M) healthy, recreational club runners performed a high-intensity interval training (HIIT) session consisting of six repetitions of 800 m. A 6-min medium intensity run was performed pre, post, and 24-h post HIIT to assess hip and knee kinematics and coordination variability. Voluntary activation and twitch force of the quadriceps, along with maximum isometric force were examined pre, post, and 24-h post significance HIIT. The time course of changes were examined using two different statistical approaches: traditional null hypothesis significance tests and “real” changes using minimum detectable change.ResultsImmediately following the run, there were significant (P < 0.05) increases in the hip frontal kinematics and coordination variability. The runners also experienced a loss of muscular strength and neuromuscular function immediately post HIIT (P < 0.05). Individual assessment, however, showed that not all runners experienced fatigue effects immediately post HIIT. Null hypothesis significance testing revealed a lack of recovery in hip frontal kinematics, coordination variability, muscle strength, and neuromuscular function at 24-h post, however, the use of minimum detectable change suggested that most runners had recovered.ConclusionHigh intensity interval training resulted in altered running kinematics along with central and peripheral decrements in neuromuscular function. Most runners had recovered within 24-h, although a minority still exhibited signs of fatigue. The runners that were not able to recover prior to their run at 24-h were identified to be at an increased risk of running-related injury.

Malaria is one of the deadliest vector-borne diseases in the world. Researchers are developing new genetic and conventional vector control strategies to attempt to limit its burden. Novel control strategies require detailed safety assessment to ensure responsible and successful deployments. Anopheles gambiae sensu stricto (s.s.) and Anopheles coluzzii, two closely related subspecies within the species complex Anopheles gambiae sensu lato (s.l.), are among the dominant malaria vectors in sub-Saharan Africa. These two subspecies readily hybridise and compete in the wild and are also known to have distinct niches, each with spatially and temporally varying carrying capacities driven by precipitation and land use factors. We model the spread and persistence of a population-modifying gene drive system in these subspecies across sub-Saharan Africa by simulating introductions of genetically modified mosquitoes across the African mainland and its offshore islands. We explore transmission of the gene drive between the two subspecies that arise from different hybridisation mechanisms, the effects of both local dispersal and potential wind-aided migration to the spread, and the development of resistance to the gene drive. Given the best current available knowledge on the subspecies' life histories, we find that an introduced gene drive system with typical characteristics can plausibly spread from even distant offshore islands to the African mainland with the aid of wind-driven migration, with resistance beginning to take over within a decade. Our model accounts for regional to continental scale mechanisms, and demonstrates a range of realistic dynamics including the effect of prevailing wind on spread and spatio-temporally varying carrying capacities for subspecies. As a result, it is well-placed to answer future questions relating to mosquito gene drives as important life history parameters become better understood.

Context: Given the growing interest in digital health interventions (DHI) and increasing number of commercial products targeting youth with ADHD, we conducted a mapping review of the current evidence for DHI for children and adolescents with ADHD. Objective: To identify DHI designed to support or extend ADHD treatment. Data sources: Electronic databases (PubMed, ACM Digital Library, and IEEE Xplore) were searched for studies published in English from January 1, 2004, through January 1, 2022. Search keywords included ADHD and terms for technology (e.g., digital, smartphone, computer) and treatment (e.g., treatment, intervention, cognitive training, neurofeedback). Study selection: Two reviewers reviewed titles, abstracts, and articles. Prior reviews and meta-analyses for two clusters of DHI (cognitive training and neurofeedback) were identified and summarized. The remaining 1,246 records focused on other DHI, and 51 studies representing 16 countries met eligibility criteria. These DHI addressed functioning in domains commonly targeted in treatments for ADHD and were classified based on targeted domains, users, technological platforms, and intended settings. Results: The 51 DHI studies described interventions delivered via serious games or e-learning, the web, mHealth, telehealth, and augmented or virtual reality. DHI targeted a range of domains relevant to ADHD treatment: cognition, social-emotional skills, behavior management, academic/organizational skills, medication adherence, vocational skills, motor behaviors, and clinical care. Twelve well-designed, adequately powered randomized clinical trials reported positive outcomes from interventions delivered using telehealth, the web, mHealth applications, exergaming, and clinician decision-making support tools. Limitations: Keyword selection, terminology usage, and digital libraries in the DHI space were not consistent within or across disciplines, nor across countries, which limited study identification. Few studies had evidence from randomized, controlled trials which limited information on the efficacy of most tools. Conclusions: Research supports the use of several DHI and describes emerging DHI, not yet available for implementation in community settings. Our review provides a map of the current field, identifies gaps and potentials for future research, and highlights the need to increase translation from early designs to robust evidence-based products.