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Background: Cutaneous leiomyosarcoma (cLMS) is a rare soft tissue neoplasm, showing smooth muscle differentiation, that arises from the mesenchymal cells of the dermis. To-date, genetic investigation of these tumours has involved studies with small sample sizes and limited analyses that identified recurrent somatic mutations in RB1 and TP53, copy number gain of MYCOD and IGF1R, and copy number loss of PTEN., Objectives: To better understand the molecular pathogenesis of cLMS, we comprehensively explored the mutational landscape of these rare tumours to identify candidate driver events., Methods: In this retrospective, multi-institutional study, we performed whole-exome sequencing and RNA sequencing on 38 cases of cLMS., Results: TP53 and RB1 were identified as significantly mutated, thus, represent validated driver genes of cLMS. COSMIC mutational signatures SBS7a/b and DBS1 were recurrent, thus, ultraviolet light exposure may be an aetiological factor driving cLMS. Analysis of significantly recurrent somatic copy number alterations, which represent candidate driver events, found focal (<10Mb) deletions encompassing TP53 and KDM6B, and amplifications encompassing ZMYM2, MYOCD, MAP2K4 and NCOR1. A larger (24 Mb) recurrent deletion encompassing CYLD was also identified as significant. Significantly recurrent broad copy number alterations, involving at least half of a chromosome arm, included deletions of 6p/q, 10p/q, 11q, 12q, 13q and 16p/q, and amplification of 15q. Notably PTEN is located on 10q, RB1 on 13q and IGFR1 on 15q. Fusion gene analysis identified recurrent CRTC1/3::MAML2 fusions, as well as many novel fusions in individual samples., Conclusions: Our analysis of the largest number of cLMS cases to-date highlights the importance of large cohort sizes and the exploration beyond small targeted gene panels when performing molecular analyses, as it allowed a comprehensive exploration of the mutational landscape of these tumours and identification of novel candidate driver events. It also uniquely afforded the opportunity to compare the molecular phenotype of cLMS with LMS of other tissue types, such as uterine and soft tissue LMS. Given that molecular profiling has resulted in the development of novel targeted treatment approaches for uterine and soft tissue LMS, our study now allows the same opportunities to become available for patients with cLMS., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

A High Purity Germanium (HPGe) detector has been used to measure the photon spectra in the majority of monoenergetic neutron fields produced at NPL (0.144, 0.250, 0.565, 2.0, 5.0 and 16.5 MeV). The HPGe was characterised and then modelled to produce a response matrix. The measured pulse height spectra were then unfolded to produce photon fluence spectra. The new spectra were used to improve the photon to neutron dose equivalent ratios from some earlier work at NPL with Geiger-Muller tubes and electronic personal dosemeters., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: In the original SPRINT article, age was categorized at 75 years, which was contrary to many previous clinical trials which is at 60 years., Methods: The SPRINT trial randomized 9,361 hypertensive patients to a target blood pressure of <120 vs. <140 mm Hg (intensive vs. standard treatment, respectively). Age was re-categorized as <60 and ≥60 years and hazard ratios (HRs) were calculated with 95% confidence intervals (CIs) for outcomes and adverse events., Results: Intensive treatment reduced primary outcome significantly in both <60 and ≥60 years of age subgroups with a relative risk reduction (RRR) of 36% and 22%, respectively, and HR of 0.58 [95% CI, 0.36-0.94] and 0.78 [95% CI, 0.65-0.93], respectively. Although the intensive treatment rendered no effect on myocardial infarction (MI) in the overall comparison, it significantly reduced MI in patients <60 years of age with an RRR of 58% and HR of 0.39 [95% CI, 0.17-0.91]. In the ≥60-year age subgroup, reduced heart failure incidence was noted after intensive treatment, including death from other cardiovascular causes; however, these were not observed in the <60-year age subgroup. Intensive treatment resulted in significant hypotension, syncope, acute renal failure, or acute kidney injury in the ≥60-year age group; conversely, the risk of these adverse effects in patients <60 years of age did not increase., Conclusions: Intensive blood pressure control is beneficial for elderly patients (age ≥60 years), albeit with increased risk of adverse events., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A significant proportion of patients with short-lasting unilateral neuralgiform headache attacks are refractory to medical treatments. Neuroimaging studies have suggested a role for ipsilateral trigeminal neurovascular conflict with morphological changes in the pathophysiology of this disorder. We present the outcome of an uncontrolled open-label prospective single-centre study conducted between 2012 and 2020, to evaluate the efficacy and safety of trigeminal microvascular decompression in refractory chronic short-lasting unilateral neuralgiform headache attacks with MRI evidence of trigeminal neurovascular conflict ipsilateral to the pain side. Primary endpoint was the proportion of patients who achieved an 'excellent response', defined as 90-100% weekly reduction in attack frequency, or 'good response', defined as a reduction in weekly headache attack frequency between 75% and 89% at final follow-up, compared to baseline. These patients were defined as responders. The study group consisted of 47 patients, of whom 31 had short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, and 16 had short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (25 females, mean age ± SD 55.2 years ± 14.8). Participants failed to respond or tolerate a mean of 8.1 (±2.7) preventive treatments pre-surgery. MRI of the trigeminal nerves (n = 47 patients, n = 50 symptomatic trigeminal nerves) demonstrated ipsilateral neurovascular conflict with morphological changes in 39/50 (78.0%) symptomatic nerves and without morphological changes in 11/50 (22.0%) symptomatic nerves. Postoperatively, 37/47 (78.7%) patients obtained either an excellent or a good response. Ten patients (21.3%, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing = 7 and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms = 3) reported no postoperative improvement. The mean post-surgery follow-up was 57.4 ± 24.3 months (range 11-96 months). At final follow-up, 31 patients (66.0%) were excellent/good responders. Six patients experienced a recurrence of headache symptoms. There was no statistically significant difference between short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and short-lasting unilateral neuralgiform headache attacks in the response to surgery (P = 0.463). Responders at the last follow-up were, however, more likely to not have interictal pain (77.42% versus 22.58%, P = 0.021) and to show morphological changes on the MRI (78.38% versus 21.62%, P = 0.001). The latter outcome was confirmed in the Kaplan-Meyer analysis, where patients with no morphological changes were more likely to relapse overtime compared to those with morphological changes (P = 0.0001). All but one patient, who obtained an excellent response without relapse, discontinued their preventive medications. Twenty-two post-surgery adverse events occurred in 18 patients (46.8%) but no mortality or severe neurological deficit was seen. Trigeminal microvascular decompression may be a safe and effective long-term treatment for patients suffering short-lasting unilateral neuralgiform headache attacks with MRI evidence of neurovascular conflict with morphological changes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Cluster headache is characterized by recurrent, unilateral attacks of excruciating pain associated with ipsilateral cranial autonomic symptoms. Although a wide array of clinical, anatomical, physiological, and genetic data have informed multiple theories about the underlying pathophysiology, the lack of a comprehensive mechanistic understanding has inhibited, on the one hand, the development of new treatments and, on the other, the identification of features predictive of response to established ones. The first-line drug, verapamil, is found to be effective in only half of all patients, and after several weeks of dose escalation, rendering therapeutic selection both uncertain and slow. Here we use high-dimensional modelling of routinely acquired phenotypic and MRI data to quantify the predictability of verapamil responsiveness and to illuminate its neural dependants, across a cohort of 708 patients evaluated for cluster headache at the National Hospital for Neurology and Neurosurgery between 2007 and 2017. We derive a succinct latent representation of cluster headache from non-linear dimensionality reduction of structured clinical features, revealing novel phenotypic clusters. In a subset of patients, we show that individually predictive models based on gradient boosting machines can predict verapamil responsiveness from clinical (410 patients) and imaging (194 patients) features. Models combining clinical and imaging data establish the first benchmark for predicting verapamil responsiveness, with an area under the receiver operating characteristic curve of 0.689 on cross-validation (95% confidence interval: 0.651 to 0.710) and 0.621 on held-out data. In the imaged patients, voxel-based morphometry revealed a grey matter cluster in lobule VI of the cerebellum (-4, -66, -20) exhibiting enhanced grey matter concentrations in verapamil non-responders compared with responders (familywise error-corrected P = 0.008, 29 voxels). We propose a mechanism for the therapeutic effect of verapamil that draws on the neuroanatomy and neurochemistry of the identified region. Our results reveal previously unrecognized high-dimensional structure within the phenotypic landscape of cluster headache that enables prediction of treatment response with modest fidelity. An analogous approach applied to larger, globally representative datasets could facilitate data-driven redefinition of diagnostic criteria and stronger, more generalizable predictive models of treatment responsiveness., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Coronavirus disease 2019 (COVID-19) has been particularly severe on older people. Past coronavirus epidemics namely Severe Acute Respiratory Syndrome and the Middle East Respiratory Syndrome have also been severe on older people. These epidemics lasted for only a limited period, however, and have proven short lived in the memories of both the public and public health systems. No lessons were learnt to mitigate the impact of future epidemics of such nature, on older people. This complacency we feel has claimed the lives of many older people during the current COVID-19 global epidemic. The nature of risks associated with acquiring infections and associated mortality among older people in respiratory epidemic situations are varied and of serious concern. Our commentary identifies demographic, biological, behavioural, social and healthcare-related determinants, which increase the vulnerability of older people to respiratory epidemics. We acknowledge that these determinants will likely vary between older people in high- and low-middle income countries. Notwithstanding these variations, we call for urgent action to mitigate the impact of epidemics on older people and preserve their health and dignity. Intersectoral programmes that recognise the special needs of older people and in unique contexts such as care homes must be developed and implemented, with the full participation and agreement of older people. COVID-19 has created upheaval, challenging humanity and threatening the lives, rights, and well-being of older people. We must ensure that we remain an age-friendly society and make the world a better place for all including older people., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Severe neonatal hyperbilirubinemia continues to occur in healthy newborns. Recent guidelines have supported using transcutaneous devices in estimating bilirubin levels. Previous studies using these devices are limited., Methods: Newborns requiring serum bilirubin level measurements before hospital discharge were recruited prospectively. The agreement between a transcutaneous bilirubin (TCB) and total serum bilirubin (TSB) level was assessed. Sensitivity analysis was conducted., Results: A total of 430 infants were enrolled. Correlation between the values was high (Pearson's correlation coefficient 0.83; Lin's concordance coefficient 0.81 [95% CI 0.77 to 0.84]; P<0.001). The mean (± SD) TSB level was 194±60 μmol/L. The TCB measurement tended to overestimate the value (mean difference 12.7), with wide 95% limits of agreement (-52 μmol/L to 77 μmol/L). Sensitivity and specificity analysis of TCB values allowed estimation of clinically important TSB levels., Conclusions: The TCB correlated, but was imprecise in predicting TSB. TCB values can be used at the time of discharge to safely plan care for jaundiced infants if the limits of agreement are considered and clinical judgment is maintained.