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Expanding the genetic spectrum of hereditary motor sensory neuropathies in Pakistan
No full textBACKGROUND: Hereditary motor and sensory neuropathy (HMSN) refers to a group of inherited progressive peripheral neuropathies characterized by reduced nerve conduction velocity with chronic segmental demyelination and/or axonal degeneration. HMSN is highly clinically and genetically heterogeneous with multiple inheritance patterns and phenotypic overlap with other inherited neuropathies and neurodegenerative diseases. Due to this high complexity and genetic heterogeneity, this study aimed to elucidate the genetic causes of HMSN in Pakistani families using Whole Exome Sequencing (WES) for variant identification and Sanger sequencing for validation and segregation analysis, facilitating accurate clinical diagnosis. METHODS: Families from Khyber Pakhtunkhwa with at least two members showing HMSN symptoms, who had not previously undergone genetic analysis, were included. Referrals for genetic investigations were based on clinical features suggestive of HMSN by local neurologists. WES was performed on affected individuals from each family, with Sanger sequencing used to validate and analyze the segregation of identified variants among family members. Clinical data including age of onset were assessed for variability among affected individuals, and the success rate of genetic diagnosis was compared with existing literature using proportional differences and Cohen's h. RESULTS: WES identified homozygous pathogenic variants in GDAP1 (c.310 + 4 A > G, p.?), SETX (c.5948_5949del, p.(Asn1984Profs*30), IGHMBP2 (c.1591 C > A, p.(Pro531Thr) and NARS1 (c.1633 C > T, p.(Arg545Cys) as causative for HMSN in five out of nine families, consistent with an autosomal recessive inheritance pattern. Additionally, in families with HMSN, a SETX variant was found to cause cerebellar ataxia, while a NARS1 variant was linked to intellectual disability. Based on American College of Medical Genetics and Genomics criteria, the GDAP1 variant is classified as a variant of uncertain significance, while variants in SETX and IGHMBP2 are classified as pathogenic, and the NARS1 variant is classified as likely pathogenic. The age of onset ranged from 1 to 15 years (Mean = 5.13, SD = 3.61), and a genetic diagnosis was achieved in 55.56% of families with HMSN, with small effect sizes compared to previous studies. CONCLUSIONS: This study expands the molecular genetic spectrum of HMSN and HMSN plus type neuropathies in Pakistan and facilitates accurate diagnosis, genetic counseling, and clinical management for affected families.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Tobacco and COPD: presenting the World Health Organization (WHO) Tobacco Knowledge Summary
No full textThe WHO recently published a Tobacco Knowledge Summary (TKS) synthesizing current evidence on tobacco and COPD, aiming to raise awareness among a broad audience of health care professionals. Furthermore, it can be used as an advocacy tool in the fight for tobacco control and prevention of tobacco-related disease. This article builds on the evidence presented in the TKS, with a greater level of detail intended for a lung-specialist audience. Pulmonologists have a vital role to play in advocating for the health of their patients and the wider population by sharing five key messages: (1) Smoking is the leading cause of COPD in high-income countries, contributing to approximately 70% of cases. Quitting tobacco is an essential step toward better lung health. (2) People with COPD face a significantly higher risk of developing lung cancer. Smoking cessation is a powerful measure to reduce cancer risk. (3) Cardiovascular disease, lung cancer and type-2 diabetes are common comorbidities in people with COPD. Quitting smoking not only improves COPD management, but also reduces the risk of developing these coexisting conditions. (4) Tobacco smoke also significantly impacts children's lung growth and development, increasing the risk of respiratory infections, asthma and up to ten other conditions, and COPD later in life. Governments should implement effective tobacco control measures to protect vulnerable populations. (5) The tobacco industry's aggressive strategies in the marketing of nicotine delivery systems and all tobacco products specifically target children, adolescents, and young adults. Protecting our youth from these harmful tactics is a top priority.0Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Exploring patient perspectives: orthognathic surgery outcomes and experiences assessed by patient-reported outcome measures and patient-reported experience measures
No full textEvaluating the effectiveness of orthognathic treatment can be difficult. To address this issue, patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) have been proposed as valuable instruments for understanding the quality of healthcare from the patients' standpoint. Therefore, the aim of this project was to employ PROMs and PREMs questionnaires to capture the patients' perspectives regarding their experience during the orthognathic treatment process, as well as their perception of their postoperative state. Preoperative and postoperative questionnaires were offered to patients at consenting appointment and at various timepoints after the surgery. The assessment of statistical relationships was carried out by means of Fisher's exact test. A total of 64 preoperative and 126 postoperative responses were received. The primary motivators for pursuing the surgery were the improvement of facial and dental aesthetics, as well as increased satisfaction with photographic and video appearances. These three factors were also cited as the most important postoperative benefits. Of the respondents, 58% reported experiencing altered sensation to the lower lip at the 24-month follow up (p = 0.02); however, the affected patients reported that this did not have an impact on their daily activities. The use of PROMs and PREMs to appraise the quality of life constitutes a valuable method for surgeons to gauge their treatment efficacy. Above all, such tools are particularly useful for evaluating patient satisfaction, which is the ultimate objective of any treatment.UnknownJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Nationwide Cross-Sectional Analysis of Mortality Trends in Patients with Sarcoidosis and Non-Ischemic Cardiovascular Disease-The Impact of Gender, Ethnicity, Geographical Location, and COVID-19 Pandemic
No full textBackground and Objectives: The epidemiological data regarding mortality rates of adults with sarcoidosis and non-ischemic cardiovascular disease (CVD) are limited. A retrospective observational analysis was conducted to identify trends and disparities related to sarcoidosis and non-ischemic cardiovascular disease mortality among the adult US population from 1999 to 2022. Methods: We used the Centers for Disease Control and Prevention (CDC) WONDER database to extract death certificate data for the adult US population (≥25 years). The age-adjusted mortality rates (AAMRs) per 100,000 persons were calculated, and annual percent changes (APCs) were determined using Joinpoint. Results: Between 1999 and 2022, 23,642 deaths were identified related to non-ischemic CVD + sarcoidosis. The overall AAMR increased from 0.2 (95% CI, 0.2 to 0.3) in 1999 to 0.5 (95% CI, 0.5 to 0.6) in 2022. Females had a higher AAMR than males (0.6 vs. 0.5). Non-Hispanic (NH) blacks had the highest AAMR, followed by NH whites and Hispanic or Latinos. The southern region had the highest AAMR (0.7: 95% CI, 0.6-0.7), followed by the Midwest (0.6, 95% CI, 0.54-0.669), the Northeast (0.5, 95% CI, 0.5 to 0.6), and the West (0.4; 95% CI, 0.3-0.4). Urban and rural areas had comparable mortality rates (0.5 vs. 0.6). People aged 65+ had the highest AAMRs. Conclusions: The overall mortality rates for non-ischemic CVD and sarcoidosis have increased in the US from 1999 to 2022. Females and NH blacks had higher AAMRs, while a minimal variation was observed based on geographical regions. Early diagnosis and prompt management are the keys to reducing the mortality burden of non-ischemic CVD plus sarcoidosis.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Virtual reality current use, facilitators and barriers to implementation in paediatric physiotherapy: cross-sectional online survey of UK paediatric physiotherapists
No full textBACKGROUND: The literature is scarce about virtual reality (VR) use and its integration into clinical practice. Given the growing interest toward using VR in healthcare in the UK, the aims of this survey were to explore its current use by paediatric physiotherapists in clinical practice in the UK, identify the facilitators and barriers to VR implementation in clinical practice and investigate the factors that will enhance intentions to use it in the future. METHODS: An online survey using Assessing Determinants of Prospective Take-Up of Virtual Reality (ADOPT-VR2) was distributed to UK paediatric physiotherapists through the Association of Paediatric Chartered Physiotherapists. Descriptive statistics and regression analysis were conducted. RESULTS: Out of 128 responses, 81 UK-based paediatric physiotherapists completed the survey. The therapists worked in the National Health Service, in the private sector and education. Most of the respondents reported not using VR in clinical practice (n = 75; 93%). Only 7% of respondents reported using VR in clinical practice. Attitudes toward VR, compatibility, and the peer influence constructs of ADOPT-VR2 all significantly predicted the behavioural intention to use VR (R(2) = 0.612, p = <0.001). CONCLUSIONS: This study shows that the current use of VR is limited. The findings from this study suggest that multiple factors need to be reconciled to enhance VR implementation. Specifically, therapists need to be provided with time, appropriate training, and financial and technical support. Stakeholders may also need to consider developing practical manuals to ensure therapists are implementing VR consistently and correctly.
The current use of VR in clinic is notably limited.The limited use of VR is not solely related to the lack of funds.Physiotherapists need to be provided with appropriate training, financial and technical support to facilitate VR clinical implementation.
engUnknown15 month embargo from time of publicatio
Efficacy and tolerability of levetiracetam in people with and without intellectual disabilities: A naturalistic case control study
No full textINTRODUCTION: People with Intellectual Disabilities (PwID) are twenty times more likely than general population to have epilepsy. Guidance for prescribing antiseizure medication (ASM) to PwID is driven by trials excluding them. Levetiracetam (LEV) is a first-line ASM in the UK. Concerns exist regarding LEV's behavioural and psychological adverse effects, particularly in PwID. There is no high-quality evidence comparing effectiveness and adverse effects in PwID to those without, prescribed LEV. METHODS: Pooled casenote data for patients prescribed LEV (2000-2020) at 18 UK NHS Trusts were analysed. Demographics, starting and maximum dose, adverse effects, dropouts and seizure frequency between ID (mild vs. moderate-profound (M/P)) and general population for a 12-month period were compared. Descriptive analysis, Mann-Whitney, Fisher's exact and logistic regression methods were employed. RESULTS: 173 PwID (mild 53 M/P 120) were compared to 200 without ID. Mean start and maximum dose were similar across all groups. PwID (Mild & M/P) were less likely to withdraw from treatment (P = 0.036). No difference was found between ID and non-ID or between ID groups (Mild vs M/P) in LEV's efficacy i.e. >50 % seizure reduction. Significant association emerged between ID severity and psychiatric adverse effects (P = 0.035). More irritability (14.2 %) and aggression (10.8 %) were reported in M/P PwID. CONCLUSION: PwID and epilepsy have high rates of premature mortality, comorbidities, treatment resistance and polypharmacy but remain poorly researched for ASM use. This is the largest studied cohort of PwID trialled on LEV compared to general population controls. Findings support prescribing of LEV for PwID as a first-line ASM.0RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Comparison of standard-dose and reduced-dose treatment of metastatic prostate cancer with enzalutamide, apalutamide or darolutamide: a rapid review
No full textOBJECTIVE: To review the efficacy and safety of low-dose versus standard-dose enzalutamide, apalutamide or darolutamide treatment for metastatic prostate cancer. METHODS AND ANALYSIS: Keyword searches in MEDLINE and EMBASE up to 1 June 2023, with forward and backward citation searches of potentially relevant studies. Studies were included if primary outcome data were reported for patients with metastatic prostate cancer who had received reduced doses of enzalutamide, apalutamide or darolutamide. Searches were limited to original full-text and English-language studies. Key outcomes included overall survival (OS), progression-free survival (PFS), prostate-specific antigen response and treatment-related adverse events. The review was performed in accordance with Cochrane Rapid Reviews Methods Group guidelines. RESULTS: Ten studies were identified that met the eligibility criteria: five phase I studies, two post-hoc analyses of phase III trials and three retrospective analyses. No consistent association between OS, PFS and drug dose was identified. Fewer severe treatment-related adverse events were observed at lower drug doses. CONCLUSION: This review provides evidence that enzalutamide, apalutamide or darolutamide could be given at a lower than the standard recommended dose without loss of antitumour activity. A prospective near-equivalence randomised trial should be undertaken to compare registered and lower doses of these agents. PROSPERO REGISTRATION NUMBER: CRD42023440371.This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo
Breast cancer risk assessment for prescription of menopausal hormone therapy in women with a family history of breast cancer: an epidemiological modelling study
No full textBACKGROUND: Menopausal hormone therapy (MHT) can alleviate menopausal symptoms but has been associated with an increased risk of breast cancer. MHT prescription should be preceded by individualised risk/benefit evaluation; however, data outlining the impact of family history alongside different MHT therapeutic approaches are lacking. AIM: To quantify the risks associated with MHT use in women with varying breast cancer family histories of developing and dying from breast cancer. DESIGN AND SETTING: An epidemiological modelling study for women in England using the BOADICEA breast cancer prediction model and data relating to MHT use and breast cancer risk taken from research by the Collaborative Group on Hormonal Factors in Breast Cancer. METHOD: The risk of developing and dying from breast cancer between the ages of 50 and 80 years was modelled in women with four different breast cancer family history profiles: 'average', 'modest', 'intermediate', and 'strong' by using 1) background risks of breast cancer by age and family history, 2) relative risks for breast cancer associated with MHT use, and 3) 10-year breast cancer-specific net mortality rates. This study modelled use of combined oestrogen-progestogen MHT (cyclical or continuous) and oestrogen-only MHT. RESULTS: For a woman of 'average' family history taking no MHT, the cumulative breast cancer risk (age 50-80 years) is 9.8%, and the risk of dying from the breast cancer is 1.7%. In this model, 5 years' exposure to combined-cyclical MHT (age 50-55 years) was calculated to increase these risks to 11.0% and 1.8%, respectively. For a woman with a 'strong' family history taking no MHT, the cumulative breast cancer risk is 19.6% (age 50-80 years), and the risk of dying from the breast cancer is 3.2%. With 5 years' exposure to MHT (age 50-55 years), this model showed that these risks increase to 22.4% and 3.5%, respectively. CONCLUSION: In this model, both family history and MHT are associated with increased risk of breast cancer. Estimates of the risks of breast cancer associated with MHT for women with different family histories can be used to support decision making around MHT prescription for women experiencing menopausal symptoms.Not permittedJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Quantifying the proportion of different cell types in the human cortex using DNA methylation profiles
No full textBACKGROUND: Due to interindividual variation in the cellular composition of the human cortex, it is essential that covariates that capture these differences are included in epigenome-wide association studies using bulk tissue. As experimentally derived cell counts are often unavailable, computational solutions have been adopted to estimate the proportion of different cell types using DNA methylation data. Here, we validate and profile the use of an expanded reference DNA methylation dataset incorporating two neuronal and three glial cell subtypes for quantifying the cellular composition of the human cortex. RESULTS: We tested eight reference panels containing different combinations of neuronal- and glial cell types and characterised their performance in deconvoluting cell proportions from computationally reconstructed or empirically derived human cortex DNA methylation data. Our analyses demonstrate that while these novel brain deconvolution models produce accurate estimates of cellular proportions from profiles generated on postnatal human cortex samples, they are not appropriate for the use in prenatal cortex or cerebellum tissue samples. Applying our models to an extensive collection of empirical datasets, we show that glial cells are twice as abundant as neuronal cells in the human cortex and identify significant associations between increased Alzheimer's disease neuropathology and the proportion of specific cell types including a decrease in NeuNNeg/SOX10Neg nuclei and an increase of NeuNNeg/SOX10Pos nuclei. CONCLUSIONS: Our novel deconvolution models produce accurate estimates for cell proportions in the human cortex. These models are available as a resource to the community enabling the control of cellular heterogeneity in epigenetic studies of brain disorders performed on bulk cortex tissue.published versionRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
European Society of Intensive Care Medicine guidelines on end of life and palliative care in the intensive care unit
No full textThe European Society of Intensive Care Medicine (ESICM) has developed evidence-based recommendations and expert opinions about end-of-life (EoL) and palliative care for critically ill adults to optimize patient-centered care, improving outcomes of relatives, and supporting intensive care unit (ICU) staff in delivering compassionate and effective EoL and palliative care. An international multi-disciplinary panel of clinical experts, a methodologist, and representatives of patients and families examined key domains, including variability across countries, decision-making, palliative-care integration, communication, family-centered care, and conflict management. Eight evidence-based recommendations (6 of low level of evidence and 2 of high level of evidence) and 19 expert opinions were presented. EoL legislation and the importance of respecting the autonomy and preferences of patients were given close attention. Differences in EoL care depending on country income and healthcare provision were considered. Structured EoL decision-making strategies are recommended to improve outcomes of patients and relatives, as well as staff satisfaction and mental health. Early integration of palliative care and the use of standardized tools for symptom assessment are suggested for patients at high risk of dying. Communication training for ICU staff and printed communication aids for families are advocated to improve outcomes and satisfaction. Methods for enhancing family-centeredness of care include structured family conferences and culturally sensitive interventions. Conflict-management protocols and strategies to prevent burnout among healthcare professionals are also considered. The work done to develop these guidelines highlights many areas requiring further research.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text