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Targeted next-generation sequencing identifies novel variants in candidate genes for Parkinson’s disease in Black South African and Nigerian patients
Abstract Background The prevalence of Parkinson’s disease (PD) is increasing in sub-Saharan Africa, but little is known about the genetics of PD in these populations. Due to their unique ancestry and diversity, sub-Saharan African populations have the potential to reveal novel insights into the pathobiology of PD. In this study, we aimed to characterise the genetic variation in known and novel PD genes in a group of Black South African and Nigerian patients. Methods We recruited 33 Black South African and 14 Nigerian PD patients, and screened them for sequence variants in 751 genes using an Ion AmpliSeq™ Neurological Research panel. We used bcftools to filter variants and annovar software for the annotation. Rare variants were prioritised using MetaLR and MetaSVM prediction scores. The effect of a variant on ATP13A2’s protein structure was investigated by molecular modelling. Results We identified 14,655 rare variants with a minor allele frequency ≤ 0.01, which included 2448 missense variants. Notably, no common pathogenic mutations were identified in these patients. Also, none of the known PD-associated mutations were found highlighting the need for more studies in African populations. Altogether, 54 rare variants in 42 genes were considered deleterious and were prioritized, based on MetaLR and MetaSVM scores, for follow-up studies. Protein modelling showed that the S1004R variant in ATP13A2 possibly alters the conformation of the protein. Conclusions We identified several rare variants predicted to be deleterious in sub-Saharan Africa PD patients; however, further studies are required to determine the biological effects of these variants and their possible role in PD. Studies such as these are important to elucidate the genetic aetiology of this disorder in patients of African ancestry.
Using Eulerian video magnification to enhance detection of fasciculations in people with amyotrophic lateral sclerosis
ABSTRACTIntroductionThis study seeks to determine whether the use of Eulerian video magnification (EVM) increases the detection of muscle fasciculations in people with amyotrophic lateral sclerosis (PALS) compared with direct clinical observation (DCO).MethodsThirty‐second‐long video recordings were taken of 9 body regions of 7 PALS and 7 controls, and fasciculations were counted by DCO during the same 30‐s period. The video recordings were then motion magnified and reviewed by 2 independent assessors.ResultsIn PALS, median fasciculation count per body region was 1 by DCO (range 0–10) and 3 in the EVM recordings (range 0–15; P < 0.0001). EVM revealed more fasciculations than DCO in 61% of recordings. In controls, median fasciculation count was 0 for both DCO and EVM.DiscussionCompared with DCO, EVM significantly increased the detection of fasciculations in body regions of PALS. When it is used to supplement clinical examination, EVM has the potential to facilitate the diagnosis of ALS. Muscle Nerve 56: 1063–1067, 2017
Cholinergic white matter pathways integrity in prodromal and early manifest Lewy body disease.
Degeneration of the nucleus basalis of Meynert (NbM), the main cholinergic source to the cerebral cortex, has been demonstrated in advanced stages of Lewy body (LB) disorders. While the lateral and medial white matter pathways connecting the NbM to the cerebral cortex have been shown to be affected in LB patients with dementia, less is known regarding their vulnerability in prodromal and early manifest patients without significant cognitive impairment, and how their integrity relates to disease manifestation and progression. Here, we used diffusion MRI (dMRI) to examine whether changes in the microstructural integrity of the white matter tracts of the NbM are already evident in prodromal LB disease (namely, isolated rapid eye movement sleep behaviour disorder (iRBD), n = 67), and in patients with early manifest LB disease (Parkinson's disease (PD), n = 73), compared to healthy controls (n = 53). Furthermore, we examined whether the microstructural integrity of these pathways relates to cognitive function at baseline and longitudinal follow-up, and to the risk of phenoconverting from iRBD to manifest neurodegenerative disease (PD or dementia with LBs). Lastly, we examined the potential role of the NbM as a disease epicentre in the two patient groups by spatially correlating its cortical structural connectivity profile with disease-specific (i.e., iRBD or PD) cortical atrophy patterns. We found higher microstructural integrity at baseline of both the lateral and medial pathways to be associated with better verbal fluency performance at baseline (β = 3.29-3.52, P < 0.05). Higher microstructural integrity of the medial pathway was also associated with slower decline in Montreal Cognitive Assessment (MoCA) over time (β = 0.05, P < 0.05). In addition, higher integrity of both pathways at baseline was associated with reduced future risk of phenoconversion in iRBD (HR < 0.51, P < 0.05). Furthermore, we found that cortical regions that are more anatomically connected to the NbM exhibited lower grey matter volumes in iRBD (r = -0.31, P < 0.05), but not PD (r = -0.08, P = 0.29), suggesting its potential role in shaping cortical pathology in iRBD. Interestingly, despite the associations observed at the subject-level, no evidence for differences in microstructural integrity of the NbM pathways was observed between patient cohorts and controls at baseline. Our findings suggest that the NbM white matter pathways have the potential to serve as non-invasive biomarkers indicating risk for clinical conversion and cortical pathology in iRBD and for baseline and longitudinal cognitive functioning in iRBD and early PD and therefore may potentially be used to stratify patients for clinical trials of disease-modifying and neuroprotective therapies.
Opioid prescribing to people on orthopaedic waiting lists during the covid-19 pandemic in England: retrospective cohort study using linked electronic health record data in OpenSAFELY-TPP
Objective To quantify the changes in opioid prescribing over time to a population with high rates of opioid use to understand the impact of longer elective wait times during the covid-19 pandemic. Design With the approval of NHS England, a retrospective cohort study using linked electronic health record data in OpenSAFELY-TPP. Setting Primary and secondary care electronic health records of people registered at general practices in England that use TPP SystmOne software, covering about 43% of the total registered population in England, linked to data from the Waiting List Minimum Dataset (WLMDS) within the OpenSAFELY-TPP platform, which is part of the NHS England OpenSAFELY covid-19 service. Participants 63 850 eligible patients on the waiting list for elective trauma procedures or orthopaedic procedures whose wait ended in admission between May 2021 and April 2022. Main outcome measures Opioid prescribing to eligible patients before referral to the waiting list, while waiting for treatment, and after discharge from treatment. Opioids were classified based on their strength (weak, moderate, or strong opioids) and duration of action (immediate release v modified release opioids). Results Of 63 850 people on elective trauma or orthopaedic waiting lists whose wait ended during the study period (median age 61 years, 54.6% female), 20.5% waited for more than 52 weeks to be admitted. In the three months before their waiting list referral date, 9890 (15.5%) participants had three or more opioid prescriptions, and 3790 (5.9%) were prescribed a strong opioid. Weekly opioid prescribing rates per 100 people on the waiting list were stable over time, with prescription rates peaking immediately after treatment and plateauing about three months after treatment. Comparing the three month period before the waiting list referral date to the period four to six months after the waiting list end date, changes in the proportion of people with three or more prescriptions for an opioid during that period were −1.6% (95% confidence interval −2.2% to −1.0%) for people on the waiting list for 18 weeks or less, −1.1% (−1.7% to −0.5%) for people waiting for 19-52 weeks, and −0.5% (−1.4% to 0.4%) for people waiting for more than 52 weeks. Conclusions In this study, one in five people who received treatment for an elective orthopaedic procedure between May 2021 and April 2022 waited for more than one year. Nearly one in seven people were prescribed opioids long term before their referral date to the waiting list, and only small reductions in long term opioid prescribing were observed after a patient’s procedure, regardless of length of time spent on the waiting list.
Exploring take-home opioid stewardship (ETHOS) in UK postoperative patients
Background Surgery is one of the most common indications for a patient’s first opioid prescription, with some patients progressing to unintended long-term use. There is no current data from the United Kingdom on how much patients use of the opioid medication dispensed at discharge from hospital. This study investigates discharge opioid prescribing and usage following common surgical procedures. Methods This cohort study was conducted at the Oxford University Hospitals NHS Foundation Trust and involved 20 of the most commonly performed adult surgical procedures. At least 20 patients per procedure were surveyed using a standardised telephone questionnaire 6–8 days after discharge to establish the amount of used and unused opioids. Opioid doses were converted to oral morphine equivalent (OME) for analysis. Results The amount of opioid given to patients after all types of surgery far exceeded requirement, with often large variations in prescribing practices for the same procedures, most notably in trauma and orthopaedics. For the cohort of 426 patients, a total of 55 080 mg OME was dispensed on discharge, with only 34.4% actually used by patients, leaving a total of 36 108.5 mg OME unused in the community, risking inappropriate opioid use, overdose, or diversion. Conclusions Opioid overprescribing is common after surgery and represents waste, expense, and risk to patients. There is a clear need to develop a procedure-specific evidence-base for discharge opioid prescribing, adopting an “enough but not too much” approach to ensure that patients have adequate analgesia to facilitate functional surgical recovery, but not more than is needed.
No place for routine use of modified-release opioids in postoperative pain management.
Modified-release opioid tablets were introduced into surgical practice in the belief that they provided superior pain relief and reduced nursing workload, and they rapidly became embedded into many perioperative pathways. Although national and international guidelines for the management of postoperative pain now advise against the use of modified-release opioids, they continue to be prescribed in many centres. Recognition that modified-release opioids show lack of benefit and increased risk of harm compared with immediate-release opioids in the acute, postoperative setting has become clear. Their slow onset and offset make rapid and safe titration of these opioids impossible, including down-titration as the patient recovers; pain relief may be less effective; they have been associated with an increased incidence of opioid-related adverse drug events, increased length of hospital stay, and higher readmission rates; and they lead to higher rates of opioid-induced ventilatory impairment and persistent postoperative opioid use. Evidence indicates that modified-release opioids should not be used routinely in the postoperative period.
Prescription of analgesia in emergency medicine (POEM) secondary analysis: an observational multicentre comparison of pain relief provided to adults and children with an isolated limb fracture and/or dislocation
BackgroundAcute pain is a common reason for emergency department (ED) attendance. Royal College of Emergency Medicine (RCEM) pain management audits have shown national variation and room for improvement. Previous evidence suggests that children receive less satisfactory pain management than adults.MethodsPrescription of analgesia in emergency medicine is a cross-sectional observational study of consecutive patients presenting to 12 National Health Service EDs with an isolated long bone fracture and/or dislocation, and was carried out between 2015 and 2017. Using the recommendations in the RCEM Best Practice Guidelines, pain management in ED was assessed for differences of age (adults vs children) and hospital type (children’s vs all patients).ResultsFrom the total 8346 patients, 38% were children (median age 8 years). There was better adherence to the RCEM guidance for children than adults (24% (766/3196) vs 11% (579/5123)) for the combined outcome of timely assessment, pain score and appropriate analgesia. In addition, children were significantly more likely than adults to receive analgesia appropriate to the pain score (of those with a recorded pain score 67% (1168/1744) vs 52% (1238/2361)). Children’s hospitals performed much better across all reported outcomes compared with general hospitals.ConclusionsIn contrast to previous studies, children with a limb fracture/dislocation are more likely than adults to have a pain score documented and to receive appropriate analgesia. Unexpectedly, children’s EDs performed better than general EDs in relation to timely and appropriate analgesia but the reasons for this are not apparent from the present study.