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The developmental origins of health and disease (DOHaD) framework has highlighted the importance of the early life period on disease risk in later life with impacts that can span generations. A primary focus to date has been around maternal health and the 'First Thousand Days' as a key developmental window whereby an adverse environment can have lasting impacts on both mother and offspring. More recently, the impact of paternal health has gathered increasing traction as a key window for early life developmental programming. However, to date, adolescents, the next generation of parents, have attracted less attention as a key DOHaD window although many behavioural traits become entrained during adolescence and track into adulthood. This systematic review examined literature focused on identifying adolescent understanding of DOHaD concepts. Consistent across the eligible articles was that overall understanding of DOHaD-related concepts in adolescents was low. Three key themes emerged: 1. Individual-level awareness of DOHaD concepts (cognitive engagement and action of the adolescents themselves); 2. Interpersonal communication and social awareness of DOHaD concepts (cognitive engagement and communication of the DOHaD concepts to family and wider community); and 3. Health literacy and the promotion of adolescence as a key DOHaD life stage. These findings highlight the need to develop strategic approaches to increase DOHaD awareness that are not only appealing to adolescents but can also support sustained changes in health behaviour. Investment in today's adolescents has the potential to act as a NCD 'circuit breaker' and thus will yield significant dividends for future generations. [ABSTRACT FROM AUTHOR]

Objective We aimed to assess prescribing practices, compliance with guidelines, and outcomes for patients who were admitted to the authors’ institution with community-acquired pneumonia (CAP). Methods We performed a single-center retrospective cross-sectional study of adults with CAP presenting during the 2019 influenza season. CAP severity was assessed using the CURB-65 risk score. The effect of CURB-65 risk score use on the rate of appropriate antimicrobial prescribing was assessed using the chi-square test and reported as odds ratio (OR). Fisher’s exact test was used to assess the relationship between prescribing appropriateness and patient outcomes. Results Patients with low-risk CAP were most likely to be inappropriately prescribed antimicrobials (OR: 4.77; 95% confidence interval: 2.44–10.47). In low-risk CAP, the most common prescribing error was overuse of ceftriaxone. In high-risk CAP, the most common errors were ceftriaxone underdosing and missed atypical coverage with azithromycin. Overall, 80% of patients were considered to have been inappropriately prescribed antimicrobials. No effect on mortality was observed. Conclusions In this study, we found low use of CAP risk scores and low adherence to antimicrobial prescribing guidelines for CAP at the authors’ institution.

Aim: To measure the effectiveness and sustainability of the Juniper UK digital weight-loss service (DWLS), which delivers 6 months of personalized, proactive lifestyle coaching supplemented with tirzepatide to patients through a multidisciplinary team (MDT)., Methods: An observer-blinded randomized controlled trial (RCT) will be conducted on a cohort of non-diabetic patients of the Juniper DWLS in the UK. Participants in both the intervention and control groups will receive weekly subcutaneous injections of 2.5 mg tirzepatide for 4 weeks, uptitrating the dose to 5.0 mg from weeks 5 to 8, and by 2.5 mg every 4 weeks until reaching 15 mg in week 21, which they will maintain until the end of the intervention period at 6 months, when participants will be taken off the medication. The intervention group will receive personalized weeklylifestyle coaching with a focus on protein intake and resistance training for 6 months. Participants in the control group will attend a diet and exercise group counselling session at programme inception and will be sent a summary of the session's content at months 2 and 4. Aside from these events, health coaches will only interact with control group participants on a reactive basis. From month 6 to month 12, participants from both groups will no longer have access to their MDTs. The trial's co-primary endpoints include weight loss, fat-free to fat-mass ratio and composite strength measures at 12 months (6 months following the end of treatment), compared with baseline. Secondary endpoints include percentage change in weight, fat-free to fat-mass ratio, and composite strength from baseline to 6 months, side effect incidence, and change in cardiometabolic risk factors at 12 months. Quality of life and programme engagement represent the study's exploratory endpoints., Results: A total of 688 participants enrolled in the study, with a mean age of 44.6 (± 11.4) years and a mean body mass index of 34.8 (± 7.5) kg/m 2 ; 81.0% of participants are women, and 72.8% are of White ethnicity. More than three-quarters of participants have at least one co-morbidity, with dyslipidaemia (42.4%), hypertension (35.3%) and high cholesterol (31.8%) being the most prevalent conditions., Conclusions: This RCT will be the first to assess the effectiveness and sustainability of a real-world intensive, multidisciplinary DWLS, and it should highlight the potential of such a service for long-term obesity treatment compared with programmes that deliver standard health counselling., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Digital weight loss services (DWLSs) that use Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated potential in contributing to a shift in global obesity rates. However, reasonable concerns have been raised about the prescribing safety of these services. Prior to this study, electronic prescribing safety had only been investigated in hospital settings and community clinics., Methods: This study retrospectively analyzed prescribing errors committed over a 6-month period in 2023 at Australia's largest GLP-1 RA-supported DWLS., Results: The analysis found that 1654 (4.4%) of the 37323 audited GLP-1 RA prescriptions contained an error. Most errors pertained to insufficient safety counselling (49.15%) and inadequate investigations of potential contraindications (30.29%). Although a large portion of prescribing errors were detected via the automated query method (64.9%), the other three auditing methods all detected a significant number of true errors (>100). Patients from the highest body mass index category (40+ kg/m 2 ) were overrepresented in the service's prescribing error data., Conclusions: These findings lay a vital foundation in the emerging literature on GLP-1 RA-supported DWLSs.

Grasspea (Lathyrus sativus L.) is an underutilised but promising legume crop with tolerance to a wide range of abiotic and biotic stress factors, and potential for climate-resilient agriculture. Despite a long history and wide geographical distribution of cultivation, only limited breeding resources are available. This paper reports a 5.96 Gbp genome assembly of grasspea genotype LS007, of which 5.03 Gbp is scaffolded into 7 pseudo-chromosomes. The assembly has a BUSCO completeness score of 99.1% and is annotated with 31719 gene models and repeat elements. This represents the most contiguous and accurate assembly of the grasspea genome to date., (© 2024. The Author(s).)

Digital weight-loss services (DWLSs) combining pharmacotherapy and health coaching have the potential to make a major contribution to the global struggle against obesity. However, the degree to which DWLSs compromise patient safety through the dispensation of Glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications is unknown. This study retrospectively analysed the rate at which patients reported GLP-1 RA dispensing errors from patient-selected and partner pharmacies of Australia's largest DWLS provider over a six-month period. The analysis found that 99 (0.35%) of the 28,165 dispensed semaglutide orders contained an error. Incorrect dose (58.6%) and unreasonable medication expiry window (21.2%) were the two most common error types. Most errors (84.9%) were deemed to have been of medium urgency, with 11.1% being considered high-urgency errors. Incorrect doses (45.5%) and supplies of the wrong medication (36.3%) comprised most errors reported in high-urgency cases. Female patients reported more dispensing errors than male patients (0.41% vs. 0.12%, p < 0.001). Similarly, reported dispensing error rates were highest among patients aged 18 to 29 years (0.6%) and 30 to 39 years (0.5%). This research provides preliminary evidence that GLP-1 RA dispensing errors within comprehensive Australian DWLSs are relatively low.

Background: Inflammatory bowel disease (IBD) is a chronic, autoimmune disorder that affects the gastrointestinal tract. Disordered eating describes irregular eating behaviors that may be a precursor to an eating disorder diagnosis. Higher rates of disordered eating have been described in chronic diseases. Screening for disordered eating is not performed in pediatric patients with IBD. The goal of this longitudinal study was to use the Eating Attitudes Test (EAT-26) to screen pediatric patients with IBD for disordered eating, estimate our population's prevalence, identify potential risk factors, and correlate positive EAT-26 screen results with evaluation in adolescent medicine clinic., Methods: Eighty patients with IBD between 10 and 21 years completed the EAT-26 questionnaire during gastroenterology clinic visit. Disease activity was measured using Pediatric Ulcerative Colitis Activity Index (PUCAI) and Pediatric Crohn's Disease Activity Index (PCDAI). Patients also rated their own disease activity on a numerical scale., Results: Five patients had a positive EAT-26 screen and were evaluated in the adolescent medicine clinic. One hundred percent of those who screened positive were diagnosed with a concomitant eating disorder once evaluated. Only 20% of those who screened positive had active IBD. Higher weight, body mass index, and patient perception of disease activity were associated with increased EAT-26 score., Conclusion: Pediatric patients with IBD are at risk for disordered eating, with a prevalence of 6% in our population, which is twice the prevalence of disordered eating in the general population. The EAT-26 questionnaire is a feasible tool to screen pediatric IBD patients for disordered eating., (© 2024 American Society for Parenteral and Enteral Nutrition.)

Nucleotide-binding domain and leucine-rich repeat (NLR) proteins are a prominent class of intracellular immune receptors in plants. However, our understanding of plant NLR structure and function is limited to the evolutionarily young flowering plant clade. Here, we describe an extended spectrum of NLR diversity across divergent plant lineages and demonstrate the structural and functional similarities of N-terminal domains that trigger immune responses. We show that the broadly distributed coiled-coil (CC) and toll/interleukin-1 receptor (TIR) domain families of nonflowering plants retain immune-related functions through translineage activation of cell death in the angiosperm Nicotiana benthamiana. We further examined a CC subfamily specific to nonflowering lineages and uncovered an essential N-terminal MAEPL motif that is functionally comparable with motifs in resistosome-forming CC-NLRs. Consistent with a conserved role in immunity, the ectopic activation of CCMAEPL in the nonflowering liverwort Marchantia polymorpha led to profound growth inhibition, defense gene activation, and signatures of cell death. Moreover, comparative transcriptomic analyses of CCMAEPL activity delineated a common CC-mediated immune program shared across evolutionarily divergent nonflowering and flowering plants. Collectively, our findings highlight the ancestral nature of NLR-mediated immunity during plant evolution that dates its origin to at least ∼500 million years ago., Competing Interests: Conflict of interest statement S.K. receives funding from industry on NLR biology. S.K. has filed patents on NLR biology., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Increasingly large numbers of people are using digital weight loss services (DWLSs) to treat being overweight and obesity. Although it is widely agreed that digital modalities improve access to care in general, obesity stakeholders remain concerned that many DWLSs are not comprehensive or sustainable enough to deliver meaningful health outcomes. This study adopted a mixed methods approach to assess why and after how long patients tend to discontinue Australia's largest DWLS, a program that combines behavioural and pharmacological therapy under the guidance of a multidisciplinary care team. We found that in a cohort of patients who commenced the Eucalyptus DWLS between January and June 2022 ( n = 5604), the mean program adherence was 171.2 (±158.2) days. Inadequate supplying of a patient's desired glucose-like peptide-1 receptor agonist medication was the most common reason for discontinuation (43.7%), followed by program cost (26.2%), result dissatisfaction (9.9%), and service dissatisfaction (7.2%). Statistical tests revealed that ethnicity and age both had a significant effect on patient adherence. These findings suggest that DWLSs have the potential to improve access to comprehensive, continuous obesity care, but care models need to improve upon the one observed in the Eucalyptus Australia DWLS to mitigate common real-world program attrition factors.

Introduction: The COVID-19 pandemic resulted in an unprecedent shift towards virtual cancer care, including the care of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The aim of this study was to evaluate the use of virtual care for GEP-NETs during the COVID-19 pandemic at a high-volume academic cancer center., Methods: This retrospective, observational study performed at the Ottawa Hospital Cancer Center in Canada evaluated adult patients with GEP-NETs seen in consultation by medical oncology between 1 June 2019 and 31 December 2022. Demographic, clinicopathologic, cancer treatment and visit data were collected. Univariable and multivariable analyses assessed the relationship between patient characteristics and virtual care use., Results: A total of 103 patients with well-differentiated GEP-NETS were included. Overall, 18/103 (17.5%) consults and 594/781 (76.1%) follow-ups were performed virtually. All consultation visits returned to in-person assessment by 2022, while 67.0% and 41.4% follow-ups remained virtual in 2022 and 2023, respectively. The year of follow-up, sex, employment and Charlston comorbidity index were associated with virtual follow-up use in the multivariable analysis., Discussion: Virtual care remained a predominant method of GEP-NET patient assessment in the peri-pandemic period. These results highlight an opportunity to improve access to subspecialty neuroendocrine cancer care through the continued use of virtual care.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2023 was held in Quebec City, Quebec 2-4 February 2023. The purpose of the conference was to develop consensus statements on emerging and evolving treatment paradigms. Participants included Canadian medical oncologists, radiation oncologists, pathologists and surgical oncologists from across Ontario, Quebec, and the Atlantic provinces. Consensus statements were developed following rapid review presentations and discussion of available literature. The recommendations proposed here represent the consensus opinions of physicians involved in the care of patients with gastrointestinal malignancies who participated in this meeting.

(1) Aim: The prevalence and incidence of small bowel NETs have increased significantly over the past two decades. This study aims to report the 10-year experience of SB-NET management at a regional cancer center in Canada. (2) Materials and methods: We conducted a retrospective study of the clinical and pathological data of patients diagnosed with biopsy-proven SB-NET at The Ottawa Hospital (TOH), Ottawa, Canada between 2011 and 2021. We report the clinicopathological characteristics of these patients, as well as their outcomes data, including survival rates. (3) Results: Between 2011 and 2021, a total of 177 SB-NET cases were identified with 51% ( n = 91) of cases being males. The most common sites of the tumors were the ileum 53% ( n = 94), followed by the duodenum 9% ( n = 16) and jejunum 7% ( n = 12). Approximately 24% ( n = 42) of the patients had symptoms for over six months prior to diagnosis and 18% ( n = 32) had functioning SB-NET during the course of the disease. The majority of patients had locally advanced or metastatic disease at the time of presentation with stage III, and stage IV representing 42% ( n = 75), and 41% ( n = 73) respectively. The majority of patients 84% ( n = 148) had well-differentiated histology. One hundred twenty patients underwent surgical resection of the primary tumor including 28 patients (16%) with limited metastatic disease. A total of 21 patients (18%) had recurrence after curative surgery. A total of 62 patients (35%) received first-line somatostatin analog (SSA) therapy for unresectable disease and seven patients had PRRT after progression on SSA. Five years OS was 100%, 91%, 97%, and 73% for stages I, II, III, and IV respectively. In univariate analysis, carcinoid symptoms, T stage, and differentiation were significant predictors for worse overall survival, but not RFS. (4) Conclusions: Compared to published historical controls, our study suggests improvement in the 5-year survival rate of SB-NETs over the last 10 years.

Background: Durum wheat (Triticum turgidum subsp. durum) is widely grown for pasta production, and more recently, is gaining additional interest due to its resilience to warm, dry climates and its use as an experimental model for wheat research. Like in bread wheat, the starch and protein accumulated in the endosperm during grain development are the primary contributors to the calorific value of durum grains., Results: To enable further research into endosperm development and storage reserve synthesis, we generated a high-quality transcriptomics dataset from developing endosperms of variety Kronos, to complement the extensive mutant resources available for this variety. Endosperms were dissected from grains harvested at eight timepoints during grain development (6 to 30 days post anthesis (dpa)), then RNA sequencing was used to profile the transcriptome at each stage. The largest changes in gene expression profile were observed between the earlier timepoints, prior to 15 dpa. We detected a total of 29,925 genes that were significantly differentially expressed between at least two timepoints, and clustering analysis revealed nine distinct expression patterns. We demonstrate the potential of our dataset to provide new insights into key processes that occur during endosperm development, using starch metabolism as an example., Conclusion: We provide a valuable resource for studying endosperm development in this increasingly important crop species., (© 2023. The Author(s).)

Background: Treatment for metastatic neuroendocrine tumors (NETs) is often with somatostatin analogues (SSA) such as lanreotide in the first-line setting. Real world use of lanreotide in Canada is not well studied., Methods: We performed a retrospective chart review of 69 patients to study real world use of lanreotide at our centre., Results: Lanreotide was the first-line of systemic treatment in 60 patients. Watch-and-wait was a common strategy and was seen in 31 patients. SSA switch strategy was seldom applied. Majority of patients on lanreotide had low-grade NETs. Standard starting dose of lanreotide 120 mg every 28 days was used in 66 patients. Dose escalation to 120 mg every 21 days occurred in 7 patients. The primary intention for treatment was tumor control in 32 patients, and both tumor and symptom control in 34 patients. Median time on treatment was 21.6 months., Conclusions: Overall, our findings were in keeping with current guidelines. It will be interesting to assess how clinical practice evolves in the future and to determine the role of dose escalation for disease control., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-1182/coif). TA is a consultant for Ipsen and involved in enrolling patients in clinical trials. MV is a consultant for Amgen, a speaker for Merck and is involved in enrolling patients in clinical trials. RG is a member of advisory board for Ipsen, Pfizer, Eisai, Roche, Bayer, AAA and Apobiologix. She is a speaker for Merck, Viatris, Pfizer and Amgen. She received independent educational grants from Pfizer and Eisai and Apobiologix. She is also involved in enrolling patients in clinical trials. The other authors have no conflicts of interest to declare., (2023 Journal of Gastrointestinal Oncology. All rights reserved.)

Physical activity (PA) is recognized as essential for positive physical and mental well-being in young people. However, participation in PA is known to decline as adolescents emerge into adulthood under the influence of complex social and structural factors. Globally, COVID-19 restrictions resulted in changes to PA and PA participation levels in youth populations, providing a unique opportunity for gaining insight into PA barriers and enablers in circumstances of challenge, limitation and change. This article details young people's self-reported PA behaviours during the 4-week 2020 COVID-19 lockdown in New Zealand. Taking a strengths-based view and drawing on the COM-B (capabilities, opportunity and motivation behaviour) model for behaviour change, the study explores factors enabling young people to sustain or increase PA during lockdown. Findings are drawn from qualitative-dominant mixed-methods analyses of responses to an online questionnaire: New Zealand Youth Voices Matter (16-24 years; N = 2014). Key insights included the importance of habit and routine, time and flexibility, social connections, incidental exercise and awareness of links between PA and well-being. Of note were the positive attitudes, creativity and resiliency demonstrated as young people substituted or invented alternatives to their usual PA. PA needs to change to adapt to new circumstances over the life course, and youth understanding and knowledge of modifiable factors may provide support for this. Thus these findings have implications for sustaining PA during late adolescence and emerging adulthood, a life phase that can be associated with significant challenge and change., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Inflammatory bowel disease (IBD) is a chronic autoimmune disorder that affects the gastrointestinal tract. Methotrexate is a folate analog immunosuppressant used in the management of pediatric IBD. Daily folic acid supplementation is currently recommended to prevent folate deficiency and reduce the side effects of methotrexate such as nausea, stomatitis, and hepatotoxicity. The aim of this study was to evaluate the safety and adequacy of once-weekly folic acid supplementation in pediatric inflammatory bowel disease patients taking methotrexate., Methods: In this single-arm observational study, we included subjects aged 2-21 years old with inflammatory bowel disease who were receiving a standard oral methotrexate dose of 10-15 mg/m 2 weekly and 800 mcg of folic acid daily. Baseline folate level, blood counts and chemistries, and a symptom questionnaire were completed. Subjects were switched to weekly 800 mcg of folic acid to be taken in conjunction with methotrexate. Monthly phone calls with a standardized questionnaire were used to assess compliance and any change in symptoms. Follow-up blood tests were obtained 6 months after enrollment. Normal folate level was defined as >5.38 ng/mL., Results: Thirty-one subjects were enrolled. Five subjects were withdrawn due to poor compliance or transition to adult gastroenterology. Twenty-one (81%) subjects had Crohn's disease (17 with ileal involvement) and five (19%) had ulcerative colitis. Twelve (39%) subjects were on methotrexate as a combination therapy with a biologic agent. At the 6-month follow-up visit, all subjects had stable folic acid levels (>5.38 μg/L) without macrocytic anemia. Monthly questionnaires found no increased symptoms, and there were no adverse events., Conclusions: Once weekly folic acid supplementation at a dose commonly found in a multivitamin may be sufficient to maintain normal folate levels without the development of adverse symptoms in pediatric patients with inflammatory bowel disease on methotrexate therapy.

Introduction: Although DNA methylation patterns are generally considered to be faithfully inherited in Arabidopsis thaliana (Arabidopsis), there is evidence of reprogramming during both male and female gametogenesis. The gynoecium is the floral reproductive organ from which the ovules develop and generate meiotically derived cells that give rise to the female gametophyte. It is not known whether the gynoecium can condition genomic methylation in the ovule or the developing female gametophyte., Methods: We performed whole genome bisulfite sequencing to characterize the methylation patterns that prevail in the genomic DNA of pre-meiotic gynoecia of wild-type and three mutants defective in genes of the RNA-directed DNA methylation pathway (RdDM): ARGONAUTE4 (AGO4), ARGONAUTE9 (AGO9), and RNA-DEPENDENT RNA POLYMERASE6 (RDR6)., Results: By globally analyzing transposable elements (TEs) and genes located across the Arabidopsis genome, we show that DNA methylation levels are similar to those of gametophytic cells rather than those of sporophytic organs such as seedlings and rosette leaves. We show that none of the mutations completely abolishes RdDM, suggesting strong redundancy within the methylation pathways. Among all, ago4 mutation has the strongest effect on RdDM, causing more CHH hypomethylation than ago9 and rdr6. We identify 22 genes whose DNA methylation is significantly reduced in ago4, ago9 and rdr6 mutants, revealing potential targets regulated by the RdDM pathway in premeiotic gyneocia., Discussion: Our results indicate that drastic changes in methylation levels in all three contexts occur in female reproductive organs at the sporophytic level, prior to the alternation of generations within the ovule primordium, offering a possibility to start identifying the function of specific genes acting in the establishment of the female gametophytic phase of the Arabidopsis life cycle., 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 © 2023 Ortiz-Vasquez, León-Martínez, Barragán-Rosillo, González-Orozco, Deans, Aldridge, Vickers, Feng and Vielle-Calzada.)

Grass pea (Lathyrus sativus L.) is a rich source of protein cultivated as an insurance crop in Ethiopia, Eritrea, India, Bangladesh, and Nepal. Its resilience to both drought and flooding makes it a promising crop for ensuring food security in a changing climate. The lack of genetic resources and the crop's association with the disease neurolathyrism have limited the cultivation of grass pea. Here, we present an annotated, long read-based assembly of the 6.5 Gbp L. sativus genome. Using this genome sequence, we have elucidated the biosynthetic pathway leading to the formation of the neurotoxin, β-L-oxalyl-2,3-diaminopropionic acid (β-L-ODAP). The final reaction of the pathway depends on an interaction between L. sativus acyl-activating enzyme 3 (LsAAE3) and a BAHD-acyltransferase (LsBOS) that form a metabolon activated by CoA to produce β-L-ODAP. This provides valuable insight into the best approaches for developing varieties which produce substantially less toxin., (© 2023. The Author(s).)

Sperm chromatin is typically transformed by protamines into a compact and transcriptionally inactive state 1,2 . Sperm cells of flowering plants lack protamines, yet they have small, transcriptionally active nuclei with chromatin condensed through an unknown mechanism 3,4 . Here we show that a histone variant, H2B.8, mediates sperm chromatin and nuclear condensation in Arabidopsis thaliana. Loss of H2B.8 causes enlarged sperm nuclei with dispersed chromatin, whereas ectopic expression in somatic cells produces smaller nuclei with aggregated chromatin. This result demonstrates that H2B.8 is sufficient for chromatin condensation. H2B.8 aggregates transcriptionally inactive AT-rich chromatin into phase-separated condensates, which facilitates nuclear compaction without reducing transcription. Reciprocal crosses show that mutation of h2b.8 reduces male transmission, which suggests that H2B.8-mediated sperm compaction is important for fertility. Altogether, our results reveal a new mechanism of nuclear compaction through global aggregation of unexpressed chromatin. We propose that H2B.8 is an evolutionary innovation of flowering plants that achieves nuclear condensation compatible with active transcription., (© 2022. The Author(s).)

Alignment-free methods are alternatives to alignment-based methods when searching sequence data sets. The output from an alignment-free sequence comparison is a similarity score, the interpretation of which is not straightforward. We propose objective functions to interpret and calibrate outputs from alignment-free searches, noting that different objective functions are necessary for different biological contexts. This leads to advantages: visualising and comparing score distributions, including those from true positives, may be a relatively simple method to gain insight into the performance of different metrics. Using an empirical approach with both DNA and protein sequences, we characterise different similarity score distributions generated under different parameters. In particular, we demonstrate how sequence length can affect the scores. We show that scores of true positive sequence pairs may correlate significantly with their mean length; and even if the correlation is weak, the relative difference in length of the sequence pair may significantly reduce the effectiveness of alignment-free metrics. Importantly, we show how objective functions can be used with test data to accurately estimate the probability of true positives. This can significantly increase the utility of alignment-free approaches. Finally, we have developed a general-purpose software tool called KAST for use in high-throughput workflows on Linux clusters., (© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

The incidence of paramphistomosis, caused by the rumen fluke, Calicophoron daubneyi , has greatly increased within Europe in the last 15-20 years. However, the production impacts of this disease are poorly understood. This study firstly aimed to investigate the prevalence of rumen fluke in England and Northern Ireland (NI) by conducting an abattoir survey of dairy and beef cattle which also allowed the impact of rumen fluke on carcass weight, conformation and fat classification to be assessed. Secondly, an experiment aimed to assess the impact of C. daubneyi infection on diarrhea score, production loss and welfare in dairy heifers, while also evaluating the impacts of treating infected heifers with oxyclozanide. Rumen fluke prevalence was greater in NI than in England, with 53.8% (95% CI 51.9 - 55.9%) of the NI cattle carcases sampled being infected compared to 16.3% (95% CI 15.8 - 16.8%) and 17.9% (95% CI 17.4 - 18.4%) detected at the two abattoirs in England. However, there was no significant difference ( P > 0.05) in the cold carcass weight between infected and non-infected cattle. Similarly, carcass conformation and fat classification were unaffected ( P > 0.05) by the presence of rumen fluke. In the second experiment, daily live weight gain (DLWG), diarrhea score and welfare score were also unaffected ( P > 0.05) by rumen fluke infection and by oxyclozanide treatment against rumen fluke. The farms in this experiment were managed to a high standard and animals had no intercurrent disease. Therefore, these findings suggest that on well-managed farms, production losses (growth rates) should not be compromised as a result of sub-clinical rumen fluke infection., 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 © 2022 Atcheson, Lagan, McCormick, Edgar, Hanna, Rutherford, McEvoy, Huson, Gordon, Aubry, Vickers, Robinson and Barley.)

Objective: To evaluate the relationship of the levels of maternal alcohol consumption during the 1 year before pregnancy recognition with childhood cardiorenal, metabolic, and neurocognitive health., Methods: In 1106 women and their children from the Growing Up in Singapore Towards healthy Outcomes mother-offspring cohort, quantity of maternal alcohol consumption in the 12 months prior to pregnancy recognition was categorized as high (≥75th percentile: 1.9 g/day), low (<1.9 g/day), and none, and frequency of alcohol consumption was categorized as high (≥2-3 times/week), low (<2-3 times/week), and none. Offspring MRI-based abdominal fat depot, kidney, and brain volumes, blood pressure, metabolic syndrome score, and cognitive intelligence scores were assessed. Child prehypertension/hypertension at age 6 years was defined using a simplified pediatric threshold of 110/70 mmHg., Results: The average maternal alcohol consumption in the year prior to pregnancy recognition was 2.5 g/day, which is lower than the daily maximal limit of one standard drink (10 g) recommended for women by Singapore's Ministry of Health. After adjusting for participant characteristics, alcohol consumption at least 1.9 g/day was associated with over two-fold higher risk (risk ratio = 2.18, P = 0.013) of child prehypertension and 15% greater kidney growth between early infancy and age 6 years (P = 0.040) compared with abstinence. Alcohol consumption was not associated with metabolic and neurocognitive health at age 6-7 years. The associations with high frequency of alcohol consumption were concordant with those obtained for quantity of alcohol consumption., Conclusion: Maternal self-reported alcohol consumption at least 1.9 g/day prior to pregnancy recognition was associated with increased risk of child prehypertension and rapid kidney growth. Our findings highlight the potential detrimental effects of low periconceptional alcohol consumption, below national guidelines on offspring cardiorenal health., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Clozapine is the most effective medication for treatment-refractory schizophrenia, but it is associated with severe cardiac adverse events including myocarditis and cardiomyopathy. To aid treatment decision-making for clinicians, patients and their carers, we conducted a systematic review and meta-analysis to identify potential risk factors for clozapine-induced myocarditis and cardiomyopathy., Methods: A systematic search was conducted of PubMed, Embase, CINAHL, Web of Science, Cochrane and PsycInfo for studies reporting myocarditis and cardiomyopathy among people on clozapine and potential risk factors. We calculated pooled effect sizes on risk factors using a random-effects meta-analytic model. Risk of publication bias was assessed using the Newcastle-Ottawa scale., Results: Seven studies met the inclusion criteria, of which six studies had quantitative data included in the meta-analysis. The odds of clozapine-induced myocarditis increased with concurrent sodium valproate use (k = 6, n = 903, pooled OR 3.58, 95% CI 1.81-7.06), but were not significantly greater with the use of quetiapine, lithium or selective serotonin reuptake inhibitors. Our qualitative review identified conflicting results reported for increasing age and higher clozapine dose as risk factors for myocarditis. No other factors, including genetic risk, sex, ethnicity, smoking, alcohol, substance abuse or cardiometabolic disease, were associated with greater odds of myocarditis. No risk factors for cardiomyopathy were identified in the literature., Conclusion: Concurrent use of sodium valproate increases the odds of clozapine-induced myocarditis. Thus, clinicians should consider the temporary cessation of sodium valproate during the initial titration phase of clozapine., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Colorectal cancer, one of the most commonly diagnosed cancers, is now being detected earlier and treatments are improving, which means that patients are living longer. Partnering with Canadian clinicians, patients and researchers, we aimed to determine research priorities for those living with early-stage colorectal cancer in Canada., Methods: We followed the well-established priority-setting partnership outlined by the James Lind Alliance to identify and prioritize unanswered questions about early-stage (i.e., stages I-III) colorectal cancer. The study was conducted from September 2018 to September 2020. We surveyed patients, caregivers and clinicians from across Canada between June 2019 and December 2019. We categorized the responses using thematic analysis to generate a list of unique questions. We conducted an interim prioritization survey from April 2020 to July 2020, with patients, caregivers and clinicians, to determine a shorter list of questions, which was then reviewed at a final meeting (involving patients, caregivers and clinicians) in September 2020. At that meeting, we used a consensus-based process to determine the top 10 priorities., Results: For the initial survey, 370 responses were submitted by 185 individuals; of the 98 individuals who provided demographic information, 44 (45%) were patients, 16 (16%) were caregivers, 7 (7%) were members of an advocacy group, 26 (27%) were health care professionals and 5 (5%) were categorized as "other." The responses were refined to create a list of 66 unique unanswered questions. Twenty-five respondents answered the interim prioritization survey: 13 patients (52%), 2 caregivers (8%), 3 advocacy group members (12%) and 7 health care professionals (28%). This led to a list of the top 30 questions. The final consensus meeting involved 20 individuals (10 patients [50%], 3 caregivers [15%] and 7 health care professionals [35%]), who agreed to the top 10 research priorities. The priorities covered a range of topics, including screening, treatment, recurrence, management of adverse effects and decision-making., Interpretation: We determined the top research priorities for early-stage colorectal cancer using a collaborative partnership of stake-holders from across Canada. The priorities covered a broad range of topics that could be addressed by future research, including improved screening practices, the role of personalized medicine, the management of adverse effects of treatment, decision-making and prevention of recurrence., Competing Interests: Competing interests: None declared., (© 2022 CMA Impact Inc. or its licensors.)

Alterations in the nutritional environment in early life can significantly increase the risk for obesity and a range of development of metabolic disorders in offspring in later life, effects that can be passed onto future generations. This process, termed development programming, provides the framework of the developmental origins of health and disease (DOHaD) paradigm. Early life nutritional compromise including undernutrition, overnutrition or specific macro/micronutrient deficiencies, results in a range of adverse health outcomes in offspring that can be further exacerbated by a poor postnatal nutritional environment. Although the mechanisms underlying programming remain poorly defined, a common feature across the phenotypes displayed in preclinical models is that of altered wiring of neuroendocrine circuits that regulate satiety and energy balance. As such, altered maternal nutritional exposures during critical early periods of developmental plasticity can result in aberrant hardwiring of these circuits with lasting adverse consequences for the offspring. There is also increasing evidence around the role of an altered epigenome and the gut-brain axis in mediating some of the central programming effects observed. Further, although such programming was once considered to result in a permanent change in developmental trajectory, there is evidence, at least from preclinical models, that programming can be reversed via targeted nutritional manipulations during early development. Further work is required at a mechanistic level to allow for identification for early markers of later disease risk, delineation of sex-specific effects and pathways to implementation of strategies aimed at breaking the transgenerational transmission of disease., (Copyright © 2021 Elsevier Ltd. All rights reserved.)