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Background: Transcriptomic changes in the essential tremor (ET)-associated cerebello-thalamo-cortical "tremor network" and their association to brain structure have not been investigated., Objective: The aim was to characterize molecular changes associated with network-level imaging-derived phenotypes (IDP) found in ET., Methods: We performed an imaging-transcriptomic study in British adults using imaging-genome-wide association study summary statistics (UK Biobank "BIG40" cohort; n = 33,224, aged 40-69 years). We imputed imaging-transcriptomic associations for 184 IDPs and analyzed functional enrichment of gene modules and aggregate network-level phenotypes. Validation was performed in cerebellar-tissue RNA-sequencing data from ET patients and controls (n = 55)., Results: Among 237,896 individual predicted gene expression levels for 6063 unique genes/transcripts, we detected 2269 genome-wide significant associations (Bonferroni P < 2.102e-7, 0.95%). These were concentrated in intracellular volume fraction measures of white matter pathways and in genes with putative links to tremor (MAPT, ARL17A, KANSL1, SPPL2C, LRRC37A4P, PLEKHM1, and FMNL1). Whole-tremor-network cortical thickness was associated with a gene module linked to mitochondrial organization and protein quality control (r = 0.91, P = 2e-70), whereas white-gray T1-weighted magnetic resonance imaging (MRI) contrast in the tremor network was associated with a gene module linked to sphingolipid synthesis and ethanolamine metabolism (r = -0.90, P = 2e-68). Imputed association effect sizes and RNA-sequencing log-fold change in the validation dataset were significantly correlated for cerebellar peduncular diffusion MRI phenotypes, and there was a close overlap of significant associations between both datasets for gray matter phenotypes (χ 2  = 6.40, P = 0.006)., Conclusions: The identified genes and processes are potential treatment targets for ET, and our results help characterize molecular changes that could in future be used for patient treatment selection or prognosis prediction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Blood-based gene expression signatures could potentially be used as biomarkers for PD. However, it is unclear whether genetically-regulated transcriptomic signatures can provide novel gene candidates for use as PD biomarkers. We leveraged on the Genotype-Tissue Expression (GTEx) database to impute whole-blood transcriptomic expression using summary statistics of three large-scale PD GWAS. A random forest classifier was used with the consensus whole-blood imputed gene signature (IGS) to discriminate between cases and controls. Outcome measures included Area under the Curve (AUC) of Receiver Operating Characteristic (ROC) Curve. We demonstrated that the IGS (n = 37 genes) is conserved across PD GWAS studies and brain tissues. IGS discriminated between cases and controls in an independent whole-blood RNA-sequencing study (1176 PD, 254 prodromal, and 860 healthy controls) with mean AUC and accuracy of 64.8% and 69.4% for PD cohort, and 78.8% and 74% for prodromal cohort. PATL2 was the top-performing imputed gene in both PD and prodromal PD cohorts, whose classifier performance varied with biological sex (higher performance for males and females in the PD and prodromal PD, respectively). Single-cell RNA-sequencing studies (scRNA-seq) of healthy humans and PD patients found PATL2 to be enriched in terminal effector CD8+ and cytotoxic CD4+ cells, whose proportions are both increased in PD patients. We demonstrated the utility of GWAS transcriptomic imputation in identifying novel whole-blood transcriptomic signatures which could be leveraged upon for PD biomarker derivation. We identified PATL2 as a potential biomarker in both clinical and prodromic PD., (© 2024. The Author(s).)

Introduction: Consistent delineation of the breast conserving surgery (BCS) tumour bed (TB) for breast cancer remains a challenge for radiation oncologists. Accurate delineation allows for better local control and reduces toxicity when planning partial breast or TB boost radiation therapy (RT)., Methods: In the operating theatre (OT) breast surgeons inserted stabilised hyaluronic acid (sHA) gel as small drops approximately one cm into the walls surrounding the resection cavity. Surgical feasibility was determined by the rate of successful sHA gel insertion procedure, the ease of insertion as rated by surgeons, the time required for insertion procedure, the quantity used, and any adverse events (AE) relating to sHA gel insertion., Results: Thirty-five patients were enrolled. All patients underwent sHA gel insertion successfully. The procedure added a median of 2.8 min to the OT time and was rated as 'easy' in 89 % of patients. There were no immediate AE in OT. Five (14 %) patients experienced a grade 2 or higher AE. Three of the five patients were prescribed oral antibiotics for breast infection. Two of the five patients experienced a grade 3 AE - haematoma which required evacuation in OT day 1 post-BCS, and infected seroma which required drainage and washout in OT 2 months post-BCS. All five patients recovered and underwent the planned adjuvant therapies for their BC. The AE data reflects common risks with standard BCS and are not clearly attributed to sHA gel insertion alone., Conclusion: We show that sHA gel is surgically feasible as a marker to help define the TB cavity for post-BCS adjuvant MRI-based RT planning., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Michael Chao reports equipment, drugs, or supplies was provided by Palette Life Sciences. Michael Chao reports a relationship with Palette Life Sciences that includes: consulting or advisory.’., (© 2024 The Author(s).)

Objectives: The condition of the home is a strong predictor of exposure to environmental contaminants, with low-income households being particularly vulnerable. Therefore, improving housing standards is a priority. Housing built to "green" standards, with improved building methods and materials, has been suggested to reduce contaminants. However, evidence is limited as to which contaminants are reduced. The Green Housing Study was conducted to address this issue. The study hypothesis was that housing built using green components has lower concentrations of environmental contaminants compared to conventional housing., Methods: A repeated-measures, 12-month cohort study was performed in three U.S. cities. Data were collected in the home at three time points throughout a year. The level of contaminants were estimated using air samples for particulate matter and black carbon, dust samples for aeroallergens and pesticides, and resident or study staff reporting evidence of mold. To investigate source(s) of PM 2.5 and black carbon, multivariable models using stepwise variable selection were developed., Results: In adjusted generalized estimating equations (GEE) models, black carbon concentration (μg/m 3 ) (β = -0.22, 95% CI = -0.38 to -0.06, p = 0.01), permethrin (OR = 0.28, 95% CI = 0.15-0.49, p < 0.0001), and reported mold (OR = 0.29, 95% CI = 0.13-0.68, p = 0.003) were significantly lower in green homes. Cockroach antigen was also lower in green homes (OR = 0.59, 95% CI = 0.33-1.08, p = 0.09), although not statistically significant. We found that 68% of PM 2.5 was explained by dwelling type and smoking and 42% of black carbon was explained by venting while cooking and use of a gas stove., Conclusions: This study provides quantitative data suggesting benefits of incorporating green building practices on the level of numerous environmental contaminants known to be associated with health. Occupant behavior, particularly smoking, is an important contributor to indoor air pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To assess the degree of pathologic complete response (pCR), postoperative surgical complication rates, and oncological outcomes in women with locally advanced breast cancer or high-risk breast cancers treated with neoadjuvant radiation therapy (NART)., Methods and Materials: This retrospective, multi-institutional review involved 138 clinically staged patients with 140 breast cancers treated with NART between January 2014 and February 2021. Treatments involved sequential neoadjuvant chemotherapy and NART, followed by mastectomy with or without axillary surgery and immediate autologous breast reconstruction. Descriptive statistics were used to assess patient and disease features, treatment regimens, pathologic response, and factors affecting postoperative complications. Kaplan-Meier curves were performed to assess locoregional recurrence-free, distant metastasis-free, and overall survival outcomes., Results: Median age was 47 years (interquartile range, 42-52). The median follow-up was 35.2 months (interquartile range, 17.1-46.5). pCR was achieved in 36.4% (as defined by Chevallier classification) or 42.1% (as defined by Miller-Payne scores) of patients. Greater pCR rates were achieved for HER2+ (73.8%-85.7%) and triple-negative phenotypes (47.6%-57.1%). There were 21 grade 3 surgical complications including 10 grade 3B breast events and 8 grade 3B donor-site events, where surgical reintervention was required. At 3-years' follow-up, the locoregional recurrence-free survival was 98.1%, distant metastasis-free survival was 83.6%, and overall survival was 95.3%%., Conclusions: NART is feasible to facilitate a single-stage mastectomy and immediate autologous breast reconstruction. This study demonstrated comparable rates of postoperative complication to standard of care, and high rates of pCR, which translates to high rates of locoregional control, distant metastasis-free survival, and overall survival., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Most diseases of the spine disproportionately impact older persons, with the modal (i.e., commonest) patient a female in their 8th decade of life. We examined the corpus of spinal RCTs to determine how many included "average" spine patients. We searched PubMed for randomized clinical trials published in the top 7 spine journals over a period of 5 years from 2016 to 2020 and extracted nominal upper age cut-offs and the distribution of ages actually recruited. We identified 186 trials of 26,238 patients. We found that only 4.8% of trials could be applied to an "average" 75-year-old patient. This age-based exclusion was not dependent on funding source. Age-based exclusion was exacerbated by explicit upper age cut-offs, however, the age-based exclusion went beyond explicit age cut-offs. Only few trials were applicable to older patients even amongst trials with no age cut-off specified. Age-based exclusion from clinical trials starts at late middle age. The mismatch between spinal patient's age seen in clinical practice and spinal patient's age in trials was so severe that over the 5 years (2016-2020) almost no RCT evidence was produced applicable to the "average" aged-patient across the body of literature available. In conclusion, age-based exclusion is ubiquitous, multifactorial, and happens on a supratrial level. Eliminating age-based exclusion involves more than an arbitrary lifting of explicitly stated upper age cut-offs. Instead, recommendations include increasing input from geriatricians and ethics committees, establishing updated or new models of cares, and creating new protocols to facilitate further research., (© 2023. Crown.)

Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac tissue remodeling. Recent evidence implicates monocytes/macrophages in the etiopathology of cardiac fibrosis, but giving their heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis, targeting these cells has been challenging. Here we focus on WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that myeloid specific deletion of WWP2 reduces cardiac fibrosis in hypertension-induced NICM. By using single cell RNA sequencing analysis of immune cells in the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase of NICM that is driven by Ccl5-expressing Ly6c high monocytes. Among cardiac macrophage subtypes, WWP2 dysfunction primarily affects Ly6c high monocytes via modulating Ccl5, and consequentially macrophage infiltration and activation, which contributes to reduced myofibroblast trans-differentiation. WWP2 interacts with transcription factor IRF7, promoting its non-degradative mono-ubiquitination, nuclear translocation and transcriptional activity, leading to upregulation of Ccl5 at transcriptional level. We identify a pro-fibrogenic macrophage subtype in non-ischemic cardiomyopathy, and demonstrate that WWP2 is a key regulator of IRF7-mediated Ccl5/Ly6c high monocyte axis in heart fibrosis., (© 2022. The Author(s).)

Objective: To describe the incidence of infertility, pregnancy complications, and breastfeeding practices among Australian and New Zealand doctors and identify factors associated with increased pregnancy complication rates., Methods: A survey of ANZ doctors using an online questionnaire during November 2021., Results: One thousand ninety-nine completed responses were received. The median age of female doctors at the time of their first child was 32.4. Fertility testing was undertaken by 37%, with 27% having in vitro fertilization. More than 60% of respondents delayed family planning due to work. Pregnancy loss occurred in 36% of respondents, and 50% suffered a pregnancy complication. There were significant differences between specialists, with surgeons working longer hours before and after pregnancy, but having greater access to maternity leave than general practitioners., Conclusion: Female doctors delay starting and completing their family due to work-related demands and structural biases in career progression, which may result in higher infertility and pregnancy complication rates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kevric, Suter, Hodgson and Chew.)

Background: A chloride test is an integral part of a basic metabolic panel that is essential for the assessment of a patient's acid-base and electrolyte status. While many methods are available commercially for the routine measurement of chloride, there is a need to address the accuracy and variability among the measurement results, especially with the prevalence of patients seeking treatment across different healthcare providers for alternative opinions., Method: A method based on sector field inductively coupled plasma isotope dilution mass spectrometry (SF-ICP-IDMS) was developed for the measurement of chloride in human serum. The SF-ICP-IDMS method was then used to assign the target values in the Health Sciences Authority (HSA) External Quality Assessment (EQA) Programme to evaluate the results of chloride test from participating clinical laboratories., Results: The accuracy of the measurements was evaluated by comparing the results with the certified values of Electrolytes in Frozen Human Serum Certified Reference Materials (SRM 956c and SRM 956d) from the National Institute of Standards and Technology (NIST) at different chloride concentration levels. Over a five-year period from 2014-2018, the number of clinical laboratories which participated in the EQA Programme increased from 23 to 33. Comparison of robust means from the laboratories' results with our assigned target values revealed a reduction in relative deviation over time. The relationship between the deviation of each brand of clinical analysers and the chloride levels was established, where a larger deviation was uncovered at low chloride concentration. The SF-ICP-IDMS method was further demonstrated to be comparable with methods used by other metrology institutes in an international comparison organised by HSA under the auspice of the Consultative Committee for Amount of Substance - Metrology in Chemistry and Biology (CCQM)., Conclusion: The use of metrologically traceable assigned target values enabled the study of method biasness from a small pool of dataset in each of the four brands of clinical analysers in HSA EQA Programme. This work underscores the need to improve the accuracy of chloride measurements by regular participation in an accuracy-based EQA Programme., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Introduction: The UK Government imposed a COVID19 lockdown (LD) restricting all but essential activities from 24th March 2020. Subsequently, there has been a significant reduction in casualty attendances nationwide including for ophthalmic emergencies. We aim to study the presentation of rhegmatogenous retinal detachments (RRD) and significant vitreous haemorrhage caused by posterior vitreous detachment (PVD-VH) in three tertiary centres covering most of the North West of England in the 6 weeks before and during the lockdown., Methods: A retrospective multicenter non-randomised consecutive case series study was designed to collect information on all cases of RRD and PVD-VH requiring surgery presenting to the vitreoretinal departments of Manchester Royal Eye Hospital, East Lancashire NHS Foundation Trust and the Lancashire NHS Foundation Trust from 11th February to 4th May 2020., Results: A total of 137 eyes of 137 patients were identified between the three centres of which 132 eyes were operated for RRD. Of these, 86 (64.7%) were operated pre-LD compared with 46 eyes (34.8%) during LD. Forty-five out of 86 eyes (52.3%) were macula-off pre-LD compared with 31 out of 46 eyes (67.3%) during LD ( p  = 0.06). There was lower proportion of non-PVD related RRD during LD (11 pre-LD to 1 during LD, p  = 0.05). PVR was present in four cases during LD compared to 2 before ( p  = 0.19)., Conclusion: There was a clinically significant reduction in the overall incidence of RRD in our centres with an increase in the proportion of macula-off and proliferative vitreoretinopathy during the LD period compared to a similar period before.