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Hypophosphatasia (HPP) is a rare inherited metabolic disorder characterized by deficient activity of tissue-nonspecific alkaline phosphatase (TNAP) caused by variants in the ALPL gene. Disease manifestations encompass skeletal hypomineralization with rickets and lung hypoplasia, vitamin B6-dependent seizures, craniosynostosis, and premature loss of deciduous teeth. The clinical presentation can comprise failure to thrive with muscular hypotonia, delayed motor development, and gait disturbances later in childhood. In adults, pseudofractures are a characteristic indicator of severely compromised enzyme activity, but non-canonical symptoms like generalized musculoskeletal pain, weakness, and fatigue, frequently accompanied by neuropsychiatric and gastrointestinal issues are increasingly recognized as key findings in patients with HPP. The diagnosis is based on clinical manifestations in combination with persistently low alkaline phosphatase (ALP) activity, elevated levels of ALP substrates, specifically inorganic pyrophosphate (PPi), pyridoxal 5'-phosphate (PLP) or urine phosphoethanolamine (PEA), and genetic confirmation of a causative ALPL variant. Considering the wide range of manifestations, treatment must be multimodal and tailored to individual needs. The multidisciplinary team for comprehensive management of HPP patients should include expertise to ensure disease state metabolic and musculoskeletal treatment, dental care, neurological and neurosurgical surveillance, pain management, physical therapy, and psychological care. Asfotase alfa as first-in-class enzyme replacement therapy (ERT) for HPP has been shown to improve survival, rickets, and functional outcomes in severely affected children, but further research is needed to refine how enzyme replacement can also address emerging manifestations of the disease. Prospectively, further elucidating the pathophysiology behind the diverse clinical manifestations of HPP is instrumental for improving diagnostic concepts, establishing novel means for substituting enzyme activity, and developing integrative, multimodal care., Competing Interests: Declarations. Disclosure: L. Seefried has received honoraria for lectures and advice from Amgen, AM-Pharma, Alexion, Biomarin, Chiesi, GedeonRichter, GSK/Haleon, Inozyme, Ipsen, KyowaKirin, Medi, Novartis, Stadapharm, Theramex, and Ultragenyx and research grants to the Institution (University of Würzburg) from Alexion, Chiesi, Kyowa Kirin. F. Genest has received honoraria for lectures from Abbvie, Alexion, and Lilly. E.T. Rush has received consulting fees from Alexion AstraZeneca Rare Disease, Ultragenyx Pharmaceuticals, Kyowa Kirin, Inozyme Pharma, Ipsen SA, Be Bio, Inc, honoraria for lectures from Alexion AstraZeneca Rare Disease, Kyowa Kirin, and Inozyme Pharma, research support from Alexion AstraZeneca Rare Disease, and Ultragenyx Pharmaceuticals. Human and Animal Rights: This overview manuscript does not report original human or animal data., (© 2025. The Author(s).)

Objective: Electronic health record (EHR) systems contain a wealth of clinical data stored as both codified data and free-text narrative notes (NLP). The complexity of EHR presents challenges in feature representation, information extraction, and uncertainty quantification. To address these challenges, we proposed an efficient Aggregated naRrative Codified Health (ARCH) records analysis to generate a large-scale knowledge graph (KG) for a comprehensive set of EHR codified and narrative features., Methods: Using data from 12.5 million Veterans Affairs patients, ARCH first derives embedding vectors and generates similarities along with associated p-values to measure the strength of relatedness between clinical features with statistical certainty quantification. Next, ARCH performs a sparse embedding regression to remove indirect linkage between features to build a sparse KG. Finally, ARCH was validated on various clinical tasks, including detecting known relationships between entity pairs, predicting drug side effects, disease phenotyping, as well as sub-typing Alzheimer's disease patients., Results: ARCH produces high-quality clinical embeddings and KG for over 60,000 codified and narrative EHR concepts. The KG and embeddings are visualized in the R-shiny powered web-API. 3 ARCH achieved high accuracy in detecting EHR concept relationships, with AUCs of 0.926 (codified) and 0.861 (NLP) for similar EHR concepts, and 0.810 (codified) and 0.843 (NLP) for related pairs. It detected drug side effects with a 0.723 AUC, which improved to 0.826 after fine-tuning. Using both codified and NLP features, the detection power increased significantly. Compared to other methods, ARCH has superior accuracy and enhances weakly supervised phenotyping algorithms' performance. Notably, it successfully categorized Alzheimer's patients into two subgroups with varying mortality rates., Conclusion: The proposed ARCH algorithm generates large-scale high-quality semantic representations and knowledge graph for both codified and NLP EHR features, useful for a wide range of predictive modeling tasks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Motivation: The increasing availability of Electronic Health Record (EHR) systems has created enormous potential for translational research. Recent developments in representation learning techniques have led to effective large-scale representations of EHR concepts along with knowledge graphs that empower downstream EHR studies. However, most existing methods require training with patient-level data, limiting their abilities to expand the training with multi-institutional EHR data. On the other hand, scalable approaches that only require summary-level data do not incorporate temporal dependencies between concepts., Methods: We introduce a DirectiOnal Medical Embedding (DOME) algorithm to encode temporally directional relationships between medical concepts, using summary-level EHR data. Specifically, DOME first aggregates patient-level EHR data into an asymmetric co-occurrence matrix. Then it computes two Positive Pointwise Mutual Information (PPMI) matrices to correspondingly encode the pairwise prior and posterior dependencies between medical concepts. Following that, a joint matrix factorization is performed on the two PPMI matrices, which results in three vectors for each concept: a semantic embedding and two directional context embeddings. They collectively provide a comprehensive depiction of the temporal relationship between EHR concepts., Results: We highlight the advantages and translational potential of DOME through three sets of validation studies. First, DOME consistently improves existing direction-agnostic embedding vectors for disease risk prediction in several diseases, for example achieving a relative gain of 5.5% in the area under the receiver operating characteristic (AUROC) for lung cancer. Second, DOME excels in directional drug-disease relationship inference by successfully differentiating between drug side effects and indications, correspondingly achieving relative AUROC gain over the state-of-the-art methods by 10.8% and 6.6%. Finally, DOME effectively constructs directional knowledge graphs, which distinguish disease risk factors from comorbidities, thereby revealing disease progression trajectories. The source codes are provided at https://github.com/celehs/Directional-EHR-embedding., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Problem: Academic promotion is important for faculty career development and retention in academic medicine. However, the promotion process is time consuming, with little guidance offered to ensure successful outcomes. The authors describe their institution's standardized approach to providing clear and reliable academic promotion support and share associated outcomes., Approach: An academic promotion support process, comprising 4 targeted preparation strategies and 3 coaching processes, was implemented in 2020 at Children's Mercy Kansas City to prepare faculty to submit promotion applications. Targeted preparation strategies include communication plans, an intent to apply process, how-to guides and templates, and institutional promotion committee review. Coaching processes include structured conversations with an immediate faculty leader, an Office of Faculty Development director, and, after committee review of applications, an institutional promotion committee reviewer. Descriptive statistics and promotion outcomes were compared preimplementation (2012-2019) and postimplementation (2020-2023)., Outcomes: In 2012-2019 (8 promotion cycles), prior to implementation of the academic promotion support process, 247 faculty applied for academic promotion. After implementation, in 2020-2023 (4 cycles), 196 faculty applied. From pre- to postimplementation, the mean volume of applications per cycle significantly increased from 31 to 49 (P = .03), and the proportion of approved promotion applications significantly increased from 89.5% (221/247) to 99.0% (194/196) (P < .001). No significant differences were observed in the proportions of applicants who were female (P = .77) or non-White (P = .51)., Next Steps: Creation of an institutional academic promotion support process can be effective in increasing the volume of applications and the likelihood of successful outcomes. Future research should focus on increasing the proportions of non-White faculty and female faculty who apply for promotion and analyzing longer-term outcomes for faculty who are promoted, such as progression to leadership roles., (Copyright © 2024 the Association of American Medical Colleges.)

Background: Fructose (50% of sucrose/sugar) is one component of free-sugars and is metabolized to uric acid, which is a known risk factor for gout and metabolic syndrome. Pacific peoples in New Zealand experience a higher prevalence of gout, type 2 diabetes, and overweight/obesity than other ethnic groups. Interestingly, despite having a similar body mass index (BMI), they tend to have a higher proportion of appendicular skeletal muscle mass (ASMM) and less fat than other ethnic groups. Given this context, this study aimed to evaluate the associations between serum uric acid (SUA), free-sugar intake, and ASMM., Methods: In a nested sub-study from the Pacific Islands Families birth-cohort study, 101 boys and 99 girls (all aged 14 and 15 years) self-reported how often they had consumed foods containing sugar in the past month. Anthropometry, body fatness, and ASMM by dual-energy X-ray absorptiometry and metabolic risk factors, including SUA were measured., Results: Overall, 43% of girls and 57% of boys consumed 'sugary drinks' twice or more a day. When analyzed by group, ASMM was positively related to SUA for both boys and girls (r = 0.593, p < 0.0001). The effect of the intake of 'sugary drinks' on SUA (r = 0.176, p = 0.013) was reduced when ASMM was considered in the relationships., Conclusions: This study shows high SUA levels in Pacific adolescents, with a positive association between ASMM and SUA in both genders. Sugary drink intake was positively associated with SUA in both boys and girls. High ASMM in Pacific people and an increased risk for raised SUA make it important to work with Pacific communities to reduce added sugar intake and adopt integrated, family-based, culturally centered, and life-course approaches to prevent chronic diseases, including gout.

Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8 + T cell receptor signaling and altered CD8 + T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8 + T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8 + T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38 + TIM3 + CD8 + T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies., Competing Interests: Declaration of interests A.R.C. is a consultant for AboundBio. J.M.K. is on consulting or scientific advisory boards of Ankyra Therapeutics, Axio Research LLC, Bristol Myers Squibb, Cancer Network, CytomX Therapeutics, DermTech, iOnctura, Iovance Biotherapeutics, IQVIA, Istari Oncology, Jazz Pharmaceuticals Inc., Lytix Biopharma AS, Magnolia Innovation LLC, Merck, Natera Inc., Novartix Pharmaceuticals, OncoCyte Corporation, PathAI Inc., Pfizer Inc., Piper Sandler & Co., PyrOjas Corporation, Regeneron Pharmaceuticals, Replimune Inc., Scopus BioPharma Inc., Takeda, and Valar Labs. J.M.K. received research trial support to institution from Amgen Inc., Bristol Myers Sqiubb, Checkmate Pharmaceuticals, Harbour BioMed, Immvira Pharma Co., Immunocore Ltd., Iovance Biotherapeutics, Lion Biotechnologies Inc., Lytix Biopharma AS, Novartis Pharmaceuticals, Takeda, and Verastem Inc. T.C.B. is a consultant for Galvanize Therapeutics, Tallac Therapeutics, Mestag Therapeutics, Attivare Therapeutics, and Kalivir Therapeutics, and is on the scientific advisory board of Tabby Therapeutics. D.A.A.V. is a cofounder and stockholder of Novasenta, Potenza, Tizona, and Trishula; is a stockholder of Oncorus and Werewolf; has patents licensed and royalties with BMS and Novasenta; is a scientific advisory board member of Tizona, Werewolf, F-Star, Bicara, Apeximmune, and T7/Imreg Bio; and is a consultant for BMS, Incyte, G1 Therapeutics, Inzen Therapeutics, Regeneron, and Avidity Partners., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: We present a case series of 5 patients diagnosed with schwannoma and 1 patient diagnosed with astrocytoma who underwent PSMA PET imaging for tumor detection. We retrospectively analyzed the records of 4 male and 2 female patients (mean age, 53.2 ± 13.2) who underwent PSMA PET imaging between March and September 2023. PET interpretation showed increased Ga-PSMA-11 accumulation in all patients with a mean SUV max of 3.11 ± 1.8. This series underscores PSMA PET's potential for CNS neoplasm detection., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hypophosphatasia (HPP) is an inborn error of metabolism with a variable presentation. We conducted a modified Delphi panel to obtain expert consensus on knowledge gaps regarding disease severity and progression in adult patients with HPP., Methods: Healthcare professionals (HCPs) with experience managing adult patients with HPP were recruited to participate in a 3-round Delphi panel (round 1: paper survey and 1:1 interview; rounds 2-3: email survey). Panelists rated the extent of their agreement with statements about disease severity and progression in adult patients with HPP. Consensus was defined as ≥ 80% agreement., Results: Ten HCPs completed round 1; nine completed rounds 2 and 3. Consensus was reached on 46/120 statements derived from steering committee input. Disease severity markers in adult patients with HPP can be bone-related (recurrent/poorly healing fractures, pseudo-fractures, metatarsal fractures, osteomalacia) or involve dentition or physiologic/functional manifestations (use of mobility devices/home modifications, abnormal gait, pain). Disease progression markers can include recurrent/poorly healing low-trauma fractures, development of ectopic calcifications, and/or impairment of functional activity. Panelists supported the development of a tool to help assess disease severity in the clinic and track changes in severity over time. Panelists also highlighted the role of a multidisciplinary team, centers with expertise, and the need to refer patients when disease severity is not clear., Conclusions: These statements regarding disease severity, progression, and assessment methods address some knowledge gaps in adult patients with HPP and may be helpful for treating HCPs, although the small sample size affects the ability to generalize the healthcare provider experience., (© 2024. The Author(s).)

In Māori and Pacific adults, the CREBRF rs373863828 minor (A) allele is associated with increased body mass index (BMI) but reduced incidence of type-2 and gestational diabetes mellitus. In this prospective cohort study of Māori and Pacific infants, nested within a nutritional intervention trial for pregnant women with obesity and without pregestational diabetes, we investigated whether the rs373863828 A allele is associated with differences in growth and body composition from birth to 12-18 months' corrected age. Infants with and without the variant allele were compared using generalised linear models adjusted for potential confounding by gestation length, sex, ethnicity and parity, and in a secondary analysis, additionally adjusted for gestational diabetes. Carriage of the rs373863828 A allele was not associated with altered growth and body composition from birth to 6 months. At 12-18 months, infants with the rs373863828 A allele had lower whole-body fat mass [FM 1.4 (0.7) vs. 1.7 (0.7) kg, aMD -0.4, 95% CI -0.7, 0.0, P = 0.05; FM index 2.2 (1.1) vs. 2.6 (1.0) kg/m 2 aMD -0.6, 95% CI -1.2,0.0, P = 0.04]. However, this association was not significant after adjustment for gestational diabetes, suggesting that it may be mediated, at least in part, by the beneficial effect of CREBRF rs373863828 A allele on maternal glycemic status., (© 2024. The Author(s).)

Background: To discover pharmacotherapy prescription patterns and their statistical associations with outcomes through a clinical pathway inference framework applied to real-world data., Methods: We apply machine learning steps in our framework using a 2006 to 2020 cohort of veterans with major depressive disorder (MDD). Outpatient antidepressant pharmacy fills, dispensed inpatient antidepressant medications, emergency department visits, self-harm, and all-cause mortality data were extracted from the Department of Veterans Affairs Corporate Data Warehouse., Results: Our MDD cohort consisted of 252,179 individuals. During the study period there were 98,417 emergency department visits, 1,016 cases of self-harm, and 1,507 deaths from all causes. The top ten prescription patterns accounted for 69.3% of the data for individuals starting antidepressants at the fluoxetine equivalent of 20-39 mg. Additionally, we found associations between outcomes and dosage change., Conclusions: For 252,179 Veterans who served in Iraq and Afghanistan with subsequent MDD noted in their electronic medical records, we documented and described the major pharmacotherapy prescription patterns implemented by Veterans Health Administration providers. Ten patterns accounted for almost 70% of the data. Associations between antidepressant usage and outcomes in observational data may be confounded. The low numbers of adverse events, especially those associated with all-cause mortality, make our calculations imprecise. Furthermore, our outcomes are also indications for both disease and treatment. Despite these limitations, we demonstrate the usefulness of our framework in providing operational insight into clinical practice, and our results underscore the need for increased monitoring during critical points of treatment., (© 2024. The Author(s).)

Background and Objectives: Evidence of effective multifactorial lifestyle interventions for primary stroke prevention is lacking, despite the significant contribution of lifestyle to stroke burden. We aimed to determine the efficacy of health and wellness coaching (HWC) for primary stroke and cardiovascular disease (CVD) prevention in adults at a moderate-to-high CVD risk., Methods: This was a parallel, 2-arm, open-label, single-blinded, phase III randomized controlled trial to determine the efficacy of HWC for primary stroke prevention in individuals 30 years and older with a 5-year CVD risk ≥10% as measured by 5-year absolute CVD risk (as measured by the PREDICT tool) at 9 months post-randomization. Eligible participants were those with a 5-year CVD risk ≥10%, with no history of stroke, transient ischemic attack, or myocardial infarction. The relative risk reduction (RRR) and odds ratios (OR) were evaluated separately in those at moderate (10%-14%) 5-year CVD risk and those at high risk (≥15%) at baseline. The Life's Simple 7 (LS7) score for lifestyle-related CVD risk, as the indicator of cardiovascular health, was a key secondary outcome., Results: Of a total of 320 participants, 161 were randomized to the HWC group and 159 to the usual care (UC) group. HWC resulted in a statistically significant RRR of -10.9 (95% CI -21.0 to -0.9) in 5-year CVD risk in the higher CVD risk group but no change in the moderate risk group. An improvement in the total LS7 score was seen in the HWC group compared with the UC group (absolute difference = 0.485, 95% CI [0.073 to 0.897], p = 0.02). Improvement in blood pressure scores was statistically significantly greater in the HWC group than in the UC group for those at high risk of CVD (OR 2.28 [95% CI 1.12 to 4.63] and 1.55 [0.80 to 3.01], respectively). No statistically significant differences in mood scores, medication adherence, quality of life, and satisfaction with life scores over time or between groups were seen., Discussion: Health and wellness coaching resulted in a significant RRR in the 5-year CVD risk compared with UC at 9 months post-randomization in patients with a high baseline CVD risk. There was no improvement in CVD risk in the moderate risk group; hence, this study did not meet the primary hypothesis. However, this treatment effect is clinically significant (number needed to treat was 43). The findings suggest that HWC has potential if further refined to improve lifestyle risk factors of stroke., Competing Interests: The authors report no relevant disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present., (© 2023. The Author(s).)

Nutritional environment in early life is a key factor for brain development and function. It is important to understand the relationship between nutrition in early life and academic achievement in adolescence. The birth cohort of the Pacific Islands Families (PIF) study was born in the year 2000. When their child was six weeks old, mothers were asked questions concerning food security over the past year. Two binary measures of food security were derived as previously used in PIF and also by the Ministry of Health (MOH). In 2020, records of academic achievement from the National Certificate of Educational Achievement (NCEA) for 649 (317 female, 332 male) cohort members showed progressive achievement at levels 1, 2, and 3 of NCEA and allowed University Entrance (UE) to be assessed. The prevalence of food insecurity was not different for sex but high at 29% and 42% using the PIF and MOH definitions of food insecurity, respectively. More females (27%) than males (18%) achieved UE as their highest qualification, and more males (40%) than females (31%) achieved NCEA levels 1 or 2 as their highest qualification. UE was achieved by 25% of those born into food-secure households and 17% from food-insecure households. Logistic regression demonstrated that the odds of achieving UE were 1.8-fold (95% CI 1.2, 2.6, p = 0.003) higher in females than males and, independently, 1.6-fold (95% CI 1.1, 2.5 p = 0.026) higher if the household was food secure. This work emphasises the importance of maternal and early-life food security for subsequent academic achievement and the well-being of future generations.

Objective: Electronic health record (EHR) systems contain a wealth of clinical data stored as both codified data and free-text narrative notes, covering hundreds of thousands of clinical concepts available for research and clinical care. The complex, massive, heterogeneous, and noisy nature of EHR data imposes significant challenges for feature representation, information extraction, and uncertainty quantification. To address these challenges, we proposed an efficient A ggregated na R rative C odified H ealth (ARCH) records analysis to generate a large-scale knowledge graph (KG) for a comprehensive set of EHR codified and narrative features., Methods: The ARCH algorithm first derives embedding vectors from a co-occurrence matrix of all EHR concepts and then generates cosine similarities along with associated p -values to measure the strength of relatedness between clinical features with statistical certainty quantification. In the final step, ARCH performs a sparse embedding regression to remove indirect linkage between entity pairs. We validated the clinical utility of the ARCH knowledge graph, generated from 12.5 million patients in the Veterans Affairs (VA) healthcare system, through downstream tasks including detecting known relationships between entity pairs, predicting drug side effects, disease phenotyping, as well as sub-typing Alzheimer's disease patients., Results: ARCH produces high-quality clinical embeddings and KG for over 60,000 EHR concepts, as visualized in the R-shiny powered web-API (https://celehs.hms.harvard.edu/ARCH/). The ARCH embeddings attained an average area under the ROC curve (AUC) of 0.926 and 0.861 for detecting pairs of similar EHR concepts when the concepts are mapped to codified data and to NLP data; and 0.810 (codified) and 0.843 (NLP) for detecting related pairs. Based on the p -values computed by ARCH, the sensitivity of detecting similar and related entity pairs are 0.906 and 0.888 under false discovery rate (FDR) control of 5%. For detecting drug side effects, the cosine similarity based on the ARCH semantic representations achieved an AUC of 0.723 while the AUC improved to 0.826 after few-shot training via minimizing the loss function on the training data set. Incorporating NLP data substantially improved the ability to detect side effects in the EHR. For example, based on unsupervised ARCH embeddings, the power of detecting drug-side effects pairs when using codified data only was 0.15, much lower than the power of 0.51 when using both codified and NLP concepts. Compared to existing large-scale representation learning methods including PubmedBERT, BioBERT and SAPBERT, ARCH attains the most robust performance and substantially higher accuracy in detecting these relationships. Incorporating ARCH selected features in weakly supervised phenotyping algorithms can improve the robustness of algorithm performance, especially for diseases that benefit from NLP features as supporting evidence. For example, the phenotyping algorithm for depression attained an AUC of 0.927 when using ARCH selected features but only 0.857 when using codified features selected via the KESER network[1]. In addition, embeddings and knowledge graphs generated from the ARCH network were able to cluster AD patients into two subgroups, where the fast progression subgroup had a much higher mortality rate., Conclusions: The proposed ARCH algorithm generates large-scale high-quality semantic representations and knowledge graph for both codified and NLP EHR features, useful for a wide range of predictive modeling tasks.

Globally, bread is a staple food and thus a promising vehicle for the delivery of nutrients from vegetables including carotenoids. The aim of this pilot/feasibility, pre-post experimental study was to measure skin (Veggie Meter™) and plasma carotenoid concentrations 1 week before (week -1), immediately prior to (week 0), and after (week 2) 14 days of daily consumption of 200 g pumpkin- and sweetcorn-enriched bread (VB). At each measurement point, total vegetable and fruit intake and specific carotenoid-rich foods were assessed by questionnaire. Participants ( n  = 10, 8 males, 2 females) were aged between 19 and 39 years and weighed 90 ± 20 kg. Vegetable and fruit intake was low and less than one serving/day of foods containing carotenoids. Prior to the intervention, measures of carotenoid-containing foods and skin or plasma carotenoids were not different when measured a week apart. Consumption of the VB did not result in statistically significant changes in either the skin or plasma carotenoid measurements. Plasma carotenoid concentrations and the carotenoid reflection scores had a large and positive ( r  = .845, 95% CI 0.697, 0.924) association. The relationship between the number of servings of carotenoid-rich foods with the plasma carotenoid and carotenoid reflection scores was positive and of moderate strength. In conclusion, carotenoid status was not measurably changed with the consumption of 200 g VB each day for 2 weeks. Subjective carotenoid-rich food intake was positively associated with objective biomarkers of carotenoids. The Veggie meter™ has the potential to provide portable measurement of circulating carotenoids and be indicative of intake of carotenoid-rich foods., Competing Interests: There is no conflict of interest., (© 2023 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Motivation: Predicting molecule-disease indications and side effects is important for drug development and pharmacovigilance. Comprehensively mining molecule-molecule, molecule-disease and disease-disease semantic dependencies can potentially improve prediction performance., Methods: We introduce a Multi-Modal REpresentation Mapping Approach to Predicting molecular-disease relations (M2REMAP) by incorporating clinical semantics learned from electronic health records (EHR) of 12.6 million patients. Specifically, M2REMAP first learns a multimodal molecule representation that synthesizes chemical property and clinical semantic information by mapping molecule chemicals via a deep neural network onto the clinical semantic embedding space shared by drugs, diseases and other common clinical concepts. To infer molecule-disease relations, M2REMAP combines multimodal molecule representation and disease semantic embedding to jointly infer indications and side effects., Results: We extensively evaluate M2REMAP on molecule indications, side effects and interactions. Results show that incorporating EHR embeddings improves performance significantly, for example, attaining an improvement over the baseline models by 23.6% in PRC-AUC on indications and 23.9% on side effects. Further, M2REMAP overcomes the limitation of existing methods and effectively predicts drugs for novel diseases and emerging pathogens., Availability and Implementation: The code is available at https://github.com/celehs/M2REMAP, and prediction results are provided at https://shiny.parse-health.org/drugs-diseases-dev/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2023. Published by Oxford University Press.)

Future warming scenarios are predicted to result in an increased frequency of high, and potentially stressful, temperatures in aquatic ecosystems. Here we examined whether the performance of wild underyearling Atlantic salmon (Salmo salar) in Scottish streams stocked with identical egg densities was influenced by thermal stress. Biomass and density declined with degree hours exceeding 23°C, indicating apparent mortality or emigration as a possible result of exposure to high temperatures. These results strengthen the need for further action such as riparian tree planting to reduce stream summer temperatures., (© 2022 The Authors. Journal of Fish Biology published by John Wiley & Sons Ltd on behalf of Fisheries Society of the British Isles.)

De novo variants in FOXP4 were recently associated with a neurodevelopmental disorder characterized by speech and language delay, growth abnormalities, hypotonia, and variable congenital abnormalities, including congenital diaphragmatic hernia, cervical spine abnormalities, strabismus, cryptorchidism, and ptosis. The variant spectrum in this small cohort was limited to de novo missense except for one frameshift, the inheritance of which was unknown. Variants tested in vitro exhibited reduced repressor transcriptional activity, indicating loss of function is the likely mechanism of disease, but only one frameshift variant was reported. Here, we report four affected individuals from two unrelated families heterozygous for a nonsense variant, c.1893C > G, p.Tyr631*, in FOXP4. The phenotype of the affected children includes developmental delay, feeding difficulties in infancy, and similar facial features. In both cases, the variant was inherited from a parent with mild or even subclinical features. Interestingly, one patient presented with congenital diaphragmatic hernia, as reported in two other FOXP4 patients. This report implicates FOXP4 truncating variants in human disease and highlights the wide phenotypic spectrum and variable expressivity., (© 2022 Wiley Periodicals LLC.)

Overcoming replicative senescence is an essential step during oncogenesis, and the reactivation of TERT through promoter mutations is a common mechanism. TERT promoter mutations are acquired in about 75% of melanomas but are not sufficient to maintain telomeres, suggesting that additional mutations are required. We identified a cluster of variants in the promoter of ACD encoding the shelterin component TPP1. ACD promoter variants are present in about 5% of cutaneous melanoma and co-occur with TERT promoter mutations. The two most common somatic variants create or modify binding sites for E-twenty-six (ETS) transcription factors, similar to mutations in the TERT promoter. The variants increase the expression of TPP1 and function together with TERT to synergistically lengthen telomeres. Our findings suggest that TPP1 promoter variants collaborate with TERT activation to enhance telomere maintenance and immortalization in melanoma.

Objective: To evaluate the performance of a UK based prediction model for estimating fat-free mass (and indirectly fat mass) in children and adolescents in non-UK settings., Design: Individual participant data meta-analysis., Setting: 19 countries., Participants: 5693 children and adolescents (49.7% boys) aged 4 to 15 years with complete data on the predictors included in the UK based model (weight, height, age, sex, and ethnicity) and on the independently assessed outcome measure (fat-free mass determined by deuterium dilution assessment)., Main Outcome Measures: The outcome of the UK based prediction model was natural log transformed fat-free mass (lnFFM). Predictive performance statistics of R 2 , calibration slope, calibration-in-the-large, and root mean square error were assessed in each of the 19 countries and then pooled through random effects meta-analysis. Calibration plots were also derived for each country, including flexible calibration curves., Results: The model showed good predictive ability in non-UK populations of children and adolescents, providing R 2 values of >75% in all countries and >90% in 11 of the 19 countries, and with good calibration (ie, agreement) of observed and predicted values. Root mean square error values (on fat-free mass scale) were <4 kg in 17 of the 19 settings. Pooled values (95% confidence intervals) of R 2 , calibration slope, and calibration-in-the-large were 88.7% (85.9% to 91.4%), 0.98 (0.97 to 1.00), and 0.01 (-0.02 to 0.04), respectively. Heterogeneity was evident in the R 2 and calibration-in-the-large values across settings, but not in the calibration slope. Model performance did not vary markedly between boys and girls, age, ethnicity, and national income groups. To further improve the accuracy of the predictions, the model equation was recalibrated for the intercept in each setting so that country specific equations are available for future use., Conclusion: The UK based prediction model, which is based on readily available measures, provides predictions of childhood fat-free mass, and hence fat mass, in a range of non-UK settings that explain a large proportion of the variability in observed fat-free mass, and exhibit good calibration performance, especially after recalibration of the intercept for each population. The model demonstrates good generalisability in both low-middle income and high income populations of healthy children and adolescents aged 4-15 years., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form and declare: this research was supported by grants from the British Heart Foundation, the Wellcome Trust, and the National Institute for Health and Care Research Applied Research Collaboration South London; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The growing availability of electronic health records (EHR) data opens opportunities for integrative analysis of multi-institutional EHR to produce generalizable knowledge. A key barrier to such integrative analyses is the lack of semantic interoperability across different institutions due to coding differences. We propose a Multiview Incomplete Knowledge Graph Integration (MIKGI) algorithm to integrate information from multiple sources with partially overlapping EHR concept codes to enable translations between healthcare systems., Methods: The MIKGI algorithm combines knowledge graph information from (i) embeddings trained from the co-occurrence patterns of medical codes within each EHR system and (ii) semantic embeddings of the textual strings of all medical codes obtained from the Self-Aligning Pretrained BERT (SAPBERT) algorithm. Due to the heterogeneity in the coding across healthcare systems, each EHR source provides partial coverage of the available codes. MIKGI synthesizes the incomplete knowledge graphs derived from these multi-source embeddings by minimizing a spherical loss function that combines the pairwise directional similarities of embeddings computed from all available sources. MIKGI outputs harmonized semantic embedding vectors for all EHR codes, which improves the quality of the embeddings and enables direct assessment of both similarity and relatedness between any pair of codes from multiple healthcare systems., Results: With EHR co-occurrence data from Veteran Affairs (VA) healthcare and Mass General Brigham (MGB), MIKGI algorithm produces high quality embeddings for a variety of downstream tasks including detecting known similar or related entity pairs and mapping VA local codes to the relevant EHR codes used at MGB. Based on the cosine similarity of the MIKGI trained embeddings, the AUC was 0.918 for detecting similar entity pairs and 0.809 for detecting related pairs. For cross-institutional medical code mapping, the top 1 and top 5 accuracy were 91.0% and 97.5% when mapping medication codes at VA to RxNorm medication codes at MGB; 59.1% and 75.8% when mapping VA local laboratory codes to LOINC hierarchy. When trained with 500 labels, the lab code mapping attained top 1 and 5 accuracy at 77.7% and 87.9%. MIKGI also attained best performance in selecting VA local lab codes for desired laboratory tests and COVID-19 related features for COVID EHR studies. Compared to existing methods, MIKGI attained the most robust performance with accuracy the highest or near the highest across all tasks., Conclusions: The proposed MIKGI algorithm can effectively integrate incomplete summary data from biomedical text and EHR data to generate harmonized embeddings for EHR codes for knowledge graph modeling and cross-institutional translation of EHR codes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Bread is a commonly consumed staple and could be a viable medium to deliver plant-based ingredients that demonstrate health effects. This review brings together published evidence on the bioactive properties of bread formulated with plant-based ingredients. Health effects associated with the consumption of bread formulated with plant-based functional ingredients was also reviewed. Bioactive properties demonstrated by the functional ingredients fruits and vegetables, legumes, nuts and tea incorporated into bread include increased phenolic and polyphenolic content, increased antioxidant activity, and extension of bread shelf-life by impairment of lipid and protein oxidation. Acute health effects reported included appetite suppression, reduced diastolic blood pressure, improvements in glycaemia, insulinaemia and satiety effect. These metabolic effects are mainly short lived and not enough for a health claim. Longer term studies or comparison of those who consume and those who do not are needed. The incorporation of plant-based functional ingredients in bread could enhance the health-promoting effects of bread., (© 2022. The Author(s).)

Background: This study examined the strength, shape and direction of associations of accelerometer-assessed overall, school- and non-school-based moderate-to-vigorous physical activity (MVPA) and sedentary time (ST) with BMI among adolescents across the world. Second, we examined whether these associations differed by study site and sex., Methods: Cross-sectional data from the IPEN Adolescent study, an observational multi-country study, were used. Participants wore an accelerometer for seven days, reported height and weight, and completed a socio-demographic survey. In total, 4852 adolescents (46.6% boys), aged 11-19 years (mean age = 14.6, SD = 1.7 years) were included in the analyses, using generalized additive mixed models., Results: Adolescents accumulated on average 41.3 (SD = 22.6) min/day of MVPA and 531.8 (SD = 81.1) min/day of ST, and the prevalence of overweight and obesity was 17.2% (IOTF), but these mean values differed by country. Linear negative associations of accelerometer-based MVPA and ST with standardized BMI scores and the likelihood of being overweight/obese were found. School-based ST and non-school-based MVPA were more strongly negatively associated to the outcomes than non-school based ST and school-based MVPA. Study site moderated the associations; adolescent sex did not. No curvilinear associations were found., Conclusions: This multi-country study confirmed the importance of MVPA as a potential protective factor against overweight/obesity in adolescents. Non-school-based MVPA seemed to be the main driver of these associations. Unexpected results were found for ST, calling for further examination in methodologically sound international studies but using inclinometers or pressure sensors to provide more precise ST measures., (© 2022. The Author(s).)

Cocoa is a major dietary source of polyphenols, including flavanols, which have been associated with reduced blood pressure (BP). While earlier systematic reviews and meta-analyses have shown significant effects of cocoa consumption on systolic BP, limitations include small sample sizes and study heterogeneity. Questions regarding food matrix and dose of polyphenols, flavanols, or epicatechins remain. This systematic review and meta-analysis aimed to investigate the effects of ≥2 weeks of cocoa consumption as a beverage or dark chocolate in those with normal or elevated (< or ≥130 mmHg) systolic BP measured in the fasted state or over 24-h. A systematic search conducted on PubMed and Cochrane Library databases up to 26 February 2022 yielded 31 suitable articles. Independent of baseline BP, cocoa consumption for ≥2 weeks was associated with reductions in systolic and diastolic BP (p < 0.05, all). Compared with cocoa, chocolate lowered the weighted mean of resting systolic BP (−3.94 mmHg, 95% CI [−5.71, −2.18]) more than cocoa beverage (−1.54 mmHg, 95% CI [−3.08, 0.01]). When the daily dose of flavanols was ≥900 mg or of epicatechin ≥100 mg, the effect was greater. Future, adequately powered studies are required to determine the optimal dose for a clinically significant effect.

Tamarillo extract is a good source of phenolic and anthocyanin compounds which are well-known for beneficial antioxidant activity, but their bioactivity maybe lost during digestion. In this study, promising prospects of tamarillo polyphenols encapsulated in cubosome nanoparticles prepared via a top-down method were explored. The prepared nanocarriers were examined for their morphology, entrapment efficiency, particle size and stability during in vitro digestion as well as potential fortification of yoghurt. Tamarillo polyphenol-loaded cubosomes showed cubic shape with a mean particle size of 322.4 ± 7.27 nm and the entrapment efficiency for most polyphenols was over 50%. The encapsulated polyphenols showed high stability during the gastric phase of in vitro digestion and were almost completely, but slowly released in the intestinal phase. Addition of encapsulated tamarillo polyphenols to yoghurt (5, 10 and 15 wt% through pre- and post-fermentation) improved the physicochemical and potential nutritional properties (polyphenols concentration, TPC) as well as antioxidant activity. The encapsulation of tamarillo polyphenols protected against pH changes and enzymatic digestion and facilitated a targeted delivery and slow release of the encapsulated compounds to the intestine. Overall, the cubosomal delivery system demonstrated the potential for encapsulation of polyphenols from tamarillo for value-added food product development with yoghurt as the vehicle.

Laird's Large tamarillo powder is high in protein (10%) essential amino acids (EAAs), gamma-aminobutyric acid (GABA) and polyphenols (0.6% phenolics plus anthocyanins) and fibre 25%. This study aimed to investigate, using a standardized static in vitro digestion model, the stability of amino acids and antioxidant capacity of polyphenols in yoghurt fortified with 5, 10 and 15% tamarillo powder either before (PRE) or after (POS) fermentation. Compared to plain yoghurt, the fruit polyphenols (rutinosides and glycosides) were retained and substantial increases in FEAAs (free essential amino acids), total phenolic content (TPC) and antioxidant activity were observed particularly at the end of intestinal phase of digestion. Together with SDS-PAGE results, peptides and proteins in tamarillo yoghurts were more easily digested and therefore may be better absorbed in the small intestine compared to the control. TPC and antioxidant activity of fortified yoghurts increased significantly after in vitro digestion. Relatively high bioaccessibilty of chlorogenic acid and kaempferol-3-rutinoside in digested PRE samples was observed. The results suggest that the yoghurt matrix might protect some compounds from degradation, increasing bioaccessibility and in the small intestine allow increased absorption and utilization possible. Fortification would deliver intact polyphenols and fibre to the large intestine and improve gut health. Further research of acceptability, shelf life, and then trials for health effects should be implemented.

Background: Mobile apps may offer a valuable platform for delivering evidence-based psychological interventions for individuals with atypical appearances, or visible differences, who experience psychosocial appearance concerns such as appearance-based social anxiety and body dissatisfaction. Before this study, researchers and stakeholders collaboratively designed an app prototype based on acceptance and commitment therapy (ACT), an evidence-based form of cognitive behavioral therapy that uses strategies such as mindfulness, clarification of personal values, and value-based goal setting. The intervention also included social skills training, an established approach for increasing individuals' confidence in managing social interactions, which evoke appearance-based anxiety for many., Objective: In this study, the authors aim to evaluate the feasibility of an ACT-based app prototype via the primary objectives of user engagement and acceptability and the secondary feasibility objective of clinical safety and preliminary effectiveness., Methods: To address the feasibility objectives, the authors used a single-group intervention design with mixed methods in a group of 36 participants who have a range of visible differences. The authors collected quantitative data via measures of program use, satisfaction ratings, and changes over 3 time points spanning 12 weeks in outcomes, including selected ACT process measures (experiential avoidance, cognitive defusion, and valued action), scales of appearance concerns (appearance-based life disengagement, appearance-fixing behaviors, appearance self-evaluation, and fear of negative appearance evaluation), and clinical well-being (depression and anxiety). Semistructured exit interviews with a subsample of 12 participants provided qualitative data to give a more in-depth understanding of participants' views and experiences of the program., Results: In terms of user engagement, adherence rates over 6 sessions aligned with the upper boundary of those reported across mobile mental health apps, with over one-third of participants completing all sessions over 12 weeks, during which a steady decline in adherence was observed. Time spent on sessions matched design intentions, and engagement frequencies highlighted semiregular mindfulness practice, mixed use of value-based goal setting, and high engagement with social skills training. The findings indicate a good overall level of program acceptability via satisfaction ratings, and qualitative interview findings offer positive feedback as well as valuable directions for revisions. Overall, testing for clinical safety and potential effectiveness showed encouraging changes over time, including favorable changes in appearance-related life disengagement, appearance-fixing behaviors, and selected ACT measures. No iatrogenic effects were indicated for depression or anxiety., Conclusions: An ACT-based mobile program for individuals struggling with visible differences shows promising proof of concept in addressing appearance concerns, although further revisions and development are required before further development and more rigorous evaluation., (©Fabio Zucchelli, Olivia Donnelly, Emma Rush, Paul White, Holly Gwyther, Heidi Williamson, The VTCT Foundation Research Team at the Centre for Appearance Research. Originally published in JMIR Formative Research (https://formative.jmir.org), 21.01.2022.)

Bright-red Laird's Large tamarillo is a unique and under-utilised fruit that is a dietary source of carotenoids, vitamins C and E, and dietary fibre. The effects of the addition of freeze-dried tamarillo powder (5-15%) to milk and yoghurt starter either before (PRE) or after (POS) fermentation on physicochemical properties were examined. Using LC-MS and GG-MS, nutrient and volatile contents of tamarillo yoghurt were also examined. The addition of tamarillo prior to fermentation was associated with a more yellow colour and higher concentrations of tocopherol compared to when tamarillo was added after fermentation. Higher elastic modulus, PUFAs, pro-vitamin A content, and vitamin C retention were observed for POS than PRE. All tamarillo yoghurts showed improvement in syneresis, lower lactose content, and higher concentrations of antioxidant vitamins than the commercial premium-assorted fruits yoghurt from New Zealand Food Composition Data. Yoghurt fortified with tamarillo powder offers the potential for the development of a high-value nutritional product that could be a good source of vitamin C and a source of vitamin E and β-carotene, and maintain the volatiles that give tamarillo its distinctive flavour.

Bread, a frequently consumed food, is an ideal vehicle for addition of ingredients that increase nutrient density and add health benefits. This experimental cross-over study sought to test the effect of a vegetable-enriched bread (VB) in comparison to commercial white bread (WB) and wheatmeal bread (WMB) on serum glucose, insulin response and subjective appetite suppression. On three separate occasions, 10 participants (23 ± 7 years) visited the laboratory and consumed after an overnight fast, in random order, a 75 g serve of WB, WMB or VB. Venous blood samples drawn twice before (0 min) and at 15, 30, 45, 60, 90 and 120 min after consumption of the bread were analysed for glucose and insulin. Participants rated their subjective feelings of hunger, fullness, satisfaction and desire to eat on a 150 mm Likert scale. The mean glucose iAUC over 120 min was not different among the breads. The mean insulin iAUC for the VB was significantly lower than the WB and WMB; difference VB and WB 12,415 pmol/L*minutes (95% CI 1918, 22,912 pmol/L*minutes, p = 0.025) and difference VB and WMB 13,800 pmol/L*minutes (95% CI 1623, 25,976 pmol/L*minutes p = 0.031). The VB was associated with a higher fullness feeling in the participants over the 120-min period. The consumption of VB was associated with less insulin release and higher satiety over 120 min which may be related to the higher fibre content and texture of VB. The role of vegetable and fruit fibres such as pectin in bread and insulin response should also be further explored.

The increasing availability of electronic health record (EHR) systems has created enormous potential for translational research. However, it is difficult to know all the relevant codes related to a phenotype due to the large number of codes available. Traditional data mining approaches often require the use of patient-level data, which hinders the ability to share data across institutions. In this project, we demonstrate that multi-center large-scale code embeddings can be used to efficiently identify relevant features related to a disease of interest. We constructed large-scale code embeddings for a wide range of codified concepts from EHRs from two large medical centers. We developed knowledge extraction via sparse embedding regression (KESER) for feature selection and integrative network analysis. We evaluated the quality of the code embeddings and assessed the performance of KESER in feature selection for eight diseases. Besides, we developed an integrated clinical knowledge map combining embedding data from both institutions. The features selected by KESER were comprehensive compared to lists of codified data generated by domain experts. Features identified via KESER resulted in comparable performance to those built upon features selected manually or with patient-level data. The knowledge map created using an integrative analysis identified disease-disease and disease-drug pairs more accurately compared to those identified using single institution data. Analysis of code embeddings via KESER can effectively reveal clinical knowledge and infer relatedness among codified concepts. KESER bypasses the need for patient-level data in individual analyses providing a significant advance in enabling multi-center studies using EHR data., (© 2021. The Author(s).)

Purpose: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype., Methods: We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations., Results: Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism., Conclusion: We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome., (© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)

Tamarillo is a nutrient-dense fruit with a unique aroma from its volatile compounds (VCs). In this study, we aimed to compare the volatile profiles: (i) of fresh and freeze-dried tamarillo; (ii) detected using Thermal Desorption-Gas Chromatography-Mass Spectrometry (TD-GC-MS) and Solid-Phase MicroExtraction-Gas Chromatography-Mass Spectrometry (SPME-GC-MS); (iii) of freeze-dried pulp and peel of New Zealand grown tamarillo. The possible antibacterial activity of freeze-dried tamarillo extracts was also investigated. We show that freeze-drying maintained most of the VCs, with some being more concentrated with the loss of water. The most abundant VC in both fresh and freeze-dried tamarillo was hexanoic acid methyl ester for pulp (30% and 37%, respectively), and (E)-3-Hexen-1-ol for peel (36% and 29%, respectively). With the use of TD-GC-MS, 82 VCs were detected for the first time, when compared to SPME-GC-MS. Methional was the main contributor to the overall aroma in both peel (15.4 ± 4.2 μg/g DW) and pulp (118 ± 8.1 μg/g DW). Compared to water as the control, tamarillo extracts prepared by water and methanol extraction showed significant antibacterial activity against E. coli , P. aeruginosa , and S. aureus with zone of inhibition of at least 13.5 mm. These results suggest that freeze-dried tamarillo has a potential for use as a natural preservative to enhance aroma and shelf life of food products.

Hidden hunger is widespread in India. Individual dietary diversity score (IDDS) is a measure of the nutrient adequacy of the diet. The FAO has set guidelines for the measurement of dietary diversity: the IDDS and the minimum dietary diversity score for women (MDD-W) to assess nutritional deficiency, but validation against nutritional biomarkers is required. Using available data among rural youth (17 years) from the Pune Maternal Nutrition Study, the validity of DDS was assessed to measure deficiencies of vitamin B12, folate and Hb. Of the 355 boys and 305 girls, 19 % were classified as underweight, 57 % as vitamin B12 deficient (<150 pmol/l) and 22 % as anaemic (<120/130 g/l). Cereals, legumes and 'other-vegetables' were the most frequently consumed foods. More boys than girls consumed milk, flesh, eggs and micronutrient-dense foods. Median IDDS of 4 (interquartile range (IQR) 3-4) and MDD-W of 6 (IQR 5-7) were low. Youth with vitamin B12 deficiency had a higher likelihood of an IDDS ≤ 4 (1·89; 95 % CI 1·24, 2·87) or an MDD-W ≤ 5 (1·40; 95 % CI 1·02, 1·94). Youth with anaemia were more likely to have an IDDS ≤ 4 (1·76; 95 % CI 1·01, 3·14) adjusted for socio-economic scores, BMI, energy intake and sex. Folate deficiency was low (3 %) and was not associated with either score. Youth with lowest plasma vitamin B12 and Hb infrequently or never consumed dairy products/non-vegetarian foods. These rural Indian youth were underweight, had low DDS and consumed foods low in good-quality proteins and micronutrients. Associations of DDS with circulating micronutrients indicate that DDS is a valid measure to predict vitamin B12 deficiency and anaemia.

Background: Given their growing popularity, mobile health (mHealth) apps may offer a viable method of delivering psychological interventions for people with an atypical appearance (ie, visible difference) who struggle with appearance-related distress. Acceptance and Commitment Therapy (ACT), a third-wave cognitive behavioral approach, has been used effectively in mHealth and is being increasingly applied clinically to common psychosocial difficulties associated with visible differences. We planned to design an ACT-based mHealth intervention (ACT It Out) for this population., Objective: The aim of this study is to gain key stakeholder input from user representatives and psychological clinicians to optimize the intervention's design for future development and uptake. To do so, we explored considerations relating to mHealth as a delivery platform for adults with visible differences and elicited stakeholders' design preferences and ideas based on initial author-created content., Methods: Within a participatory design framework, we used a mix of qualitative methods, including usability sessions and a focus group in a face-to-face workshop, and interviews and textual feedback collected remotely, all analyzed using template analysis. A total of 6 user representatives and 8 clinicians were recruited for this study., Results: Our findings suggest that there are likely to be strengths and challenges of mHealth as an intervention platform for the study population, with key concerns being user safeguarding and program adherence. Participants expressed design preferences toward relatable human content, interactive and actionable features, flexibility of use, accessibility, and engaging content., Conclusions: The findings offer valuable design directions for ACT It Out and related interventions, emphasizing the need to carefully guide users through the intervention while acknowledging the limited time and space that mHealth affords., (©Fabio Zucchelli, Olivia Donnelly, Emma Rush, Harriet Smith, Heidi Williamson, The VTCT Foundation Research Team. Originally published in JMIR Formative Research (http://formative.jmir.org), 24.03.2021.)

Characteristics of food that influence liking and ease-of-chewing and swallowing are not well-understood. Reformulation of bread to improve nutrient density may improve liking, ease-of-chewing and swallowing which could improve dietary intake particularly with aging. The study aimed to compare objectively and subjectively four breads of increasing nutrient density: $1 white (WB) and wheatmeal (WMB) commercial breads and two in-house formulations of vegetable-enriched breads (VB75 or VB100) which incorporated drum-dried pumpkin and sweet corn flours for physical, sensory and ease-of-chewing and swallowing properties. Each bread underwent instrumental texture analysis. The commercial and vegetable-enriched breads were not different by hardness or springiness but the vegetable breads were up to 25% less cohesive, less gummy and less chewy than the commercial breads. Questionnaires and Likert scale (150 mm) responses were completed by 50 physically active volunteers aged 50+ years. Overall liking of the VB75 and VB100 was rated 40% higher than the white and wheatmeal breads. Vegetable-enriched breads were rated as almost 50% easier to chew (mean ± SD; WB 70.53 ± 39.46 mm, WMB 77.68 ± 33.13 mm, VB75 104.78 ± 30.69 mm, VB100 107.58 ± 24.90 mm) and swallow (WB 70.29 ± 37.98 mm, WMB 77.53 ± 34.88 mm, VB75 104.63 ± 28.25 mm, VB100 104.90 ± 25.54 mm). Vegetable-enriched breads compared to white and wheatmeal breads were instrumentally and subjectively less gummy, cohesive and chewy than commercial breads and have the potential to both improve nutrition and "ease of swallowing" in older people. New areas of research should explore other underutilized vegetables for bread enrichment and their ability to aid swallowing and improve nutrition status., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Amoah, Cairncross and Rush.)

Background: Since 2004, Sport Waikato has delivered Project Energize, a through-school nutrition and physical activity program to primary schools in the Waikato. As part of the program's continued assessment and quality control, the programme was evaluated in 2011 and 2015. This paper's aim was to compare the cardiorespiratory fitness (time to run 550 m (T 550 )) levels of children participating in Project Energize in 2011 and 2015., Methods: In the 2011 evaluation of Project Energize, gender specific- T 550 -for-age Z scores (T 550 AZ) were derived from the T 550 of 4832 Waikato children (2527 girls; 2305 boys; 36% Māori) aged between 6 and 12 years. In 2015, T 550 was measured for 4798 (2361 girls; 2437 boys; 32% Māori) children, representative of age, gender and school socioeconomic status (SES). The T 550 AZ for every child in the 2015 study and 2011 evaluation were derived and differences in T 550 between 2015 and 2011 by gender, SES and age were determined using independent t-tests. Multiple regression analysis predicted T550 Z score and run time, using year of measurement, gender, ethnicity, age and school SES., Results: With and without adjustment, children in 2015 ran 550 m faster than in 2011 (adjusted Z score 0.06, time 11 s). Specifically, girls ran at a similar speed in 2015 as 2011 but boys were faster than in 2011 (Z score comparison P  < 0.001, mean difference 0.18 95%CI 0.12, 0.25). Regression analysis showed time taken to run 550 m was 11 s less in 2015 compared with 2011. Boys ran it 13 s faster than girls (Z score 0.07) and for each 1 year age increase, children were 8 s slower (Z score 0.006). For each 10% decrease in SES, children were 3 s slower (Z score 0.004) and Māori children were 5 s slower than Non-Māori children (Z score 0.15)., Conclusions: The findings from this study support the continuation of the delivery of Project Energize in the Waikato region of New Zealand, as cardiorespiratory fitness scores in 2015, compared to 2011, were improved, particularly for lower SES schools and for Māori children. Ethnically diverse populations, schools with higher deprivation and girls, continue to warrant further attention to help achieve equity., Competing Interests: Competing interestsThe authors report no conflict of interest., (© The Author(s) 2020.)

Electronic health records (EHRs) provide a wealth of data for phenotype development in population health studies, and researchers invest considerable time to curate data elements and validate disease definitions. The ability to reproduce well-defined phenotypes increases data quality, comparability of results and expedites research. In this paper, we present a standardized approach to organize and capture phenotype definitions, resulting in the creation of an open, online repository of phenotypes. This resource captures phenotype development, provenance and process from the Million Veteran Program, a national mega-biobank embedded in the Veterans Health Administration (VHA). To ensure that the repository is searchable, extendable, and sustainable, it is necessary to develop both a proper digital catalog architecture and underlying metadata infrastructure to enable effective management of the data fields required to define each phenotype. Our methods provide a resource for VHA investigators and a roadmap for researchers interested in standardizing their phenotype definitions to increase portability., (©2020 AMIA - All rights reserved.)

Background: Osteogenesis imperfecta, fibrous dysplasia/McCune-Albright syndrome and X-linked hypophosphatemia are three rare musculoskeletal diseases characterised by bone deformities, frequent fractures and pain. Little high-quality research exists on appropriate treatment and long-term management of these conditions in adults. This is further worsened by limited research funding in rare diseases and a general mismatch between the existing research priorities and those of the patients. This partnership adopted the James Lind Alliance approach to identify the top 10 research priorities for rare musculoskeletal diseases in adults through joint patient, carer and healthcare professional collaboration., Results: The initial survey for question collection recruited 198 respondents, submitting a total of 988 questions. 77% of the respondents were patients with a rare musculoskeletal disease. Following out-of-scope question exclusion, repeating query grouping and scientific literature check for answers, 39 questions on treatment and long-term management remained. In the second public survey, 220 respondents, of whom 85% were patients with a rare musculoskeletal disease, their carers, relatives or friends, prioritised these uncertainties, which allowed selection of the top 25. In the last stage, patients, carers and healthcare professionals gathered for a priority setting workshop to reach a consensus on the final top 10 research priorities. These focus on the uncertainties surrounding appropriate treatment and holistic long-term disease management, highlighting several aspects indirect to abnormal bone metabolism, such as extra-skeletal symptoms, psychological care of both patients and their families and disease course through ageing., Conclusions: This James Lind Alliance priority setting partnership is the first to investigate rare bone diseases. The priorities identified here were developed jointly by patients, carers and healthcare professionals. We encourage researchers, funding bodies and other stakeholders to use these priorities in guiding future research for those affected by rare musculoskeletal disorders.

Background/objectives: It has not been reported that previously how much food New Zealand (NZ), population 4.9 million (M), exports and imports in terms of how many people this food would feed if the food-based dietary guidelines (FBDG) were followed. In New Zealand, 40% of adults and 20% of children live in a household with severe to moderate food insecurity., Methods: Official data for foods and beverages exported and imported between 2016 and 2018 was obtained from Statistics New Zealand. Harmonised food classifications were matched to either a food group or as discretionary foods or ingredients. Standard serving sizes in grams and number of servings/day from each food group viz; vegetables, 5 servings/day; fruit, 2 servings/day; grains 6 servings/day; meat and protein foods 2.5 servings/day: and dairy 2.5 servings/day were used to determine how many people would be fed each year with the food traded. Together these servings should meet a daily energy intake in the order of 8 MJ. The trade of discretionary foods and ingredients, alcoholic beverages, butter and sugar was also examined., Results: According to the guidelines the quantity of food exported each year by NZ had enough numbers of servings to feed 39 M dairy, 11.5 M meat, seafood and other protein, 2 M vegetables and 10 M fruit day/year. Imports were dominated by grains, enough to feed 9 M six servings a day/year. Total food energy exported and imported was enough to meet the energy requirements for 20 M (30% from butter) and 10 M (27% from sugar), respectively., Conclusions: The high prevalence of food insecurity and obesity in NZ could be partially attributed to the disconnect between the quantity, nutritional quality and diversity of foods imported and exported.

Aims: To evaluate the effectiveness of a culturally adapted, church-based lifestyle intervention among Australian Samoans living in Sydney., Methods: This was a prospective, pre-post study of a church-wide education and support programme delivered by Community Coach Facilitators and Peer Support Facilitators to prevent, and promote self-management of, Type 2 diabetes. Participants completed questionnaires, anthropometric and HbA1c measurements before and 3-8 months after the intervention. The primary outcome was HbA1c., Results: Overall, 68/107(63.5%) participants completed both before and after intervention data collection (mean age 48.9 ± 14.2 years; 57.2% female). HbA1c dropped significantly between baseline and follow-up among participants with known diabetes (8.1 ± 2.4% (65 mmol/mol) vs 7.4 ± 1.8% (57 mmol/mol); p = 0.040) and non-significantly among participants with newly diagnosed diabetes (8.0 ± 2.1% (64 mmol/mol) vs 7.1 ± 2.3 (54 mmol/mol); p = 0.131). Participants with no diabetes increased their weekly moderate and vigorous physical activity (316.1 ± 291.6mins vs 562.4 ± 486.6mins; p = 0.007) and their diabetes knowledge also improved post-intervention (42.0 ± 13.5% to 61.3 ± 20.2%; p < 0.001). There were no significant reductions in blood pressure, BMI or waist circumference at follow-up., Conclusions: A structured, church-based, culturally tailored lifestyle intervention showed a number of improvements in diabetes risk among Samoans in Sydney. The intervention however, requires a more rigorous testing in a larger randomised controlled trial over a longer time period., Competing Interests: Declarations of Competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Carotenoids, orange-coloured pigments found in vegetables, fruit, eggs and dairy foods, act as antioxidants and vitamin A precursors in the human body. Skin carotenoid concentration is a biomarker of vegetable and fruit intake. The aim was to identify determinants of skin carotenoid concentration by measuring "Veggie Meter™" carotenoid reflection spectroscopy scores (CRS) from the fingertip of adults with a range of ages, ethnicity and body size. Frequencies of daily intake of vegetables and fruit and weekly intake of pumpkin and carrot, dark green leafy vegetables (DGLV), eggs (yolk), and dairy were determined from a self-completed food-frequency-questionnaire. A total of 571 (324 Women, 247 Men) adults, aged 16 to 85 years, completed measurements. The CRS ranged from 83 to 769, with a median of 327. Women and men did not score differently. For all participants there were negative correlations of CRS with weight ( r = -0.312) and BMI ( r = -0.338) and positive correlations with weekly intakes of DGLV ( r = 0.242) and carrots and pumpkin ( r = 0.202). Based on a review of health outcomes associated with plasma carotenoids, 82% of the participants in the current study are at moderate risk, or more, of negative health outcomes. Determinants of carotenoid status were body size, intake of DGLV, carrots and pumpkin, and ethnicity.

The research aim was to investigate associations between objectively-assessed built environment attributes and metabolic risk in adolescents of Pacific Islands ethnicity, and to consider the possible mediating effect of physical activity and sedentary time. Youth ( n = 204) undertook a suite of physical assessments including body composition, blood sampling, and blood pressure measurements, and seven day accelerometry. Objective measures of the neighbourhood built environment were generated around individual addresses. Logistic regression and linear modelling were used to assess associations between environment measures and metabolic health, accounting for physical activity behaviours. Higher pedestrian connectivity was associated with an increase in the chance of having any International Diabetes Federation metabolic risk factors for males only. Pedestrian connectivity was related to fat free mass in males in unadjusted analyses only. This study provides evidence for the importance of pedestrian network connectivity for health in adolescent males. Future research is required to expand the limited evidence in neighbourhood environments and adolescent metabolic health.

Early-life intervention to reduce obesity and poor dental health through early-life nutrition will improve health outcomes in later life. This study examined the prevalence of overweight and obesity and visual dental decay in 4-year old children in New Zealand between 2013 and 2017, and the impact of a nutrition and physical activity intervention programme, Under-5-Energize (U5E), on prevalence of these conditions within ethnic groups and by deprivation. The data set included 277,963 4-year-old children, including 25,140 from the Waikato region children of whom 8067 attended one of the 121 early childhood centres (ECC) receiving the U5E programme from 2014. Purposively the U5E-ECC selected were attended by higher proportions of indigenous Māori children and children living in higher deprivation areas than non-U5E-ECC. From 2013 to 2017, the overall prevalence of obesity, as defined by World Health Organisation criteria, declined slightly but rates of dental decay did not change. In the Waikato region, the prevalence of obesity declined in non-Māori children from 2015 to 2017 and children attending U5E-ECC had lower rates of dental decay than non-U5E children. Binary logistic regression showed that between 2015 and 2017 visible dental decay was more likely in children who were Māori (3.06×3.17), living in high deprivation (1.54×1.66) and male (1.10) but less likely if attending an U5E-ECC (0.83×0.79). Early-life intervention had efficacy at reducing dental decay, and demonstrated that the origins of disparities in health such as ethnicity and deprivation need to be addressed further to break the intergenerational cycles of poor health.

We know that eating a variety of vegetables every day is associated with favorable health across the lifecourse. Internationally, food-based dietary guidelines encourage the consumption of a variety of vegetables and fruit but globally,people are not eating enough vegetables to meet the three-or-more-a-day guideline. Vegetables are good sources of vitamins and minerals, fiber, and many bioactive compounds that promote health and provide energy. They also help reduce hidden hunger (micronutrient deficiencies) and support the healthy growth and development of children. New Zealand is a world leader in the production of diverse nutrients and foods yet poverty and other environmental barriers mean only one in two children eats three-or-more servings of vegetables a day. Price and availability are limiting factors. The proliferation of community, school and home vegetable gardens and vegetable cooperatives may improve access. On a macro level, upstream policies such as a "living wage," affordable housing, and land-use planning are required. International dietary solutions include an agricultural shift to intensified horticulture with a focus on vegetables. The consumption of more plant-based foods including vegetables would reduce green-house gases, reduce land clearing, and help prevent diet-related disease if consumed daily across the lifecourse.

A significant reduction in rice starch digestibility and subsequent postprandial blood glucose responses following extended cold treatment (at 4 °C for 24 h) have been demonstrated in both in vitro and in vivo studies, respectively. The impact of cold treatment was more significant for parboiled rice compared to other rice varieties. This study aimed to investigate consumer liking of sensory characteristics that may influence consumer acceptability of three available rice products in the Auckland region (medium grain white, medium grain brown and parboiled rice, which were either freshly boiled or cold-treated and reheated). The consumer liking of sensory characteristics (colour, taste, flavour, and texture) of each rice sample were accessed using visual analogue scales (VAS) in a randomized single blind setting. In the second stage, the participants evaluated their acceptability on VAS after the nutritional value and the characteristics of the rice samples were revealed. Sixty-four rice consumers reported higher likings of sensory characteristics of cold-treated parboiled rice and medium grain brown rice. The effect of cold treatment on the liking of sensory characteristics was more significant for parboiled rice ( p < 0.05). Participants who are between 36 and 55 years old and consume rice domestically more than 10 times per month preferred cold-treated brown rice (73.8% of the participants' population (67.4%, 80.2%)) and parboiled rice (74.3% of the participants' population (67.9%, 80.7%)) ( p < 0.001). As a result, cold-treated reheated parboiled rice received higher likings and acceptability and could be recommended and accepted as a healthier replacement of the daily staple meal.