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Rising rates of insulin resistance and an ageing population are set to exact an increasing toll on individuals and society. Here we examine the contribution of age and insulin resistance to the association of cerebral blood flow and glucose metabolism; both critical process in the supply of energy for the brain. Thirty-four younger (20-42 years) and 41 older (66-86 years) healthy adults underwent a simultaneous resting state MR/PET scan, including arterial spin labelling. Rates of cerebral blood flow and glucose metabolism were derived using a functional atlas of 100 brain regions. Older adults had lower cerebral blood flow than younger adults in 95 regions, reducing to 36 regions after controlling for cortical atrophy and blood pressure. Lower cerebral blood flow was also associated with worse working memory and slower reaction time in tasks requiring cognitive flexibility and response inhibition. Younger and older insulin sensitive adults showed small, negative correlations between relatively high rates of regional cerebral blood flow and glucose metabolism. This pattern was inverted in insulin resistant older adults, who showed hypoperfusion and hypometabolism across the cortex, and a positive correlation. In insulin resistant younger adults, the association showed inversion to positive correlations, although not to the extent seen in older adults. Our findings suggest that the normal course of ageing and insulin resistance alter the rates of and associations between cerebral blood flow and glucose metabolism. They underscore the criticality of insulin sensitivity to brain health across the adult lifespan., (© 2024. The Author(s).)

Introduction: Patient and public involvement is vital for high-quality research. Integrating patients' and providers' perspectives early in research enhances the feasibility and relevance of study results. Within our family practice-based research network ForN, we established a standing patient advisory board (PAB) to include patients with diverse conditions and experiences. In this paper, we aim to describe the establishment and functioning of a standing PAB in family medicine research from patients' and researchers' perspectives., Methods: After each PAB meeting, patients and researchers were asked to name anonymously positive and challenging moments in a feedback form with open questions. Researchers were also asked to reflect on how they implemented the discussion content in their research projects. The responses from both groups were transferred to MAXQDA 2018 and analyzed separately using thematic analysis., Results: We analyzed 40 feedback forms from patients and 14 feedback forms from researchers. The dominant theme in the patients' feedback was 'exchange': They positively emphasized the 'exciting and open discussions' and the exchange of perspectives with one another and researchers. The clarity of the researchers' presentations and the research topics were appreciated. Researchers also positively highlighted the open atmosphere of the discussions. Presenting their research to the PAB helped most researchers reflect on their research topics from patients' perspectives and implement changes. However, researchers also mentioned several barriers to the implementation of PAB members' feedback., Conclusion: The establishment of a standing PAB in family practice research is feasible and productive both from patients' and researchers' perspectives., Patient or Public Contribution: This study reports the evaluation of the establishment of a standing PAB in family practice research. Board members are involved in the design of studies, the co-production of interventions and information material, and the interpretation of data., (© 2024 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Inteins are proteins that excise themselves out of host proteins and ligate the flanking polypeptides in an auto-catalytic process called protein splicing. In nature, inteins are either contiguous or split. In the case of split inteins, the two fragments must first form a complex for the splicing to occur. Contiguous inteins have previously been artificially split in two fragments because split inteins allow for distinct applications than contiguous ones. Even naturally split inteins have been split at unnatural split sites to obtain fragments with reduced affinity for one another, which are useful to create conditional inteins or to study protein-protein interactions. So far, split sites in inteins have been heuristically identified. We developed Int&in, a web server freely available for academic research (https://intein.biologie.uni-freiburg.de) that runs a machine learning model using logistic regression to predict active and inactive split sites in inteins with high accuracy. The model was trained on a dataset of 126 split sites generated using the gp41-1, Npu DnaE and CL inteins and validated using 97 split sites extracted from the literature. Despite the limited data size, the model, which uses various protein structural features, as well as sequence conservation information, achieves an accuracy of 0.79 and 0.78 for the training and testing sets, respectively. We envision Int&in will facilitate the engineering of novel split inteins for applications in synthetic and cell biology., (© 2024 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Competing Interests: AB reports unrelated research grants from Boehringer Ingelheim and Astra Zeneca, consulting fees paid to her institution from Boehringer Ingelheim, speaker fees paid to her institution from Hologic and General Electrics Healthcare, and is an advisory board member for Inventiva. PB reports speaker fees from Chiesi Farmaceutici and is a member of advisory boards for Sandoz, Biotest, and Kedrion. MB reports unrelated research grants from Gilead, consulting fees from Gilead, GSK, AbbVie, and Altimmune and speaker fees from Gilead, AbbVie, and Altimmune. PC reports unrelated research grants from Intercept and ANRS/MIE and INCA. PG reports unrelated grants from Gilead and Grifols, consulting fees from Gilead, RallyBio, SeaBeLife, MSD, Ocelot Bio, and Behring, and lecture fees from Pfizer. SH reports research grants from the National Institute for Health and Care Research, UK, and Public Health Scotland, NHS Scotland, and meeting support from EASL. THK reports consulting fees from MSD, Falk Pharma, and Albireo, speaker fees from Gilead, and he has owned stocks in Ultimovacs (unrelated to this topic). AK reports unrelated research grants from Novo Nordisk Foundation, Astra Zeneca, EU Horizon 2020, Innovationfund Denmark, Danish National Research Foundation, and Region of Southern Denmark, consulting fees from Resalis Therapeutics, AlphaSights, Takeda, and Zealand Pharma, royalties from Gyldendal, patents from Region of Southern Denmark and University of Southern Denmark, speaker fees from Norgine, Siemens, Novo Nordisk, and Nordic Bioscience, is an advisory board member for Norgine, Novo Nordisk, Boehringer Ingelheim, and Siemens, is a board member and co-founder of Evido (a small university spinout company developing data models for detection of chronic liver disease in primary care; he has no revenue in the company and receives no payment), and declares receipt of drugs, equipment, or services from Norgine, Siemens, Echosense, and Nordic Bioscience. MPM reports consulting fees from Assembly Bio, Bristol Myers Squibb, Falk Pharma, Gilead, GSK, Inventiva, MSD, Novartis, Otsuka/Visterra, Precision Biosciences, and Preglem/Gedeon Richter, speaker fees from AbbVie, Bristol Myers Squibb, Falk Pharma, Gilead, and MSD, unrelated travel support from AbbVie, Bristol Myers Squibb, Falk Pharma, Gilead, Merck (MSD), and Novartis, and is an advisory board member for Falk Pharma, Gilead, MSD, and Novartis. GS reports lecture fees from Otsuka Lundbeck. SZ-S reports consulting fees from Siemens and unrelated travel support from AbbVie. SK is the Deputy Editor of The Lancet. All other authors declare no competing interests. AK is Secretary General, MB is Public Health Councillor, and SZ-S is Public Health Councillor elect of EASL. The Commissioners are Harry Rutter, Patrizia Carrieri, Shira Zelber-Sagi, Eivind Engebretsen, Sharon Hutchinson, Kristin Voigt, Neil Guha, Annalisa Berzigotti, Georg Schomerus, Pere Gines, Maria Buti, Patrizia Burra, Michael P Manns, Aleksander Krag, Phil Newsome, Vlad Ratziu, Philippe Mathurin, Nuria Fabrellas, Michele Cecchini, Erika Duffell, Volkan Yomuk, Thomas Berg, Achim Kautz, Marcelo Naveira, Liana Gheorghe, and Tom H Karlsen. A Steering Committee governs the work of the Commission, formed by Aleksander Krag, Sabine Kleinert, Patrizia Burra, Michael P Manns, Maria Buti, and Shira-Zelber Sagi, and chaired by Tom H Karlsen.

Perinatal mortality (PM) is a common issue on dairy farms, leading to calf losses and increased farming costs. The current knowledge about PM in dairy cattle is, however, limited and previous studies lack comparability. The topic has also primarily been studied in Holstein-Friesian cows and closely related breeds, while other dairy breeds have been largely ignored. Different data collection techniques, definitions of PM, studied variables and statistical approaches further limit the comparability and interpretation of previous studies. This article aims to investigate the factors contributing to PM in two underexplored breeds, Simmental (SIM) and Brown Swiss (BS), while comparing them to German Holstein on German farms, and to employ various modelling techniques to enhance comparability to other studies, and to determine if different statistical methods yield consistent results. A total of 133,942 calving records from 131,657 cows on 721 German farms were analyzed. Amongst these, the proportion of PM (defined as stillbirth or death up to 48 hours of age) was 6.1%. Univariable and multivariable mixed-effects logistic regressions, random forest and multimodel inference via brute-force model selection approaches were used to evaluate risk factors on the individual animal level. Although the balanced random forest did not incorporate the random effect, it yielded results similar to those of the mixed-effect model. The brute-force approach surpassed the widely adopted backwards variable selection method and represented a combination of strengths: it accounted for the random effect similar to mixed-effects regression and generated a variable importance plot similar to random forest. The difficulty of calving, breed and parity of the cow were found to be the most important factors, followed by farm size and season. Additionally, four significant interactions amongst predictors were identified: breed-calving ease, breed-season, parity-season and calving ease-farm size. The combination of factors, such as secondiparous SIM breed on small farms and experiencing easy calving in summer, showed the lowest probability of PM. Conversely, primiparous GH cows on large farms with difficult calving in winter exhibited the highest probability of PM. In order to reduce PM, appropriate management of dystocia, optimal heifer management and a wider use of SIM in dairy production are possible ways forward. It is also important that future studies are conducted to identify farm-specific contributors to higher PM on large farms., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zablotski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The transition of patients between inpatient and outpatient care can lead to adverse events and medication-related problems due to medication and communication errors, such as medication discontinuation, the frequency of (re-)hospitalizations, and increased morbidity and mortality. Older patients with multimorbidity and polypharmacy are particularly at high risk during transitions of care. Previous research highlighted the need for interventions to improve transitions of care in order to support information continuity, coordination, and communication. The HYPERION-TransCare project aims to improve the continuity of medication management for older patients during transitions of care., Methods and Findings: Using a qualitative design, 32 expert interviews were conducted to explore the perspectives of key stakeholders, which included healthcare professionals, patients and one informal caregiver, on transitions of care. Interviews were conducted between October 2020 and January 2021, transcribed verbatim and analyzed using content analysis. We narratively summarized four main topics (stakeholders' tasks, challenges, ideas for solutions and best practice examples, and patient-related factors) and mapped them in a patient journey map. Lacking or incomplete information on patients' medication and health conditions, inappropriate communication and collaboration between healthcare providers within and across settings, and insufficient digital support limit the continuity of medication management., Conclusions: The study confirms that medication management during transitions of care is a complex process that can be compromised by a variety of factors. Legal requirements and standardized processes are urgently needed to ensure adequate exchange of information and organization of medication management before, during and after hospital admissions. Despite the numerous barriers identified, the findings indicate that involved healthcare professionals from both the inpatient and outpatient care settings have a common understanding., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dinh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Post-surgical reproductive performance following ovine caesarean section has not been well studied. To assess any direct effects of surgical delivery in the absence of confounders such as dystocia or underlying diseases, we studied elective surgery performed in healthy animals for teaching purposes. Four hundred and eleven paired breeding records following vaginal delivery ( n = 233), elective caesarean section ( n = 122), and subsequent further vaginal deliveries in animals with a history of one prior elective caesarean operation ( n = 56) were evaluated retrospectively. The overall subsequent pregnancy rate was 95%. Multivariable statistical analyses did not reveal any significant influence of planned caesarean surgery on subsequent conception, stillbirth, perinatal lamb mortality, lamb birth weights, or the incidence of premature foetal death (mummification and abortion). A significantly higher number of mating attempts was, however, necessary. Also, a significant reduction in litter size was seen in the first pregnancy immediately following a surgical delivery in comparison to animals which had previously only delivered vaginally ( p = 0.001), but litter size returned to pre-caesarean levels in further follow-up pregnancies in animals with a history of one elective caesarean section ( p = 0.436). Subsequent long-term reproductive performance of sheep following elective caesarean section is thus excellent, and the results encourage retention for breeding.

The incorporation of non-canonical amino acids (ncAAs) into proteins is a powerful technique used in various research fields. Genetic code expansion (GCE) is the most common way to achieve this: a specific codon is selected to be decoded by a dedicated tRNA orthogonal to the endogenous ones. In the past 30 years, great progress has been made to obtain novel tRNA synthetases (aaRSs) accepting a variety of ncAAs with distinct physicochemical properties, to develop robust in vitro assays or approaches for codon reassignment. This sparked the use of the technique, leading to the accumulation of publications, from which gathering all relevant information can appear daunting. Here we present iNClusive (https://non-canonical-aas.biologie.uni-freiburg.de/), a manually curated, extensive repository using standardized nomenclature that provides organized information on ncAAs successfully incorporated into target proteins as verified by mass spectrometry. Since we focused on tRNA synthetase-based tRNA loading, we provide the sequence of the tRNA and aaRS used for the incorporation. Derived from more than 687 peer-reviewed publications, it currently contains 2432 entries about 466 ncAAs, 569 protein targets, 500 aaRSs and 144 tRNAs. We foresee iNClusive will encourage more researchers to experiment with ncAA incorporation thus contributing to the further development of this exciting technique., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)