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The Wellcome Trust has today announced five-year funding for 14 major research centres, including a centre for neuroimaging in Oxford
Associations of sarcopenia, sarcopenia components and sarcopenic obesity with cancer incidence: A prospective cohort study of 414,094 participants in UK Biobank
AbstractSarcopenia is characterised by low grip strength, muscle quantity or quality, and physical performance. This study investigated the associations of sarcopenia and its components with cancer incidence. A prospective cohort study was conducted utilising data from the UK Biobank. Sarcopenia and its components were defined according to the European Working Group on Sarcopenia in Older People criteria (EWGSOP2 2019). Cox proportional hazard models adjusted for sociodemographic, lifestyle, and health‐related factors were performed. Overall, 63,379 out of 414,094 study participants had an incident diagnosis of cancer during a median follow‐up of 11.7 years. In total, 32,286 participants had probable sarcopenia and 934 confirmed/severe sarcopenia at recruitment. Combined probable, confirmed, and severe sarcopenia was associated with a higher risk of liver (hazard ratio [HR] = 1.65, 95% confidence interval [CI]: 1.17–2.33), haematological (HR = 1.22, 95% CI: 1.01–1.46), and colorectal cancer (HR = 1.21, 95% CI: 1.04–1.41) in males, but not in females. The components of sarcopenia were associated with a higher risk of several cancers, including low grip strength (with liver, haematological and colorectal cancer in males), low muscle mass index (oesophageal in females and oral cancer in males), and slow walking pace (liver and lung in males, lung and overall cancer in females). Compared to participants with non‐sarcopenic obesity, those with sarcopenic obesity had a higher risk of colorectal cancer in males (HR = 1.31, 95% CI: 1.03–1.68). Our study suggests that sarcopenia, sarcopenia components, and sarcopenic obesity can be associated with risk for several cancers, mainly of the gastrointestinal tract and in males. Thus, early identification of sarcopenia components may benefit cancer prevention.
Neurosurgery
The nervous system is the principal means with which we negotiate the outside world. Injury to the nervous system (brain, spinal cord and nerves) therefore may result not simply in physical impairments, but psychological, social and economic impairments too. Legal proceedings therefore may focus upon the effect of medical errors on claimants’ psychological, economic or social capacities, not simply on physical harm. The role of neurosurgery in many disorders of the nervous system concerns prevention of secondary injury: despite the sophistication of modern medicine, damage to the nervous system caused by a primary event (for example, head injury, spontaneous bleed, acutely prolapsed disc) is often irreversible and may set a spiral of deterioration in motion that may be beyond the abilities of physicians to halt.The scope of this chapter is to describe current management strategies of nervous system disorders in which a neurosurgeon would be reasonably expected to play a lead role, although not necessarily an exclusive role. Neurosurgery is a ‘tertiary service’ in the NHS, meaning a patient may have been managed by another hospital-based specialist, or even pre-hospital specialist, prior to transfer to the care of a neurosurgeon. Neurosurgeons may therefore become involved in complaints arising from problems with delayed diagnosis or timely transfer to neurosurgical care, in addition to surgical and post-surgical care.
Genetic testing for monogenic forms of motor neuron disease/amyotrophic lateral sclerosis in unaffected family members
AbstractMotor neuron disease (MND), also referred to as amyotrophic lateral sclerosis (ALS), is a monogenic disease in a minority of cases, with autosomal dominant inheritance. Increasing numbers of people with MND are requesting genetic testing, and indeed receiving a genetic diagnosis. Consequently, requests for genetic counselling and predictive testing (i.e. of unaffected family members) are similarly expected to rise, alongside pre-symptomatic clinical trials. Despite this, there is no evidence-based guideline for predictive genetic testing in MND. This paper provides an overview of the genomic basis of MND, focusing specifically on the most common monogenic causes of MND. It then lays out the complexities of MND predictive testing, including the genetic landscape characterised by incomplete penetrance, clinical and genetic heterogeneity, and an oligogenic mechanism of pathogenesis in some cases. Additionally, there is limited research on the psychosocial impact of predictive genetic testing for MND, with studies suggesting potential difficulty in adjusting to the news, in part due to a lack of support and follow-up. This underscores a case for evidence-based, disease-specific guidance for predictive testing in MND.
Identification of diagnostic candidates in Mendelian disorders using an RNA sequencing-centric approach
Abstract Background RNA sequencing (RNA-seq) is increasingly being used as a complementary tool to DNA sequencing in diagnostics where DNA analysis has been uninformative. RNA-seq enables the identification of aberrant splicing and aberrant gene expression, improving the interpretation of variants of unknown significance (VUSs), and provides the opportunity to scan the transcriptome for aberrant splicing and expression in relevant genes that may be the cause of a patient’s phenotype. This work aims to investigate the feasibility of generating new diagnostic candidates in patients without a previously reported VUS using an RNA-seq-centric approach. Methods We systematically assessed the transcriptomic profiles of 86 patients with suspected Mendelian disorders, 38 of whom had no candidate sequence variant, using RNA from blood samples. Each VUS was visually inspected to search for splicing abnormalities. Once aberrant splicing was identified in cases with VUS, multiple open-source alternative splicing tools were used to investigate if they would identify what was observed in IGV. Expression outliers were detected using OUTRIDER. Diagnoses in cases without a VUS were explored using two separate strategies. Results RNA-seq allowed us to assess 71% of VUSs, detecting aberrant splicing in 14/48 patients with a VUS. We identified four new diagnoses by detecting novel aberrant splicing events in patients with no candidate sequence variants from prior DNA testing (n = 32) or where the candidate VUS did not affect splicing (n = 23). An additional diagnosis was made through the detection of skewed X-inactivation. Conclusion This work demonstrates the utility of an RNA-centric approach in identifying novel diagnoses in patients without candidate VUSs. It underscores the utility of blood-based RNA analysis in improving diagnostic yields and highlights optimal approaches for such analyses.
Tailored antisense oligonucleotides designed to correct aberrant splicing reveal actionable groups of mutations for rare genetic disorders
AbstractEffective translation of rare disease diagnosis knowledge into therapeutic applications is achievable within a reasonable timeframe; where mutations are amenable to current antisense oligonucleotide technology. In our study, we identified five distinct types of abnormal splice-causing mutations in patients with rare genetic disorders and developed a tailored antisense oligonucleotide for each mutation type using phosphorodiamidate morpholino oligomers with or without octa-guanidine dendrimers and 2′-O-methoxyethyl phosphorothioate. We observed variations in treatment effects and efficiencies, influenced by both the chosen chemistry and the specific nature of the aberrant splicing patterns targeted for correction. Our study demonstrated the successful correction of all five different types of aberrant splicing. Our findings reveal that effective correction of aberrant splicing can depend on altering the chemical composition of oligonucleotides and suggest a fast, efficient, and feasible approach for developing personalized therapeutic interventions for genetic disorders within short time frames.
SNR‐efficient whole‐brain pseudo‐continuous arterial spin labeling perfusion imaging at 7 T
AbstractPurposeTo optimize pseudo‐continuous arterial spin labeling (PCASL) parameters to maximize SNR efficiency for RF power constrained whole brain perfusion imaging at 7 T.MethodsWe used Bloch simulations of pulsatile laminar flow to optimize the PCASL parameters for maximum SNR efficiency, balancing labeling efficiency and total RF power. The optimization included adjusting the inter‐RF pulse spacing (TRPCASL), mean B1+ (B1+ave), slice‐selective gradient amplitude (Gmax), and mean gradient amplitude (Gave). In vivo data were acquired from six volunteers at 7 T to validate the optimized parameters. Dynamic B0‐shimming and flip angle adjustments were used to avoid needing to make the PCASL parameters robust to B0/B1+ variations.ResultsThe optimized PCASL parameters achieved a significant (3.3×) reduction in RF power while maintaining high labeling efficiency. This allowed for longer label durations and minimized deadtime, resulting in a 118% improvement in SNR efficiency in vivo compared to a previously proposed protocol. Additionally, the static tissue response was improved, reducing the required distance between labeling plane and imaging volume.ConclusionThese optimized PCASL parameters provide a robust and efficient approach for whole brain perfusion imaging at 7 T, with significant improvements in SNR efficiency and reduced specific absorption rate burden.
"The traditional healer said, 'I had a genie that scared me in my eyes, and that is why I fall": An ethnographic study in Mahenge, Tanzania.
BACKGROUND: In many low-income countries, individuals with epilepsy often turn to traditional healers as their first source of treatment after the onset of seizures. However, their experiences with traditional healing practices remain poorly understood. This study examines the perceptions and experiences of people with epilepsy in relation to traditional healing in Mahenge, Tanzania. METHODS: A culturally specific ethnographic approach, centred on oral history, was employed to capture rich, contextually grounded narratives. A total of 45 oral history interviews were conducted with individuals living with epilepsy from 21 villages in Mahenge. Participants were purposively selected based on the following criteria: being at least 18 years of age, having a diagnosis of epilepsy, and the ability to recount their experiences in Swahili, the primary language spoken in the region. Data were manually analysed using thematic analysis. RESULTS: Traditional healers often attribute epilepsy to supernatural causes, such as curses or witchcraft, linking seizure onset to past events believed to have triggered the condition. Their treatment practices are frequently accompanied by strict behavioural restrictions, which can be challenging for individuals with epilepsy to follow and are sometimes cited as reasons for treatment failure. Moreover, some participants reported experiences of physical, emotional, and even sexual harassment during their encounters with traditional healers. CONCLUSION: There is a strong reliance on traditional healing practices for epilepsy, where cultural beliefs and rituals can hinder accurate diagnosis and effective care. Raising awareness about epilepsy, its medical management, and the rights of people with epilepsy, both among traditional healers and the broader community, is essential to improve care and protect the well-being of those affected.
Novel NIBS in psychiatry: Unveiling TUS and TI for research and treatment
Mental disorders pose a significant global burden and constitute a major cause of disability worldwide. Despite strides in treatment, a substantial number of patients do not respond adequately, underscoring the urgency for innovative approaches. Traditional non-invasive brain stimulation techniques show promise, yet grapple with challenges regarding efficacy and specificity. Variations in mechanistic understanding and reliability among non-invasive brain stimulation methods are common, with limited spatial precision and physical constraints hindering the ability to target subcortical areas often implicated in the disease aetiology. Novel techniques such as transcranial ultrasonic stimulation and temporal interference stimulation have gained notable momentum in recent years, possibly addressing these shortcomings. Transcranial ultrasonic stimulation (TUS) offers exceptional spatial precision and deeper penetration compared with conventional electrical and magnetic stimulation techniques. Studies targeting a diverse array of brain regions have shown its potential to affect neuronal excitability, functional connectivity and symptoms of psychiatric disorders such as major depressive disorder. Nevertheless, challenges such as target planning and addressing acoustic interactions with the skull must be tackled for its widespread adoption in research and potentially clinical settings. Similar to transcranial ultrasonic stimulation, temporal interference (TI) stimulation offers the potential to target deeper subcortical areas compared with traditional non-invasive brain stimulation, albeit requiring a comparatively higher current for equivalent neural effects. Promising yet still sparse research highlights TI’s potential to selectively modulate neuronal activity, showing potential for its utility in psychiatry. Overall, recent strides in non-invasive brain stimulation methods like transcranial ultrasonic stimulation and temporal interference stimulation not only open new research avenues but also hold potential as effective treatments in psychiatry. However, realising their full potential necessitates addressing practical challenges and optimising their application effectively.
Birth weight and the development of functional gastrointestinal disorders in infants
Purpose: To assess the association between birth weight and the development of functional gastrointestinal disorders (FGIDs) in the first year of life. Methods: This is a secondary analysis of a prospective cohort multicenter study including neonates, consecutively enrolled at birth, and followed up for one year. At birth all infants were classified by birth weight as extremely low (ELBW), very low, or low when <1,000, <1,500, and <2,500 g, respectively, and by birth weight for gestational age as appropriate (AGA, weight in the 10-90th percentile), small (SGA, weight <10th percentile), and large (LGA, weight >90th percentile) for gestational age. FGIDs were classified according to the Rome III criteria and assessed at 1, 3, 6, and 12 months of life. Results: Among 1,152 newborns enrolled, 934 (81.1%) completed the study: 302 (32.3%) were preterm, 35 (3.7%) were ELBW, 104 (11.1%) were SGA, 782 (83.7%) were AGA, and 48 (5.1%) were LGA infants. Overall, throughout the first year of life, 718 (76.9%) reported at least one FGID. The proportion of infants presenting with at least one FGID was significantly higher in ELBW (97%) compared to LBW (74%) (p=0.01) and in LGA (85.4%) and SGA (85.6%) compared to AGA (75.2%) (p=0.0001). On multivariate analysis, SGA was significantly associated with infantile colic. Conclusion: We observed an increased risk of FGIDs in ELBW, SGA, and LGA neonates. Our results suggest that prenatal factors determining birth weight may influence the development of FGIDs in infants. Understanding the role of all potential risk factors may provide new insights and targeted approaches for FGIDs.
Neonatal Antibiotics and Prematurity Are Associated with an Increased Risk of Functional Gastrointestinal Disorders in the First Year of Life
Objective: To assess the prevalence of functional gastrointestinal disorders (FGIDs) in the first year of life and the influence of different neonatal factors on development of FGIDs. Study design: A prospective cohort multicenter study including neonates, consecutively enrolled at birth, and followed up until 1 year. Gestational age, neonatal antibiotic administration, duration of hospitalization, mode of delivery, birth weight, and feeding pattern were recorded. FGIDs were classified according to Rome III criteria and assessed at 1, 3, 6, and 12 months of life. Results: Among 1152 newborns enrolled, 934 (81.1%) completed the study, 302 (32%) were newborns born preterm, 320 (34%) had neonatal antibiotics, and 718 (76.9%) had at least 1 FGID according to Rome III criteria (443 [47.4%] infantile colic, 374 [40.0%] regurgitation, 297 [31.8%] infant dyschezia, 248 [26.6%] functional constipation, and 34 [3.6%] functional diarrhea) throughout the first year of life. The proportion of infants born preterm presenting with FGIDs (86%) was significantly greater compared with infants born full term (72.5%) (χ2 = 21.3, P = .0001). On multivariate analysis, prematurity and neonatal use of antibiotics was significantly associated with at least 1 FGID. Conclusions: We found a high rate FGIDs in infants, likely related to the population recruited, the long observation period, the diagnosis based on Rome III criteria, and parental reports. Preterm delivery and neonatal use of antibiotics in the first months of life are associated with an increased incidence of FGIDs, particularly infantile colic and regurgitation. In our population, cesarean delivery and feeding pattern at 1 month of life emerged as additional risk factors for infant dyschezia and functional diarrhea. Other neonatal factors associated with FGIDs need to be further explored.
A Review of the Ocular Phenotype and Correlation with Genotype in Poretti-Boltshauser Syndrome.
Background and Objectives: Poretti-Boltshauser syndrome (PBS) is a rare, autosomal recessive disorder caused by pathogenic variants in the LAMA1 gene, resulting in laminin dysfunction. This manifests as a cerebellar malformation with cysts, and patients present with developmental delay and ataxia; however, ocular features are not well-characterised. We aimed to summarise the ocular phenotypes of PBS based on cases reported in the literature. Materials and Methods: A literature search was conducted on Medline, Embase, and PubMed on PBS and its ocular associations. Genetically confirmed PBS cases were reviewed, and genotype-phenotype correlations were investigated. Results: Comprehensive reporting of genotypes and associated systemic and ocular phenotypes was available in 51 patients with PBS, who had 52 distinct variants in LAMA1. Most patients carried homozygous variants. The most common genotype was a c.2935delA homozygous mutation, followed by the c.768+1G>A; c.6701delC compound heterozygous mutation. High myopia was the most common ocular phenotype (n = 39), followed by strabismus (n = 27) and ocular motor apraxia (n = 26). A wide range of other ocular manifestations, including retinal dystrophy, retinal neovascularisation, retinal detachment, strabismus, nystagmus, optic disc and iris hypoplasia, were reported. Patients with the same genotype exhibited variable expressivity. Conclusions: PBS has a broad ocular phenotypic spectrum, and characterisation of this variability is important for making an accurate diagnosis and informing genetic counselling.
The gut–brain axis in early Parkinson’s disease: from prodrome to prevention
Abstract Parkinson’s disease is the second most common neurodegenerative disorder and fastest growing neurological condition worldwide, yet its etiology and progression remain poorly understood. This disorder is characterized pathologically by the prion-like spread of misfolded neuronal alpha-synuclein proteins in specific brain regions leading to Lewy body formation, neurodegeneration, and progressive neurological impairment. It is unclear what triggers Parkinson’s and where α-synuclein protein aggregation begins, although proposed induction sites include the olfactory bulb and dorsal motor nucleus of the vagus nerve. Within the last 20 years, there has been increasing evidence that Parkinson’s could be triggered by early microbiome changes and α-synuclein accumulation in the gastrointestinal system. Gut microbiota dysbiosis that alters gastrointestinal motility, permeability, and inflammation could enable prion-like spread of α-synuclein from the gut-to-brain via the enteric nervous system. Individuals with isolated rapid eye movement sleep behavior disorder have a high likelihood of developing Parkinson’s and might represent a prodromal ‘gut-first’ subtype of the condition. The gut-first model of Parkinson’s offers novel gut-based therapeutic avenues, such as anti-, pre-, and pro-biotic preparations and fecal microbiota transplants. Crucially, gut-based interventions offer an avenue to treat Parkinson’s at early prodromal stages with the aim of mitigating evolution to clinically recognizable Parkinson’s disease characterized by motor impairment.