Prenatal Choline Supplementation Protects against Postnatal Neurotoxicity

Choline, a dietary compound present in many foods, has recently been classified as an essential nutrient for humans. There is evidence from animal models that the availability of choline during the prenatal period influences neural and cognitive development. Here we report that choline supplementation during a 6 d gestational period protects against neurodegeneration in the posterior cingulate and retrosplenial cortices of female adolescent rats produced by peripheral administration of the NMDA receptor antagonist dizocilpine (MK-801). These data show that availability of a single nutrient, choline, during a brief period of prenatal development diminishes vulnerability to neurotoxicity in adolescent offspring

Use of genome sequencing to hunt for cryptic second-hit variants: analysis of 31 cases recruited to the 100 000 Genomes Project

Background: Current clinical testing methods used to uncover the genetic basis of rare disease have inherent limitations, which can lead to causative pathogenic variants being missed. Within the rare disease arm of the 100 000 Genomes Project (100kGP), families were recruited under the clinical indication ‘single autosomal recessive mutation in rare disease’. These participants presented with strong clinical suspicion for a specific autosomal recessive disorder, but only one suspected pathogenic variant had been identified through standard-of-care testing. Whole genome sequencing (WGS) aimed to identify cryptic ‘second-hit’ variants. Methods: To investigate the 31 families with available data that remained unsolved following formal review within the 100kGP, SVRare was used to aggregate structural variants present in <1% of 100kGP participants. Small variants were assessed using population allele frequency data and SpliceAI. Literature searches and publicly available online tools were used for further annotation of pathogenicity. Results: Using these strategies, 8/31 cases were solved, increasing the overall diagnostic yield of this cohort from 10/41 (24.4%) to 18/41 (43.9%). Exemplar cases include a patient with cystic fibrosis harbouring a novel exonic LINE1 insertion in CFTR and a patient with generalised arterial calcification of infancy with complex interlinked duplications involving exons 2–6 of ENPP1. Although ambiguous by short-read WGS, the ENPP1 variant structure was resolved using optical genome mapping and RNA analysis. Conclusion: Systematic examination of cryptic variants across a multi-disease cohort successfully identifies additional pathogenic variants. WGS data analysis in autosomal recessive rare disease should consider complex structural and small intronic variants as potentially pathogenic second hits

Home dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference

Home dialysis modalities (home hemodialysis [HD] and peritoneal dialysis [PD]) are associated with greater patient autonomy and treatment satisfaction compared with in-center modalities, yet the level of home-dialysis use worldwide is low. Reasons for limited utilization are context-dependent, informed by local resources, dialysis costs, access to healthcare, health system policies, provider bias or preferences, cultural beliefs, individual lifestyle concerns, potential care-partner time, and financial burdens. In May 2021, KDIGO (Kidney Disease: Improving Global Outcomes) convened a controversies conference on home dialysis, focusing on how modality choice and distribution are determined and strategies to expand home-dialysis use. Participants recognized that expanding use of home dialysis within a given health system requires alignment of policy, fiscal resources, organizational structure, provider incentives, and accountability. Clinical outcomes across all dialysis modalities are largely similar, but for specific clinical measures, one modality may have advantages over another. Therefore, choice among available modalities is preference-sensitive, with consideration of quality of life, life goals, clinical characteristics, family or care-partner support, and living environment. Ideally, individuals, their care-partners, and their healthcare teams will employ shared decision-making in assessing initial and subsequent kidney failure treatment options. To meet this goal, iterative, high-quality education and support for healthcare professionals, patients, and care-partners are priorities. Everyone who faces dialysis should have access to home therapy. Facilitating universal access to home dialysis and expanding utilization requires alignment of policy considerations and resources at the dialysis-center level, with clear leadership from informed and motivated clinical teams

What should a person with relapsing-remitting multiple sclerosis know? - Focus group and survey data of a risk knowledge questionnaire (RIKNO 2.0)

Background: Risk knowledge is relevant to make informed decisions in multiple sclerosis (MS). The risk knowledge questionnaire for relapsing-remitting MS (RIKNO 1.0) was developed and piloted in Germany. Objective: To produce a revised RIKNO 2.0 questionnaire using mixed methodology in a European setting. Methods: The questionnaire was translated in seven languages. MS patient and health professional (HP) expert feedback was obtained from Germany, Italy, Estonia, Serbia, and the UK. A German web-based survey of RIKNO 2.0 compared the tool with the MS Knowledge Questionnaire (MSKQ), each one used with two versions (with/without a “don’t know” DN option). Results: While RIKNO 2.0 was considered difficult, it was rated as highly educational. One item was reframed, and two new items were added. The web-based German survey (n = 708 completers) showed that the DN version did not increase participation rate and did not produce significantly higher scores. Internal consistency (Cronbach alpha) without SN response was 0.73. RIKNO 2.0 scores showed normality distribution irrespective of the answering format. Item difficulty was high ranging from 0.07 to 0.79. Less than 50% of questions were answered correctly (mean 8.9) compared to 80.4% in the MSKQ (mean 20.1). Higher numeracy competency and education were significantly, albeit weakly, associated to higher scores for both RIKNO 2.0 and MSKQ. Conclusion: Including “don’t know” options in knowledge questionnaires does not increase percentage of correct replies. RIKNO 2.0 is a complex questionnaire to be used in an educational context and studies on patient information. The tool is now available in seven languages

Attitudes of farmers towards cattle dehorning

To better understand how farmers decide to manage animals with or without horns and how they choose the method they use to dehorn, 9 group interviews were carried out in Italy, Germany and France in different regions, different production systems and among different cattle breeds, in the framework of the EU-Project ALCASDE (alternatives to castration and dehorning). The groups gathered 94 cattle farmers. Ultimately, managing animals with or without horns is not a mere detail but is rooted in different views on the farming profession, on the human–animal relationship, and on the practical and daily work with the animals. Farmer safety and animal safety is often pointed out in connection to loose housing. In favour of keeping horns, different aspects are combined: ethical considerations towards the animals (integrity of the animal, avoidance of pain and stress), a strong farmer–animal relationship, and in rustic breeds, aesthetic and tourism considerations. Practical and material aspects play a role, such as, for example, the type of housing system and equipment, the amount of available time, and the organisation and equipment for carrying out dehorning if needed. Many farmers are convinced that disbudding or dehorning are painful but their sensitivities differ largely. Among the farmers who dehorn their animals, some expressed a real unease on this subject during the interviews. On the one hand, they express a concern for the animals and their welfare, and on the other hand, they voluntarily implement a practise that they know is accompanied by pain, although it is intended to improve animal welfare during the animals’ life span. For most of the farmers we met, adult dehorning is to be avoided, as it is too stressful and painful for the animals, and disbudding at a young age is preferable. Using polled (genetically hornless) cattle is still rare, and opinions are divided. Most farmers do not think that it is feasible at short notice to have polled cattle with a high quality of production and reproduction