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Message passing neural networks (MPNNs) on molecular graphs generate continuous and differentiable encodings of small molecules with state-of-the-art performance on protein-ligand complex scoring tasks. Here, we describe the proximity graph network (PGN) package, an open-source toolkit that constructs ligand-receptor graphs based on atom proximity and allows users to rapidly apply and evaluate MPNN architectures for a broad range of tasks. We demonstrate the utility of PGN by introducing benchmarks for affinity and docking score prediction tasks. Graph networks generalize better than fingerprint-based models and perform strongly for the docking score prediction task. Overall, MPNNs with proximity graph data structures augment the prediction of ligand-receptor complex properties when ligand-receptor data are available.

Background Care for infants born at 22–24 weeks’ gestation varies globally, with an increasing willingness to provide survival-focused (‘active’) care for infants born at 22 weeks’ gestation in recent years. This study aims to report changes in care for infants born at 22–24 weeks before and after the introduction of a statewide guideline for extreme prematurity (EP).Methods A retrospective cohort study was conducted, including all live births at 22–24 weeks in tertiary perinatal centres from 1 January 2015 to 31 December 2022 in Victoria, Australia. Medical records were reviewed to obtain antenatal history and perinatal outcomes. Data on in utero referral and transfer to tertiary perinatal centres were sourced from the statewide perinatal emergency retrieval service (Paediatric Infant Perinatal Emergency Retrieval, PIPER) database. Changes in PIPER referrals and transfers, survival-focused care and survival at 28 days preguideline and postguideline were assessed using logistic regression.Results Following the guideline, at 22 weeks’ gestation, there was an increase in referrals to PIPER and a 3.31 (95% CI 1.84 to 5.95) higher likelihood of in utero transfer to tertiary centres.Following the guideline, infants had a 6.67 (95% CI 1.40 to 31.72) higher likelihood of receiving survival-focused care at 22 weeks, and a 5.57 (95% CI 1.22 to 25.44) higher likelihood at 23 weeks. All 24-week live births received survival-focused care at birth. The 28-day survival for infants who received survival-focused care was unchanged preguideline and postguideline.Conclusion Following the publication of the EP guideline in Victoria, in utero referrals and transfers at 22 weeks’ gestation have increased, as has survival-focused management of inborn live births at 22–24 weeks.

ABSTRACTThe presence of meaning in life (MiL) and character strengths (CS) are protective factors for adolescents’ mental health. The main objective of the present study was to explore transculturally the relationship between MiL and CS with anxiety and depression in the context of the COVID-19 pandemic among adolescents. Adolescents (N = 577) aged 14 to 18 (319 Russians and 258 Spaniards) completed online questionnaires during the pandemic. The results showed that in both samples, zest, gratitude, and love were the most robust predictors of depression symptoms; zest, hope, and love in girls, and self-regulation, hope, and presence of MiL in boys more robustly predicted anxiety symptoms. The findings provide data on the resilience function of CS and the presence of MiL during the COVID-19 pandemic and have important preventive practical implications.

Machine learning-based drug discovery success depends on molecular representation. Yet traditional molecular fingerprints omit both the protein and pointers back to structural information that would enable better model interpretability. Therefore, we propose LUNA, a Python 3 toolkit that calculates and encodes protein-ligand interactions into new hashed fingerprints inspired by Extended Connectivity FingerPrint (ECFP): EIFP (Extended Interaction FingerPrint), FIFP (Functional Interaction FingerPrint), and Hybrid Interaction FingerPrint (HIFP). LUNA also provides visual strategies to make the fingerprints interpretable. We performed three major experiments exploring the fingerprints' use. First, we trained machine learning models to reproduce DOCK3.7 scores using 1 million docked Dopamine D4 complexes. We found that EIFP-4,096 performed (R2 = 0.61) superior to related molecular and interaction fingerprints. Second, we used LUNA to support interpretable machine learning models. Finally, we demonstrate that interaction fingerprints can accurately identify similarities across molecular complexes that other fingerprints overlook. Hence, we envision LUNA and its interface fingerprints as promising methods for machine learning-based virtual screening campaigns. LUNA is freely available at https://github.com/keiserlab/LUNA.

Summary: Cultivated meat (also known as cultured meat) is a promising technology that faces substantial cost barriers, which are currently driven by the price of media components. Particularly, growth factors such as fibroblast growth factor 2 (FGF2) drive the cost of serum-free media for relevant cells, including muscle satellite cells. Here, we engineered immortalized bovine satellite cells (iBSCs) for inducible expression of FGF2 and/or mutant RasG12V to overcome media growth factor requirements through autocrine signaling. Engineered cells were able to proliferate over multiple passages in FGF2-free medium, thereby eliminating the need for this costly component. Additionally, cells maintained their myogenicity, albeit with reduced myotube formation. Ultimately, this offers a proof of principle for lower-cost cultured meat production through cell line engineering. Science for society: Cultivated meat is an emerging technology that aims to produce meat through cell culture rather than conventional animal agriculture. By decoupling meat from animals, cultivated meat is projected to dramatically reduce the environmental impact of meat while simultaneously improving animal welfare and human health. To date, however, cultivated meat production is hindered by high costs, which are driven by the cell culture media. In particular, recombinant growth-promoting factors such as fibroblast growth factor 2 (FGF2) contribute a majority of the cost of these media. Here, we engineer bovine muscle stem cells to endogenously activate the growth-promoting signaling cascades that are typically triggered by exogenous FGF2, thereby eliminating the need for this costly media component. This approach offers a step toward engineering cultivated meat cells for expansion in recombinant protein-free media, an approach that would dramatically lower the cost of production.

Background: Vitamin D deficiency is common in pregnant women. There is scarce information in the Asia-Pacific region on the understanding of vitamin D screening and supplementation in pregnancy among health care professionals. Methods: We performed a cross-sectional study among health care professionals who are part of the Integrated Platform for Research in Advancing Metabolic Health outcomes of Women and Children (IPRMAHO) international study group on their understanding and perception of Vitamin D screening and supplementation in pregnancy. The cross-sectional survey comprised 4 main sections: demographics, existing policies, nutrient supplementation in pregnancy and various practices on screening, treatment and perceptions, with a total of 22 questions. A total of 15 responses were obtained from attendees from distinct health facilities across eleven participating Asia-Pacific countries. Results: Majority of the surveyed hospitals (11/15, 78.6 %) did not have a national policy or regional guideline regarding Vitamin D screening and supplementation in pregnancy. More than half of respondents were (9/14, 64.3 %) were unsure of the percentage of women seen with Vitamin D deficiencies each year and were unsure of Vitamin D dosage prescribed to pregnant women with (8/15, 53.3 %) or without (6/14, 42.9 %) Vitamin D deficiency. Vitamin D was rarely prescribed in pregnancy when compared to other nutrient supplements such as folic acid and iron. Majority of respondents (9/11, 72.7 %) indicated that their hospital did not screen for Vitamin D deficiencies in pregnancy, even amongst high risk pregnant women. Nevertheless, majority of respondents indicated a need (12/15, 80.0 %) for a guideline or consensus regarding Vitamin D screening and supplementation in pregnancy. Conclusion: While majority of the surveyed hospitals did not have a national policy or regional guideline regarding Vitamin D screening and supplementation in pregnancy, majority of respondents indicated a need for the policy or guideline. There were varying clinical knowledge gaps and different perceptions on Vitamin D screening and supplementation in pregnancy among healthcare professionals.

Microvillus inclusion disease (MVID), caused by loss-of-function mutations in the motor protein myosin Vb (MYO5B), is a severe infantile disease characterized by diarrhea, malabsorption, and acid/base instability, requiring intensive parenteral support for nutritional and fluid management. Human patient–derived enteroids represent a model for investigation of monogenic epithelial disorders but are a rare resource from MVID patients. We developed human enteroids with different loss-of function MYO5B variants and showed that they recapitulated the structural changes found in native MVID enterocytes. Multiplex immunofluorescence imaging of patient duodenal tissues revealed patient-specific changes in localization of brush border transporters. Functional analysis of electrolyte transport revealed profound loss of Na+/H+ exchange (NHE) activity in MVID patient enteroids with near-normal chloride secretion. The chloride channel–blocking antidiarrheal drug crofelemer dose-dependently inhibited agonist-mediated fluid secretion. MVID enteroids exhibited altered differentiation and maturation versus healthy enteroids. γ-Secretase inhibition with DAPT recovered apical brush border structure and functional Na+/H+ exchange activity in MVID enteroids. Transcriptomic analysis revealed potential pathways involved in the rescue of MVID cells including serum/glucocorticoid-regulated kinase 2 (SGK2) and NHE regulatory factor 3 (NHERF3). These results demonstrate the utility of patient-derived enteroids for developing therapeutic approaches to MVID.

Today, spiritual health is recognized as one of the most important aspects of human health; Because the role of spirituality in the mental and consequently physical health of man is undeniable. On the other hand, the religion of Islam has paid much attention to the spiritual and divine aspect. God in the Holy Quran mentions the heart as a source and container of spiritual health and in this regard, it names different types of hearts, of which 8 indicate health and indicate ill health. Now the question arises, to what extent are these hearts related to spiritual health in humans? For this reason, this article, using descriptive and analytical methods and referring to interpretive sources, and in order to prevent lengthy speech, has only examined the relationship between healthy hearts and spiritual health. First, a definition of heart and spiritual health is presented and then the relationship between the eight hearts and spiritual health was explained and analyzed. Finally, the common point of these hearts is in the tendency to monotheism, and considering that the heart is a container for its contents, the more this monotheistic heart enjoys, the more it enjoys spiritual health Therefore, a healthier heart has the highest level of spiritual health, after that, in order, the heart of Mokhbet, the heart of Mahdi, the heart of Munib, the heart of Taqi, the heart of Muotmaan, the heart of Wajal and the heart of Hie. They have some degrees of spiritual health.

Microvillus inclusion disease (MVID), caused by loss-of-function mutations in the motor protein myosin Vb (MYO5B), is a severe infantile disease characterized by diarrhea, malabsorption, and acid/base instability, requiring intensive parenteral support for nutritional and fluid management. Human patient-derived enteroids represent a model for investigation of monogenic epithelial disorders but are a rare resource from MVID patients. We developed human enteroids with different loss-of function MYO5B variants and showed that they recapitulated the structural changes found in native MVID enterocytes. Multiplex immunofluorescence imaging of patient duodenal tissues revealed patient-specific changes in localization of brush border transporters. Functional analysis of electrolyte transport revealed profound loss of [Na.sup.+]/[H.sup.+] exchange (NHE) activity in MVID patient enteroids with near-normal chloride secretion. The chloride channel-blocking antidiarrheal drug crofelemer dose-dependently inhibited agonist-mediated fluid secretion. MVID enteroids exhibited altered differentiation and maturation versus healthy enteroids. [gamma]-Secretase inhibition with DAPT recovered apical brush border structure and functional [Na.sup.+]/[H.sup.+] exchange activity in MVID enteroids. Transcriptomic analysis revealed potential pathways involved in the rescue of MVID cells including serum/glucocorticoid-regulated kinase 2 (SGK2) and NHE regulatory factor 3 (NHERF3). These results demonstrate the utility of patient-derived enteroids for developing therapeutic approaches to MVID., Introduction Microvillus inclusion disease (MVID) is a rare congenital diarrhea and enteropathy (CoDE) caused by loss-of-function mutations in the motor protein myosin Vb (MYO5B) (1-5). In general, patients with severe [...]

Abstract Introduction The supportive care needs of men with prostate cancer (PCa) have been well documented, but little is known about how an online portal may address these. This study sought to determine priority issues facing men with PCa, barriers and enablers to accessing care and whether health professionals (HPs) and men would support the inclusion of a patient‐reported outcome (PRO) comparator tool. Methods We conducted four online focus groups with HPs recruited from healthcare services in Victoria, followed by seven online codesign workshops with men with PCa, recruited through the Victorian Prostate Cancer Outcomes Registry, Prostate Cancer Foundation Australia and the Cancer Council Victoria. Men were eligible to participate if they had lived experience of PCa and access to the internet. We analysed focus groups thematically. Workshops were analysed using descriptive‐content analysis. Results HPs (n = 39) highlighted that men had shifting priorities over time, but noted the importance of providing information to men in lay terms to assist in treatment decision‐making and side‐effect management. HPs identified key enablers to men accessing support services such as practice nurses, partners and having men share their stories with each other. HPs raised financial, cultural, geographic and emotional barriers to accessing supportive care. Inclusion of a PRO comparator tool received mixed support from HPs, with 41% (n = 16) supportive, 49% (n = 19) unsure and 10% (n = 4) not supportive. Men involved in workshops (n = 28) identified informational needs to assist in treatment decision‐making and side‐effect management as the top priority throughout care. Men described support groups and practice nurses as key enablers. Short consultation times and complex information were described as barriers. Unlike HPs, all men supported the inclusion of a PRO comparator tool in a portal. Conclusions Our findings suggest that a patient support portal should provide information in lay terms that address the shifting priorities of men with PCa. Men with PCa would welcome the development of a portal to centralize support information and a PRO comparator tool to prompt health‐seeking behaviour. Future research will implement these findings in the development of a portal, and pilot and evaluate the portal within a population‐based sample. Patient or Public Contribution This project adopted a codesign approach including both men with PCa and HPs involved in PCa care. Men with PCa also formed part of the study's steering committee and consumer advisory groups. HPs were consulted in a serious of online focus groups. Subsequently, men with PCa and their support persons participated in workshops. Men with PCa were also involved in the preparation of this manuscript.

A substitution of FBS in culturing of bovine satellite cells for the purpose of culturing meat is presented, addressing both basal media and growth factors in relation to proliferating and differentiating cells.

Background: Diabetic retinopathy (DR) may worsen during pregnancy, but its course in the postpartum remains poorly understood. Understanding the natural history of DR during and after pregnancy can help determine when sight‐threatening DR treatment should be administered. Methods: A prospective longitudinal cohort study recruited pregnant women with pre‐existing type 1 (T1D) or type 2 diabetes from two tertiary Diabetes Antenatal Clinics in Melbourne, Australia. Eye examination results in early pregnancy, late pregnancy, and up to 12‐months postpartum were compared to determine DR changes. Two‐field fundus photographs and optical coherence tomography scans were used to assess DR severity. Results: Overall, 105 (61.4%) women had at least two eye examinations during the observation period. Mean age was 33.5 years (range 19–51); 54 women (51.4%) had T1D; 63% had HbA1c <7% in early pregnancy. DR progression rate was 23.8% (95% CI 16.4–32.6). Having T1D (RR 4.96, 95% CI 1.83–13.46), pre‐existing DR in either eye (RR 4.54, 95% CI 2.39–8.61), and elevated systolic blood pressure (adjusted RR 2.49, 95% CI 1.10–5.66) were associated with increased risk of progression. Sight‐threatening progression was observed in 9.5% of women. Among the 19 eyes with progression during pregnancy, 15 eyes remained stable, three eyes progressed, and only one eye regressed in the postpartum. Conclusions: Nearly 1 in 4 women had DR progression from conception through to 12‐months postpartum; almost half of these developing sight‐threatening disease. DR progression occurring during pregnancy was found to predominantly remain unchanged, or worsen, after delivery, with very few eyes spontaneously improving postpartum. [ABSTRACT FROM AUTHOR]

ObjectivesMicrovillus inclusion disease (MVID) is a severe form of neonatal diarrhea, caused mainly by mutations in MYO5B. Inactivating mutations in MYO5B causes depolarization of enterocytes in the small intestine, which gives rise to chronic, unremitting secretory diarrhea. While the pathology of the small intestine in MVID patients is well described, little is known about extraintestinal effects of MYO5B mutation.MethodsWe examined stomach, liver, pancreas, colon, and kidney in Navajo MVID patients, who share a single homozygous MYO5B-P660L (1979C>T p.Pro660Leu, exon 16). Sections were stained for markers of the apical membrane to assess polarized trafficking.ResultsNavajo MVID patients showed notable changes in H/K-ATPase-containing tubulovesicle structure in the stomach parietal cells. Colonic mucosa was morphologically normal, but did show losses in apical ezrin and Syntaxin 3. Hepatocytes in the MVID patients displayed aberrant canalicular expression of the essential transporters MRP2 and BSEP. The pancreas showed small fragmented islets and a decrease in apical ezrin in pancreatic ducts. Kidney showed normal primary cilia.ConclusionsThese findings indicate that the effects of the P660L mutation in MYO5B in Navajo MVID patients are not limited to the small intestine, but that certain tissues may be able to compensate functionally for alterations in apical trafficking.

Abstract Background The application of advanced imaging in pediatric research trials introduces the challenge of how to effectively handle and communicate incidental and reportable findings. This challenge is amplified in underserved populations that experience disparities in access to healthcare as recommendations for follow-up care may be difficult to coordinate. Therefore, the purpose of the present report is to describe the process for identifying and communicating findings from a research MRI to low-income Latino children and families. Methods Latino adolescents (n = 86) aged 12–16 years old with obesity and prediabetes underwent a research MRI (3 Tesla Philips Ingenia®) as part of a randomized controlled diabetes prevention trial. The research MRIs were performed at baseline and 6 months to assess changes in whole-abdominal fat distribution and organ fat in response to the intervention. An institutional pathway was developed for identifying and reporting findings to participants and families. The pathway was developed through a collaborative process with hospital administration, research compliance, radiology, and the research team. All research images were reviewed by a board-certified pediatric radiologist who conveyed findings to the study pediatrician for determination of clinical actionability and reportability to children and families. Pediatric sub-specialists were consulted as necessary and a primary care practitioner (PCP) from a free community health clinic agreed to receive referrals for uninsured participants. Results A total of 139 images (86 pre- and 53 post-intervention) were reviewed with 31 findings identified and 23 deemed clinically actionable and reportable. The only reportable finding was severely elevated liver fat (> 10%, n = 14) with the most common and concerning incidental findings being horseshoe kidney (n = 1) and lung lesion (n = 1). The remainder (n = 7) were less serious. Of youth with a reportable or incidental finding, 18 had a PCP but only 7 scheduled a follow-up appointment. Seven participants without a PCP were referred to a safety-net clinic for follow-up. Conclusions With the increased utilization of high-resolution imaging in pediatric research, additional standardization is needed on what, when, and how to return incidental and reportable findings to participants, particularly among historically underrepresented populations that may be underserved in the community. Trial registration Preventing Diabetes in Latino Youth, NCT02615353

Abstract Background Gestational diabetes mellitus (GDM) is a serious public health issue affecting 9–15% of all pregnancies worldwide. Recently, it has been suggested that extracellular vesicles (EVs) play a role throughout gestation, including mediating a placental response to hyperglycaemia. Here, we investigated the EV-associated miRNA profile across gestation in GDM, assessed their utility in developing accurate, multivariate classification models, and determined the signaling pathways in skeletal muscle proteome associated with the changes in the EV miRNA profile. Methods Discovery: A retrospective, case–control study design was used to identify EV-associated miRNAs that vary across pregnancy and clinical status (i.e. GDM or Normal Glucose Tolerance, NGT). EVs were isolated from maternal plasma obtained at early, mid and late gestation (n = 29) and small RNA sequencing was performed. Validation: A longitudinal study design was used to quantify expression of selected miRNAs. EV miRNAs were quantified by real-time PCR (cases = 8, control = 14, samples at three times during pregnancy) and their individual and combined classification efficiencies were evaluated. Quantitative, data-independent acquisition mass spectrometry was use to establish the protein profile in skeletal muscle biopsies from normal and GDM. Results A total of 2822 miRNAs were analyzed using a small RNA library, and a total of 563 miRNAs that significantly changed (p 90%. We identified a set of proteins in skeletal muscle biopsies from women with GDM associated with JAK-STAT signaling which could be targeted by the miRNA-92a-3p within circulating EVs. Interestingly, overexpression of miRNA-92a-3p in primary skeletal muscle cells increase insulin-stimulated glucose uptake. Conclusions During early pregnancy, differently-expressed, EV-associated miRNAs may be of clinical utility in identifying presymptomatic women who will subsequently develop GDM later in gestation. We suggest that miRNA-92a-3p within EVs might be a protected mechanism to increase skeletal muscle insulin sensitivity in GDM.

Abstract Background Australian guidelines recommend that all people aged 50–70 years old actively consider taking daily low-dose aspirin (100–300 mg per day) for 2.5 to 5 years to reduce their risk of colorectal cancer (CRC). Despite the change of national CRC prevention guidelines, there has been no active implementation of the guidelines into clinical practice. We aim to test the efficacy of a health consultation and decision aid, using a novel expected frequency tree (EFT) to present the benefits and harms of low dose aspirin prior to a general practice consultation with patients aged 50–70 years, on informed decision-making and uptake of aspirin. Methods Approximately five to seven general practices in Victoria, Australia, will be recruited to participate. Patients 50–70 years old, attending an appointment with their general practitioner (GP) for any reason, will be invited to participate in the trial. Two hundred fifty-eight eligible participants will be randomly allocated 1:1 to intervention or active control arms using a computer-generated allocation sequence stratified by general practice, sex, and mode of trial delivery (face-to-face or teletrial). There are two co-primary outcomes: informed decision-making at 1-month post randomisation, measured by the Multi-dimensional Measure of Informed Choice (MMIC), and self-reported daily use of aspirin at 6 months. Secondary outcomes include decisional conflict at 1-month and other behavioural changes to reduce CRC risk at both time points. Discussion This trial will test the efficacy of novel methods for implementing national guidelines to support informed decision-making about taking aspirin in 50–70-year-olds to reduce the risk of CRC and other chronic diseases. Trial registration The Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620001003965 . Registered on 10 October 2020.

The article analyzes one of the levels of local identity - memorial identity, understood as a temporal (retrospective) connection of an individual or a collective with the social and/or spatial environment. In practice, this connection can be embodied in the perception of a city (village, region - any locus) as a kind of scene for the unfolding of events of personal biography (personalized type of memorial identity) or as a mirror in which significant milestones of national or world history are reflected (socialized type of memorial identity). Using the example of Chelyabinsk and Magnitogorsk, two largest industrial cities of the South Urals, the author identifies the main features of the memorial identity of their residents. On the one hand, there is a high axiological status of the past, assessment of history as a source of pride for their city (mainly in the context of the contribution of South Ural residents to the victory in the Great Patriotic War), justification of personal attachment to the city as a place of birth, childhood, and youth. On the other hand, there is an extremely low level of real engagement in private and official memorial practices, passivity in creation of media retrocontent. It is concluded that against the background of a quite critical attitude of the population to the current situation in the region (mainly related to environmental problems), the memorial component of local identity can be perceived as an effective tool of cultural policy - it allows reducing the level of social tension, leveling the acuteness of perception of existing problems, and strengthening the degree of attachment of the population to their hometown.