Explore the vast range of titles available.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. The incidence of MH reactions ranges from 1:10,000 to 1: 250,000 anesthetics. However, the prevalence of the genetic abnormalities may be as great as one in 400 individuals. MH affects humans, certain pig breeds, dogs and horses. The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. An increase in end-tidal carbon dioxide despite increased minute ventilation provides an early diagnostic clue. In humans the syndrome is inherited in an autosomal dominant pattern, while in pigs it is autosomal recessive. Uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation leads to the pathophysiologic changes. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 400 variants have been identified in the RYR1 gene located on chromosome 19q13.1, and at least 34 are causal for MH. Less than 1 % of variants have been found in CACNA1S but not all of these are causal. Diagnostic testing involves the in vitro contracture response of biopsied muscle to halothane, caffeine, and in some centres ryanodine and 4-chloro-m-cresol. Elucidation of the genetic changes has led to the introduction of DNA testing for susceptibility to MH. Dantrolene sodium is a specific antagonist and should be available wherever general anesthesia is administered. Increased understanding of the clinical manifestation and pathophysiology of the syndrome, has lead to the mortality decreasing from 80 % thirty years ago to <5 % in 2006.

Background Non-melanoma skin cancer (NMSC) is common among Caucasians, particularly in elderly patients, with rising incidence due to aging populations. Primary risk factors include cumulative sun exposure, advanced age and immunosuppression. While surgery and radiation therapy (RT) are standard treatments, RT is often preferred for elderly patients with large tumors or comorbidities. Hypofractionated RT schedules are effective but can cause significant side effects. Enhancing radiosensitivity through water-filtered infrared-A (wIRA) hyperthermia may reduce required radiation doses and mitigate side effects. Methods This two-arm, prospective, open-label, randomized controlled phase 2 non-inferiority trial will compare local control outcomes between high-dose RT alone versus de-escalated RT, immediately following mild wIRA-hyperthermia in treating NMSC. The study aims to demonstrate noninferiority with a -10% margin and 80% power (alpha = 0.1, one-sided), enrolling 100 patients. The intervention group will receive wIRA-hyperthermia combined with RT (6 fractions of 5 Gy each over 3 weeks), while the control group will receive standard RT (12 fractions of 4 Gy each over 4 weeks). The primary endpoint is local control after two years, defined as ‘no need for further intervention’. Secondary endpoints include acute and late toxicities and quality of life (QoL), assessed using the QLQ-ELD14 questionnaire. Inclusion criteria are histologically confirmed invasive NMSC, tumor stage ≥ T2, local recurrence allowed after non-RT treatment > 6 months ago, age ≥ 65 years, and ECOG performance status 0–2. Exclusion criteria are non-basal/squamous cell carcinoma histology, T1 tumors, node-positive status, post-resection cancers < 6 months, tumor thickness > 2 cm, critical area invasion, multiple lesions exceeding treatment capacity, recent or concurrent chemo- or immunotherapy, connective tissue disorders, proximity to previously irradiated areas, medical immunosuppression, and wIRA-incompatible conditions (e.g., tattoos, increased photosensitivity). Discussion This study aims to determine whether de-escalated RT following wIRA-hyperthermia can achieve comparable local control rates to standard RT in treating NMSC, potentially offering a treatment with fewer side effects and shorter durations. Success in this trial could lead to improved treatment protocols for elderly patients with NMSC, reducing side effects and enhancing QoL. Trial registration The trial has been registered prospectively on ClinicalTrials.gov under the identifier NCT06384053, as of April 25th, 2022.

Magnetic fluid hyperthermia (MFH) treatment makes use of a suspension of superparamagnetic iron oxide nanoparticles, administered systemically or locally, in combination with an externally applied alternating magnetic field, to ablate target tissue by generating heat through a process called induction. The heat generated above the mammalian euthermic temperature of 37°C induces apoptotic cell death and/or enhances the susceptibility of the target tissue to other therapies such as radiation and chemotherapy. While most hyperthermia techniques currently in development are targeted towards cancer treatment, hyperthermia is also used to treat restenosis, to remove plaques, to ablate nerves and to alleviate pain by increasing regional blood flow. While RF hyperthermia can be directed invasively towards the site of treatment, non-invasive localization of heat through induction is challenging. In this review, we discuss recent progress in the field of RF magnetic fluid hyperthermia and introduce a new diagnostic imaging modality called magnetic particle imaging that allows for a focused theranostic approach encompassing treatment planning, treatment monitoring and spatially localized inductive heating.

Core body temperature is normally tightly regulated to within a few tenths of a degree. The major thermoregulatory defences in humans are sweating, arteriovenous shunt vasoconstriction, and shivering. The core temperature triggering each response defines its activation threshold. General anaesthetics greatly impair thermoregulation, synchronously reducing the thresholds for vasoconstriction and shivering. Neuraxial anaesthesia also impairs central thermoregulatory control, and prevents vasoconstriction and shivering in blocked areas. Consequently, unwarmed anaesthetised patients become hypothermic, typically by 1–2°C. Hypothermia results initially from an internal redistribution of body heat from the core to the periphery, followed by heat loss exceeding metabolic heat production. Complications of perioperative hypothermia include coagulopathy and increased transfusion requirement, surgical site infection, delayed drug metabolism, prolonged recovery, shivering, and thermal discomfort. Body temperature can be reliably measured in the oesophagus, nasopharynx, mouth, and bladder. The standard-of-care is to monitor core temperature and to maintain normothermia during general and neuraxial anaesthesia.

ObjectiveTo compare hyperthermia and physiological dehydration risk during exercise heat stress between children of different ages and adults and evaluate an existing adult sweat rate calculator in children.Methods68 fit and recreationally active children aged 10–16 years (31 girls), and 24 adults aged 18–40 years (11 females) completed three separate 45 min treadmill walking/running trials at different intensities on different days at 30°C, 40% relative humidity (RH) (WARM) or 40°C, 30% RH (HOT). Exposures were randomised to elicit intensities scaled to (1) fitness, (2) mass and (3) surface area. Core (gastrointestinal (Tgi)) temperature was measured continuously and dehydration determined using body mass changes.ResultsExcept for 60% V̇O2peak in WARM, in which adults exhibited a greater Tgi rise compared with 10–13 years, there was no effect of age on Tgi during exercise (p≥0.176). Physiological rates of dehydration were not affected by age in WARM (p≥0.08) or HOT (p≥0.08). Mean predicted sweat rate error was +0.08 kg/hour (95% CIs: −0.10, +0.25) across WARM and HOT, and 80.5% of variability in sweating was explained by the adult sweat rate calculator.ConclusionsUsing the most comprehensive paediatric exercise heat stress dataset from a single study to date, we show that children aged 10–16 years are at a similar risk of hyperthermia and dehydration as adults during exercise up to 40°C. This supports recent changes to paediatric sport heat policies that were based on limited data. Practitioners can potentially reduce behavioural dehydration risks from inadequate fluid consumption using an existing adult sweat rate calculator for children.

Background At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. Methods In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3–4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. Discussion The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. Trial registration clinicaltrials.gov NCT03348150 ; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing.

Background Warm compresses are the routine treatment for Meibomian gland dysfunction (MGD) in daily life, but in order to achieve satisfactory efficacy, the treatment needs to be sustained over a long time, which can have an impact on the patient compliance. A more convenient warm compresses will help improve the patient compliance. Therefore, the purpose of the study is to investigate the efficacy and safety of the disposable eyelid warming masks for treatment of dry eye disease (DED) due to MGD. Methods This was a randomized, controlled, non-masked, two-center clinical trial. One hundred and forty-four patients were treated by the masks or the hot towel twice daily for 12 weeks. Patients were evaluated at baseline, 4-week and 12-week visits for subjective symptoms, objective signs and safety assessments, including ocular symptom scores, ocular surface disease index (OSDI), tear break-up time (BUT), corneal fluorescein staining (CFS), Schirmer I test (SIT), meibum quality, meibum expressibility, and adverse events (AEs). Results A totle of 134 patients were followed in the study. The mean age of the masks group (14 males and 52 females) and the hot towel group (20 males and 48 females) was 43.7 ± 13.5 years and 39.5 ± 13.9 years, respectively. At 4-week visit, there were significant statistical differences in ocular symptom scores, OSDI and CFS between two groups ( P  < 0.05). Except for SIT, the treatment group showed a greater improvement in subjective symptoms and objective signs than the control group at 12-week visit. ( P  < 0.05). In addition, 40 AEs occurred in 27 patients (37.5%) in the treatment group, and 34 AEs occurred in 21 patients (29.17%) in the control group. No serious AEs were reported. Conclusions The masks had a good efficacy and safety in the treatment of DED due to MGD, and might offer an attractive treatment option for some patients. Trial registration The study was registered at Chinese Clinical Trial Registry (ChiCTR1900025443) on August 26, 2019.

Ryanodine Receptors (RyRs) are massive channels that release Ca 2+ from the endoplasmic and sarcoplasmic reticulum. Hundreds of mutations are linked to malignant hyperthermia (MH), myopathies, and arrhythmias. Here, we explore the first MH mutation identified in humans by providing cryo-EM snapshots of the pig homolog, R615C, showing that it affects an interface between three solenoid regions. We also show the impact of apo-calmodulin (apoCaM) and how it can induce opening by bending of the bridging solenoid, mediated by its N-terminal lobe. For R615C RyR1, apoCaM binding abolishes a pathological ‘intermediate’ conformation, distributing the population to a mixture of open and closed channels, both different from the structure without apoCaM. Comparisons show that the mutation primarily affects the closed state, inducing partial movements linked to channel activation. This shows that disease mutations can cause distinct pathological conformations of the RyR and facilitate channel opening by disrupting interactions between different solenoid regions. Ryanodine Receptors (RyRs) release Ca2+ from the endoplasmic and sarcoplasmic reticulum. Mutations in RyR are linked to malignant hyperthermia (MH), myopathies, and arrhythmias. Here, a collection of cryoEM structures provides insights into the molecular consequences of MHrelated RyR mutation R615C, and how apoCaM opens RyR1.

Abstract BACKGROUND Despite the multitude of available treatments, glioblastoma (GBM) remains an aggressive and uniformly fatal tumor. Laser interstitial thermal therapy (LITT) is a novel, minimally invasive treatment that holds promise for treating patients with GBM who are not candidates for traditional open craniotomy. However, due to the recent introduction of LITT into clinical practice, large series that evaluate safety and long-term outcomes after LITT are lacking. OBJECTIVE To present our institution's series of over 50 GBM patients treated with LITT, with regard to safety, efficacy, and outcomes. METHODS We performed a retrospective descriptive study of patients with histologically proven GBM who underwent LITT. Data collected included demographics, tumor location and volume, tumor genetic markers, treatment volume, perioperative complications, and long-term follow-up data. RESULTS We performed 58 LITT treatments for GBM in 54 patients over 5.5 yr. Forty-one were recurrent tumors while 17 were frontline treatments. Forty GBMs were lobar in location, while 18 were in deep structures (thalamus, insula, corpus callosum). Average tumor volume was 12.5 ± 13.4 cm3. Average percentage of tumor treated with the yellow thermal damage threshold (TDT) line (dose equivalent of 43°C for 2 min) was 93.3% ± 10.6%, and with the blue TDT line (dose equivalent of 43°C for 10 min) was 88.0% ± 14.2%. There were 7 perioperative complications (12%) and 2 mortalities (3.4%). Median overall survival after LITT for the total cohort was 11.5 mo, and median progression-free survival 6.6 mo. CONCLUSION LITT appears to be a safe and effective treatment for GBM in properly selected patients. Graphical Abstract Graphical Abstract Video Abstract 10.1093/neuros/nyy375 Video Abstract 10.1093.neuros.nyy375 5821902691001