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Abstract Identification of interacting vulnerabilities is essential to reduce maternal and perinatal mortality in sub-Saharan Africa (SSA). High parity (≥ 5 previous births) is an underemphasized biological vulnerability linked to poverty and affecting a sizeable proportion of SSA births. Despite increased risk, high parity women rarely use hospitals for childbirth. We assessed whether emergency referral during childbirth was associated with adverse events in high parity women in hospitals in Benin, Malawi, Tanzania and Uganda. We used e-registry data collected in 16 hospitals included in the Action Leveraging Evidence to Reduce perinatal morbidity and morTality (ALERT) trial. Main outcomes were severe maternal outcomes and in-facility peripartum death (fresh stillbirth or very early neonatal death). Main exposure was parity; emergency (in-labour) referral was included as effect modifier with potential confounders. We used multivariable logistic regression including parity/referral interaction and post-regression margins analysis. Among 80,663 births, 4,742 (5.9%) were to high parity women. One third reached hospital following emergency referral. Severe maternal outcomes and peripartum mortality were over 2.5-fold higher in high parity women with emergency referral compared to the lowest risk group. To avert these adverse events, emergency referral must be avoided by ensuring high parity women give birth in hospitals. Trial registration Pan African Clinical Trial Registry ( www.pactr.org ): PACTR202006793783148. Registered on 17th June 2020.

Abstract Background Glycogen storage disease (GSD) Ia is an ultra-rare inherited disorder of carbohydrate metabolism. Patients often present in the first months of life with fasting hypoketotic hypoglycemia and hepatomegaly. The diagnosis of GSD Ia relies on a combination of different biomarkers, mostly routine clinical chemical markers and subsequent genetic confirmation. However, a specific and reliable biomarker is lacking. As GSD Ia patients demonstrate altered lipid metabolism and mitochondrial fatty acid oxidation, we built a machine learning model to identify GSD Ia patients based on plasma acylcarnitine profiles. Methods We collected plasma acylcarnitine profiles from 3958 patients, of whom 31 have GSD Ia. Synthetic samples were generated to address the problem of class imbalance in the dataset. We built several machine learning models based on gradient-boosted trees. Our approach included hyperparameter tuning and feature selection and generalization was checked using both nested cross-validation and a held-out test set. Results The binary classifier was able to correctly identify 5/6 GSD Ia patients in a held-out test set without generating significant amounts of false positive results. The best model showed excellent performance with a mean received operator curve (ROC) AUC of 0.955 and precision-recall (PR) curve AUC of 0.674 in nested CV. Conclusions This study demonstrates an innovative approach to applying machine learning to ultra-rare diseases by accurately identifying GSD Ia patients based on plasma free carnitine and acylcarnitine concentrations, leveraging subtle acylcarnitine abnormalities. Acylcarnitine features that were strong predictors for GSD Ia include C16-carnitine, C14OH-carnitine, total carnitine and acetylcarnitine. The model demonstrated high sensitivity and specificity, with selected parameters that were not only robust but also highly interpretable. Our approach offers potential prospect for the inclusion of GSD Ia in newborn screening. Rare diseases are underrepresented in machine learning studies and this work highlights the potential for these techniques, even in ultra-rare diseases such as GSD Ia.

Abstract Aims Acute myocarditis, although a rare disease, can be associated with sudden cardiac death or the need for transplantation in both children and young adults. To date, there is no definitive evidence to support the routine use of immunosuppressive therapy or treatment targeting inflammation in patients with myocarditis. Animal models of cardiovascular (CV), as well as neurological diseases, have demonstrated that cannabidiol has significant anti‐inflammatory properties and may represent a promising therapy in acute myocarditis. This efficacy has been shown in a murine model of autoimmune myocarditis as well as in in vitro and in vivo models of heart failure (HF). Methods and results We present the rationale and design of the ARCHER Trial, an international multicentre, double‐blind, randomized, placebo‐controlled, phase II study examining the safety and efficacy of a pharmaceutically produced cannabidiol formulation, in patients with mild to moderate acute myocarditis. Eligible patients are those with acute myocarditis, randomized within 10 days of the diagnostic cardiac MRI (CMR), which has met defined diagnostic criteria for myocarditis. Oral treatment (cannabidiol or placebo) is titrated from 2.5 mg/kg of body weight up to 10 mg/kg of body weight b.i.d. (or highest tolerated dose) and taken for 12 weeks in addition to standard of care therapy for HF. The primary endpoints are defined as changes in global longitudinal strain (GLS) and extra cellular volume (ECV), measured by CMR at 12 weeks. Assuming 80% power, a 5% alpha risk and 25% missing CMR follow‐up data at Week 12, 100 patients are required to demonstrate the desired treatment effect of 18%. The change in left ventricular ejection fraction (LVEF) from baseline to Week 12 was selected as the secondary endpoint. Additional exploratory endpoints include changes in hs‐troponin, NT‐proBNP, markers of inflammation and endothelial function during the 12‐week treatment period. The trial is ongoing but is now more than 50% recruited. As enrolment in the trial continues, no interim data are available for inclusion in this Design paper. Conclusions The ongoing ARCHER Trial is an international, multicentre, double‐blind, randomized, placebo‐controlled phase II study, designed to determine the effect of a pharmaceutically produced cannabidiol formulation on CMR parameters in patients presenting with acute myocarditis. Enrolment of 100 patients is expected to conclude in Q3 2024. Study results will be available in early 2025.

Abstract Background Regaining walking ability is a key target in geriatric rehabilitation. This study evaluated the prevalence of walking ability at (pre‐)admission and related clinical characteristics in a cohort of geriatric rehabilitation inpatients; in inpatients without walking ability, feasibility and effectiveness of progressive resistance exercise training (PRT) were assessed. Methods Inpatients within RESORT, an observational, longitudinal cohort of geriatric rehabilitation inpatients, were stratified in those with and without ability to walk independently (defined by Functional Ambulation Classification (FAC) score ≤ 2) at admission; further subdivision was performed by pre‐admission walking ability. Clinical characteristics at admission, length of stay, and changes in physical and functional performance throughout admission were compared depending on (pre‐)admission walking ability. Feasibility (relative number of PRT sessions given and dropout rate) and effectiveness [change in Short Physical Performance Battery, FAC, independence in (instrumental) activities of daily living (ADL/IADL)] of PRT (n = 11) in a subset of inpatients without ability to walk independently at admission (able to walk pre‐admission) were investigated compared with usual care (n = 11) (LIFT‐UP study). Results Out of 710 inpatients (median age 83.5 years; 58.0% female), 52.2% were not able to walk independently at admission, and 7.6% were not able to walk pre‐admission. Inpatients who were not able to walk independently at admission, had a longer length of stay, higher prevalence of cognitive impairment and frailty and malnutrition risk scores, and a lower improvement in independence in (I)ADL compared with inpatients who were able to walk at both admission and pre‐admission. In LIFT‐UP, the relative median number of PRT sessions given compared with the protocol (twice per weekday) was 11 out of 44. There were no dropouts. PRT improved FAC (P = 0.028) and ADL (P = 0.034) compared with usual care. Conclusions High prevalence of inpatients who are not able to walk independently and its negative impact on independence in (I)ADL during geriatric rehabilitation highlights the importance of tailored interventions such as PRT, which resulted in improvement in FAC and ADL.

Establishing early academic momentum via credit accumulation is strongly associated with community college student success. Using data from one of the nation's largest and most racially diverse community college systems, our quasi-experimental study examined how different first-semester credit loads influenced persistence. For part-time students (less than 12 semester credit hours), enrolling in one additional course (3 more credits) significantly improved their chances of persistence to the subsequent term and next academic year. For part-time students, an increased credit load was significantly and positively related to persistence. However, for full-time students, an increase from 12 to 15 credits was not related to persistence. These patterns were consistent across subgroups by students' level of academic preparation (developmental education status) and degree objective (workforce credential or transfer associate degree). Moreover, the increased course load did not significantly hinder students' early academic performance as measured by GPA for any group and in some cases was related to increased GPA. We discuss the implications of these findings for academic advising, course scheduling, and completion initiatives at community colleges.

BackgroundMental illness is one of the top causes of preventable pregnancy-related deaths in the United States. There are many barriers that interfere with the ability of perinatal individuals to access traditional mental health care. Digital health interventions, including app-based programs, have the potential to increase access to useful tools for these individuals. Although numerous mental health apps exist, there is little research on developing programs to address the unique needs of perinatal individuals. In an effort to fill this gap, a multidisciplinary team of experts in psychology, psychiatry, obstetrics, and pediatric primary care collaborated to develop the novel Perinatal Skills Program within Maya, a flexible and customizable cognitive-behavioral skills app. Maya-Perinatal Skills Program (M-PSP) uses evidence-based strategies to help individuals manage their mood and anxiety symptoms during pregnancy and post partum. ObjectiveThis pilot study aims to assess the feasibility, acceptability, and usability of M-PSP and explore links between program use and symptoms of anxiety and low mood. MethodsThis single-arm trial will recruit 50 pregnant or postpartum individuals with mild-to-moderate anxiety or mood symptoms. Participants will be recruited from a variety of public and private insurance-based psychiatry, obstetrics, and primary care clinics at a large academic medical center located in New York City. Participants will complete all sessions of M-PSP and provide feedback. Outcome measures will include qualitative and quantitative assessments of feasibility, acceptability, and usability, passively collected program usage data, and symptom measures assessing mood, anxiety, and trauma. Planned data analysis includes the use of the grounded theory approach to identify common themes in qualitative feedback, as well as an exploration of possible associations between quantitative data regarding program use and symptoms. ResultsThe recruitment began on August 2023. As of October 2024, a total of 32 participants have been enrolled. The recruitment will continue until 50 participants have been enrolled. ConclusionsDigital health interventions, like M-PSP, have the potential to create new pathways to reach individuals struggling with their mental health. The results of this study will be the groundwork for future iterations of M-PSP in the hopes of providing an accessible and helpful tool for pregnant and postpartum individuals. Trial RegistrationClinicalTrials.gov NCT05897619; https://classic.clinicaltrials.gov/ct2/show/NCT05897619 International Registered Report Identifier (IRRID)PRR1-10.2196/59461

IntroductionThe effective management of depression, anxiety, and other forms of psychological distress depends on individuals’ readiness to seek and accept help for their mental suffering. Understanding which personality traits relate to help-seeking can help better tailor mental healthcare to individual needs. However, findings regarding associations of personality traits with help-seeking have been inconsistent.MethodsThis systematic review and meta-analysis focused on English-language research studies on the association of personality (encompassing personality disorders, Five Factor –Big Five– dimensions, and other measures of personality) with depression, anxiety, or unspecified psychological distress in adults aged 18 years and older. Procedures followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy included two concepts: personality and help-seeking and was carried out on PubMed, Embase, Web of Science, and PsycINFO. Reference tracking and searches on Google Scholar were additionally performed. Sufficiently homogeneous subsections were analyzed by meta-analysis.ResultsA total of 48 studies described in 47 records reported on the association between personality and help-seeking. Nine assessed personality disorders, 29 Five Factor dimensions, and 13 other personality constructs. Twenty-three studies investigated attitudes towards help-seeking while 25 studies investigated help-seeking behaviors. Of the studies investigating behavior, three used external observations, the rest relied on self-reports/clinician-administered questionnaires. Evidence highlighted a dissociation between attitudes and behavior for schizotypal and borderline personality disorders, and neuroticism, which displayed negative help-seeking attitudes but more help-seeking behavior. By contrast, paranoid, schizoid and obsessive-compulsive personality disorders related to both negative help-seeking attitudes and behavior across studies. Limited evidence linked extraversion to social support seeking and conscientiousness to care seeking behaviors. Meta-analyses on the Five Factor dimensions and help-seeking attitudes supported robust negative associations with neuroticism, as well as positive associations with agreeableness, albeit less reliably. Other personality traits mostly corroborated the above relationships, while also contributing new perspectives, such as help-seeking behavior’s negative associations with reality weakness and cynicism, and positive associations with abasement and rigidity.DiscussionFuture research should investigate help-seeking behavior using external observations and longitudinal designs. Assessing personality in clinical settings can help identify populations at risk of keeping to themselves when mentally distressed.

BackgroundThe increased use of digital data in health research demands interdisciplinary collaborations to address its methodological complexities and challenges. This often entails merging the linear deductive approach of health research with the explorative iterative approach of data science. However, there is a lack of structured teaching courses and guidance on how to effectively and constructively bridge different disciplines and research approaches. ObjectiveThis study aimed to provide a set of tools and recommendations designed to facilitate interdisciplinary education and collaboration. Target groups are lecturers who can use these tools to design interdisciplinary courses, supervisors who guide PhD and master’s students in their interdisciplinary projects, and principal investigators who design and organize workshops to initiate and guide interdisciplinary projects. MethodsOur study was conducted in 3 steps: (1) developing a common terminology, (2) identifying established workflows for research question formulation, and (3) examining adaptations of existing study workflows combining methods from health research and data science. We also formulated recommendations for a pragmatic implementation of our findings. We conducted a literature search and organized 3 interdisciplinary expert workshops with researchers at the University of Zurich. For the workshops and the subsequent manuscript writing process, we adopted a consensus study methodology. ResultsWe developed a set of tools to facilitate interdisciplinary education and collaboration. These tools focused on 2 key dimensions— content and curriculum and methods and teaching style—and can be applied in various educational and research settings. We developed a glossary to establish a shared understanding of common terminologies and concepts. We delineated the established study workflow for research question formulation, emphasizing the “what” and the “how,” while summarizing the necessary tools to facilitate the process. We propose 3 clusters of contextual and methodological adaptations to this workflow to better integrate data science practices: (1) acknowledging real-life constraints and limitations in research scope; (2) allowing more iterative, data-driven approaches to research question formulation; and (3) strengthening research quality through reproducibility principles and adherence to the findable, accessible, interoperable, and reusable (FAIR) data principles. ConclusionsResearch question formulation remains a relevant and useful research step in projects using digital data. We recommend initiating new interdisciplinary collaborations by establishing terminologies as well as using the concepts of research tasks to foster a shared understanding. Our tools and recommendations can support academic educators in training health professionals and researchers for interdisciplinary digital health projects.

Summary: Background: Little is known about the practices and resources employed by general practitioners (GPs) in Singapore to manage late-life depression. As the country is stepping up its efforts to promote collaborative care across community mental health and geriatric care, understanding GPs’ current practices when managing late-life depression appears timely. Methods: This qualitative descriptive study explored the perspectives on late-life depression of 28 private GPs practicing in Singapore through online semi-structured group and individual interviews. GPs were purposively sampled across age, gender, and ethnicity. Analysis followed a reflexive thematic approach and focused on physician- and system-related factors. Findings: Clinical instinct, experience, and knowledge of appropriate resources for specific patients played an important role for GPs during late-life depression care. GPs paid particular attention to communicating with patients tactfully during initial assessments and diagnosis, although some GPs chose to be upfront with patients with whom they had already established rapport. Using non-English languages when communicating about depression could mitigate stigma in some cases but added confusion in others. GPs relied primarily on their own professional support network to manage late-life depression. Although GPs acknowledged the usefulness of public care services, they felt that collaborative care was hindered by a lack of efficient communication channels between providers and appropriate financial coverage to coordinate the frequently complex care of depressed older adults. Interpretation: Current resources and practices to manage late-life depression vary greatly between private GPs in Singapore. This needs to be considered during ongoing reforms to achieve effective collaborative care. Funding: This work was funded by the Division of Family Medicine Research Capabilities Building Budget under the project “Technology and Compassion: Improving Patient Outcomes Through Data Analytics and Patients’ Voice in Primary Care” [NUHSRO/2022/049/NUSMed/DFM].

Abstract Calcium supplementation in pregnancy is recommended in contexts with low dietary calcium intake to reduce the risk of pre‐eclampsia and its complications. The World Health Organisation suggested high‐dose calcium supplementation (1500–2000 mg/day), divided into three doses and taken at different times from daily iron‐folic supplements. We conducted a mixed methods evaluation study to assess experiences, acceptability and barriers to high‐dose calcium supplementation from the perspectives of pregnant women and antenatal health care providers at two public health facilities in Dar es Salaam, Tanzania. Descriptive statistics and thematic analysis were used to characterise acceptability, barriers and overall experiences of using high‐dose calcium supplementation. Pregnant women in the cohort were aged 19–41 years, with 32.4% being primiparous. The proportion of pregnant women who liked calcium supplements ‘a lot’ decreased from 50.2% at the first visit to 31.8% at the last antenatal follow‐up visit. Adherence was 71.3% (interquartile range: 50.5%, 89.3%), with only 24.0% of the participants taking 90% or more of the required supplements. Although participants expressed positive attitudes towards using calcium supplements, they also voiced concerns about the large size, side effects, the potential to forget and the burden of taking calcium supplements three times per day. Antenatal health care providers also affirmed the high burden of taking calcium supplements in addition to iron‐folic acid supplements. Participants expressed the acceptability of using calcium supplements during pregnancy, but adherence to three doses per day posed challenges to pregnant women. Reducing the number of calcium supplement doses per day may improve adherence.

Category: Other Introduction/Purpose: Current literature suggests that patients feel medical exam gloves are often overused or used inappropriately, while also having concerns about the possibility of cross-contamination with glove utilization. Additionally, there is very little research on the effect that glove use has on patient’s perceptions of physical exam quality and surgeon personability. The purpose of this research project is to determine whether patients that are having their foot and ankle examined prefer their orthopaedic surgeon to wear medical exam gloves. Methods: Anonymous surveys were administered and collected during clinic for two different fellowship trained foot and ankle orthopaedic surgeons at a single institution. Any patient willing to sign a consent form was included. Patient age, gender, and reason for visit were collected along with a survey of 5 questions on glove utilization. Survey questions were scored on a Likert scale, with 1=strongly agree, 2=agree, 3=neutral, 4=disagree, and 5=strongly disagree. Descriptive statistics, data normalcy, and appropriate significance tests were used to analyze results while controlling for glove utilization (yes or no), gender (female or male), and age group (< 39, 40-49, 50-59, 60-69, and 70+), at p< 0.05 significance. Results: In total, 99 patients agreed to complete the survey (53.5% female and 36.4% male, with a mean age of 55.3 and 54.8, respectively). Overall, physicians used gloves more with male than female patients (33.3 vs 9.43%, p =0.059), although males were slightly more agreeable to preferring no gloves (2.86 vs. 3.17). When the physician wore gloves, patients were more agreeable to glove use for themselves (2.5 vs. 3.24, p=0.001) and for others (2.21 vs. 3.0, p< 0.001). Patients across all groups were agreeable with glove use when examining wounds (range 1.74–2.47.) For all patients, gender, glove use, and age had no effect on agreeing that their physical exam was thorough (average 1.61±0.726) and on disagreeing that gloves effected provider demeanor (average 3.32±0.874). Conclusion: In general, glove use by foot and ankle orthopaedic surgeons did not negatively impact patient perception of physical examination thoroughness, nor did it confer less personability onto their physician. While patients across all groups demonstrated a slight preference for glove use during wound examinations, glove use preference in general was otherwise neutral. These results suggest that, on average, the utilization of gloves does not impact patient care and may therefore be up to the discretion of the provider.

Monitoring reproductive physiology in wildlife can be a useful tool for assessing population dynamics for conservation and management purposes. Utilizing non-invasive approaches for this, such as quantifying reproductive hormone metabolites from faeces, can be challenging when defaecation events are not observed, or when cryptic species like African clawless otters (Aonyx capensis) are involved. Additionally, test systems for quantifying hormone metabolites in a species for the first time must first be reliably validated prior to use. Our results indicate that Epiandrosterone and Progesterone EIAs are most suitable for determining fAM and fPM concentrations in African clawless otter spraints. The fAM:fPM ratio and respective thresholds are more reliable in sex identification compared to the separate use of individual hormone classes. Sex-related hormone metabolite concentrations remained comparable for up to 12hrs post-defaecation in both sexes. • We screened two androgen and two progestagen enzyme-immunoassays (EIAs) for suitability and reliable quantification of faecal androgen metabolites (fAM) and faecal progestagen metabolites (fPM) in African clawless otters. • We assessed whether the ratio of fAM:fPM concentrations can be used to assign sex to faecal samples from unknown individuals. • We tested the stability of fAM and fPM concentrations post-defaecation to determine the effects of environmental exposure and bacterial metabolism.

Grazia Lazzari,1 Ilaria Benevento,1 Antonietta Montagna,1 Barbara D’Andrea,1 Giuseppina De Marco,2 Giovanni Castaldo,1 Antonella Bianculli,3 Raffaele Tucciariello,3 Vito Metallo,1 Angela Pia Solazzo1 1Radiation Oncology Unit, IRCCS, CROB, Rionero in Vulture, PZ, Italy; 2Radiation Oncology Unit, University Vanvitelli, Napoli, NA, Italy; 3Physic Unit, Radiation Oncology Unit, IRCCS, CROB, Rionero in Vulture, PZ, ItalyCorrespondence: Grazia Lazzari, Radiation Oncology Unit, IRCCS, CROB, Rionero in Vulture, PZ, 85028, Italy, Email lazzarigrazia@gmail.comPurpose: We administered a new breast cancer (BC) adjuvant therapy sequence that delivered postoperative radiotherapy (PORT) before chemotherapy (CT). Our aim was to assess the gain in time to start PORT and the G2–G3 acute–subacute toxicity rate of whole breast adjuvant hypofractionated radiotherapy (AH-RT) administered up-front to the third-generation adjuvant CT (A-CT) in high-risk nodal positive BC in a preliminary report at 2 years.Methods: This retrospective study analysed the duration of treatment and safety of AH-RT administered up-front to A-CT in high-risk nodal positive BC patients (pts). Data on 45 pts treated between 2022– 2023 were collected. All pts underwent the third-generation A-CT after AH-RT 15– 5 fractions with or without a boost. Acute toxicity was scored according to CTCAE v5.0 for skin, pulmonary, and cardiac adverse events. Univariate and multivariate analyses were conducted to assess significant prognosticators for skin/lung/heart acute toxicities in the AH-RT 5– 15 fractions arms and CT (p < 0.005).Results: A reduction in the time to PORT initiation and overall adjuvant treatment time was recorded. RT was initiated 5 median weeks after surgery, and A-CT was performed 9 median weeks after surgery. The median duration of the entire adjuvant treatment was 35 weeks after surgery. At 6 months mean follow-up, no significant differences in G2–G3 toxicity were noted between the different hypofractionated RT arms, irrespective of the CT schedules, irradiated volumes, or boost (SIB or sequential) in univariate and multivariate analyses. In the multivariate analysis, no significant effects in CT schedules and AH-RT 5– 15 arms for skin/lung acute toxicities (p = 0.077 and p = 0.68; 0.67 and 0.87, respectively) were recorded.Conclusion: As a new PORT approach in BC, AH-RT up-front to the third-generation A-CT appeared safe with a low acute toxicity profile, providing an advantage in shortening the time from surgery to PORT initiation and the overall adjuvant treatment time.Keywords: PORT, third-generation chemotherapy, hypofractionated radiotherapy

Background: Contradictory findings link trait conscientiousness in mid- and late life to increased healthspan and lifespan, as well as to death by suicide. It remains unclear whether conscientiousness is associated with higher odds of attempting suicide or with more severe suicidal behavior among attempters, and whether its relationship to suicide risk varies with aging-related stressors, such as declining health. Methods: In this cross-sectional study comprising 313 depressed adults aged ≥40 years and participating in the Longitudinal Research Program in Late-Life Suicide (Pittsburgh, USA), we employed logistic and linear regression to test whether conscientiousness was associated with the presence of recent suicidal behavior (≤2 years) and with intent severity in recent attempters (n = 84). We further tested whether the above relationships varied based on mental, cognitive, and physical health status, measured as depression severity, cognitive functioning, and the presence/absence of severe physical illness. Results: Participants were 62.1 years old on average (SD = 7.6), 85% White, and 53% female. Recent attempters had a mean age of 61.8 years at their most recent attempt (SD = 8.5), had lower cognitive functioning and were more likely severely physically ill than comparisons. Conscientiousness was positively associated with a higher likelihood of recent suicidal behavior overall (adjusted OR = 1.44, 95% CI = 1.09, 1.90, p = .010), but not in case of co-occurring severe physical illness (interaction OR = 0.54, 95% CI = 0.30, 0.97, p = .039). Conscientiousness was also positively associated with suicidal intent at the most recent attempt (adjusted β = 1.60, SE = 0.62, p = .012), explaining 7% of its variance, although this association lost significance after adjusting for other personality dimensions. Conclusions: Highly conscientious middle-aged and older adults may be at increased risk of resolute suicidal behavior, although conscientiousness may not confer additional suicide risk among those severely physically ill.

Background Intratumoral heterogeneity (ITH) and subclonal antigen expression blunt antitumor immunity and are associated with poor responses to immune-checkpoint blockade immunotherapy (ICB) in patients with cancer. The underlying mechanisms however thus far remained elusive, preventing the design of novel treatment approaches for patients with high ITH tumors.Methods We developed a mouse model of lung adenocarcinoma with defined expression of different neoantigens (NeoAg), enabling us to analyze how these impact antitumor T-cell immunity and to study underlying mechanisms. Data from a large cancer patient cohort was used to study whether NeoAg architecture characteristics found to define tumor immunogenicity in our mouse models are linked to ICB responses in patients with cancer.Results We demonstrate that concurrent expression and clonality define NeoAg architectures which determine the immunogenicity of individual NeoAg and drive immune evasion of tumors with heterogenous NeoAg expression. Mechanistically, we identified concerted interplays between concurrent T-cell responses induced by cross-presenting dendritic cells (cDC1) mirroring the tumor NeoAg architecture during T-cell priming in the lymph node. Depending on the characteristics and clonality of respective NeoAg, this interplay mutually benefited concurrent T-cell responses or led to competition between T-cell responses to different NeoAg. In tumors with heterogenous NeoAg expression, NeoAg architecture-induced suppression of T-cell responses against branches of the tumor drove immune evasion and caused resistance to ICB. Therapeutic RNA-based vaccination targeting immune-suppressed T-cell responses synergized with ICB to enable control of tumors with subclonal NeoAg expression. A pan-cancer clinical data analysis indicated that competition and synergy between T-cell responses define responsiveness to ICB in patients with cancer.Conclusions NeoAg architectures modulate the immunogenicity of NeoAg and tumors by dictating the interplay between concurrent T-cell responses mediated by cDC1. Impaired induction of T-cell responses supports immune evasion in tumors with heterogenous NeoAg expression but is amenable to NeoAg architecture-informed vaccination, which in combination with ICB portrays a promising treatment approach for patients with tumors exhibiting high ITH.

Summary: Background: Detection and management of late-life depression largely relies on primary care. Yet in Singapore, older adults are unlikely to seek help for their mental health from their primary care providers. This qualitative descriptive study explores how late-life depression manifests to general practitioners (GPs) in the Singaporean primary care setting. Methods: Twenty-eight private GPs practicing in Singapore were asked about their clinical experience with late-life depression during semi-structured group and individual discussions conducted online. Participants were purposively sampled across age, gender, and ethnicity (Chinese, Malay, Indian). Transcripts were analysed with reflexive thematic analysis. Findings: To GPs, depression in older patients often manifests through somatic symptoms or subtle behavioural changes, only detectable through follow-ups or collateral history. GPs reported that older patients attribute depressive symptoms to normal ageing or do not mention them, particularly within an Asian culture encouraging stoic endurance. GPs perceived late-life depression as reactions to ageing-related stressors, with male, low-income, or institutionalised patients being at particular risk of insidious, severe depression. GPs noted ethnic differences regarding families’ involvement in care, which they described as helpful, but sometimes stress-provoking for patients. Fear of burdensomeness or loss of autonomy/social role could prompt rejection of diagnosis and treatment in patients. GPs considered good patient-doctor rapport as a facilitator at every step of the care process, noting more favourable prognosis in care-concordant patients. Interpretation: Depression in older adults in Singapore can be covert, with favourable outcomes relying on GPs’ ability to pick up on subtle changes, assess patients holistically, and build rapport with patients and families. Funding: This work was funded by the Division of Family Medicine Research Capabilities Building Budget under the project “Technology and Compassion: Improving Patient Outcomes Through Data Analytics and Patients’ Voice in Primary Care” [NUHSRO/2022/049/NUSMed/DFM].

Complementing discourse following a February 2023 event on dietary protein needs in Southeast Asia (SEA), this symposium report summarizes the region’s protein intake, while simultaneously examining the impact of dietary shift toward complementary and alternative proteins and their health implications. It highlights the importance of protein quality in dietary evaluations, optimal intake, and sustainability, advocating for environmentally conscious protein production and innovation in future foods. Discussion points, expert opinions, national nutrition data, and relevant literature, addressing protein intake and quality, their impact on human health, and various technologies for future foods production, have been included. Despite increased protein supply in SEA, protein requirements, particularly during crucial life stages, are often unmet owing to insufficient focus on protein quality. Factoring in amino acids content and bioaccessibility are crucial for assessing nutritional requirement and sustainability evaluations, rather than solely relying on protein quantity alone. Different food sources of protein also have different key conutrients for health relevance such as vitamin B-12 and ω-3 fatty acids. Innovations in food structure, processing, and technology are key to developing nutritious, sustainable, and appealing future foods, including from complementary and alternative protein sources, while considering safety aspects, especially allergenicity. Addressing protein needs in SEA requires a dual focus on protein quantity and quality, underlining the role of public health policies and guidelines that consider key nutritional differences of animal-source and plant-based proteins. To address regional demands, future food innovations should aim at creating unique yet needful food categories or supplementing current existing sources, rather than mimicking current products.

This single-participant case study examines the feasibility of using custom virtual reality (VR) gaming software in the home environment for low-dose Hand Arm Bimanual Intensive Training (HABIT). A 10-year-old with right unilateral cerebral palsy participated in this trial. Fine and gross motor skills as well as personal goals for motor outcomes were assessed before and after the intervention using the Box and Blocks Test, Nine-Hole Peg Test, and Canadian Occupational Performance Measure. Movement intensities collected via the VR hardware accelerometers, VR game scores, and task accuracy were recorded via the HABIT-VR software as indices of motor performance. The child and family were instructed to use the HABIT-VR games twice daily for 30 minutes over a 14-day period and asked to record when they used the system. The child used the system and completed the 14-hour, low-dose HABIT-VR intervention across 22 days. There was no change in Box and Blocks Test and Nine-Hole Peg Test scores before and after the intervention. Canadian Occupational Performance Measure scores increased but did not reach the clinically relevant threshold, due to high scores at baseline. Changes in motor task intensities during the use of VR and mastery of the VR bimanual tasks suggested improved motor efficiency. This case study provides preliminary evidence that HABIT-VR is useful for promoting adherence to HABIT activities and for the maintenance of upper extremity motor skills in the home setting.

Background Perioperative management in autologous breast reconstruction has gained focus in recent years. This study compares two pain management protocols in patients undergoing abdominal-based free flap breast reconstruction: a past protocol (PP) and a current protocol (CP)—both intended to reduce opioid consumption postoperatively. The PP entails use of a pain catheter in the abdominal wound and the CP consists of an intraoperative nerve block in addition to refinements in the oral pain management. We hypothesize that the CP reduces opioid consumption compared to PP.

This study aimed to explore whether early developmental abilities are related to future executive function (EF) in children with motor delays. Fourteen children with motor delays (Mean age = 10.76, SD = 2.55) were included from a larger study. Object interaction and developmental outcomes (Bayley-III) were evaluated at baseline and 3, 6, and 12 months post-baseline. Bayley-III and EF assessments (Minnesota Executive Function Scale) were conducted at 36 months post-baseline. Children with high EF demonstrated advanced early bimanual, visual–bimanual, receptive language, expressive language, and fine motor skills compared to children with low EF. Significant positive correlations between later Bayley-III and EF scores were found for cognitive, expressive language, and fine motor scores. These preliminary results suggest that early developmental skills support the emergence of EF in children with motor delays.