Daily Chlorhexidine Bath for Health Care Associated Infection Prevention (CLEAN-IT): protocol for a multicenter cluster randomized crossover open-label trial.

BACKGROUND: Critically ill patients are at increased risk of health care-associated infections due to various devices (central line-associated bloodstream infection, catheter-associated urinary tract infection, and ventilator-associated pneumonia), which pose a significant threat to this population. Among several strategies, daily bathing with chlorhexidine digluconate, a water-soluble antiseptic, has been studied as an intervention to decrease the incidence of health care-associated infections in the intensive care unit; however, its ability to reduce all health care-associated infections due to various devices is unclear. We designed the Daily Chlorhexidine Bath for Health Care Associated Infection Prevention (CLEAN-IT) trial to assess whether daily chlorhexidine digluconate bathing reduces the incidence of health care-associated infections in critically ill patients compared with soap and water bathing. METHODS: The CLEAN-IT trial is a multicenter, open-label, cluster randomized crossover clinical trial. All adult patients admitted to the participating intensive care units will be included in the trial. Each cluster (intensive care unit) will be randomized to perform either initial chlorhexidine digluconate bathing or soap and water bathing with crossover for a period of 3 to 6 months, depending on the time of each center's entrance to the study, with a 1-month washout period between chlorhexidine digluconate bathing and soap and water bathing transitions. The primary outcome is the incidence of health care-associated infections due to devices. The secondary outcomes are the incidence of each specific health care-associated infection, rates of microbiological cultures positive for multidrug-resistant pathogens, antibiotic use, intensive care unit and hospital length of stay, and intensive care unit and hospital mortality. CONCLUSION: The CLEAN-IT trial will be used to study feasible and affordable interventions that might reduce the health care-associated infection burden in critically ill patients.

Role of ultra-processed foods in modulating the effect of Mediterranean diet on human and planet health-study protocol of the PROMENADE randomized controlled trial.

BACKGROUND: The Mediterranean diet (MD), globally recognized for its sustainability and health benefits, traditionally emphasizes the consumption of plant-based foods in raw or minimally processed forms. However, shifting lifestyles, even in Mediterranean regions, have led to an increasing consumption of ultra-processed foods (UPF). Epidemiological evidence suggests that UPF consumption may be detrimental to human health, but there is only one clinical trial on this topic which is largely debated in the scientific community. This study aims to investigate the impact of the inclusion of UPF within a Mediterranean-based dietary pattern on cardiometabolic markers, gut microbiota, and other markers of human and planet health. METHODS: Fifty clinically healthy individuals showing overweight and presenting a low-to-moderate cardiovascular risk profile will be recruited for a 7-month randomized, open, cross-over dietary trial. Eligible participants will be randomly assigned to a 3-month high-UPF MD (intervention group) or a low-UPF MD (control group), with a 1-month wash-out period. Both intervention diets will have identical food group compositions, with the intervention group consuming 5 servings/day of selected UPF items, and the control group consuming raw/minimally processed items from the same food group. Blood, urine, and fecal samples, alongside food/lifestyle diaries, will be collected from each participant before and after the dietary interventions. The primary endpoint will be the change in plasma LDL-cholesterol levels from baseline. Additional markers include blood pressure, anthropometric parameters, chemical parameters, glucose and lipid-related metabolic markers, incretins, inflammatory and oxidative stress markers, fecal microbiota composition, and short-chain fatty acids. Finally, food waste production will be evaluated through specific validated food diaries. The study has been approved by the Ethical Committee of the University of Milan and the Tuscany Regional Ethics Committee of the Azienda Ospedaliera Universitaria (AOU) - Careggi, Florence. DISCUSSION: Results from the PROMENADE study will improve knowledge about the impact of UPF consumption on human and planet health and will contribute to the scientific debate on this topic. TRIAL REGISTRATION: ClinicalTrials.gov NCT06314932. Registered on March 13, 2024.

Effects of coffee intake on skeletal muscle microvascular reactivity at rest and oxygen extraction during exercise: a randomized cross-over trial.

PURPOSE: The effects of coffee ingestion on skeletal muscle microvascular function are not well understood. This study aimed to investigate the acute effects of coffee intake with varying levels of caffeine on skeletal muscle microvascular reactivity at rest and oxygen extraction during maximal incremental exercise in physically active individuals. METHODS: Twenty healthy young male participants were administered coffee with low caffeine (3 mg/kg body weight; LC), high caffeine (6 mg/kg body weight; HC), and placebo (decaf) in different sessions. Skeletal muscle reactivity indexes, including tissue saturation index 10s slope (TSI10) and TSI half time recovery (TSI ½) following 5-minute ischemia were measured at rest and were measured at baseline and post-coffee consumption using near-infrared spectroscopy (NIRS). Post-coffee intake, NIRS was also used to measure microvascular oxygen extraction during exercise via maximal incremental exercise. Peak oxygen consumption and peak power output (Wpeak) were simultaneously evaluated. RESULTS: Post-coffee consumption, TSI10 was significantly higher in the LC condition compared to placebo (p = 0.001) and significantly higher in the HC condition compared to placebo (p < 0.001). However, no difference was detected between LC and HC conditions (p = 0.527). HC condition also showed significant less TSI ½ compared to placebo (p = 0.005). However, no difference was detected for microvascular oxygen extraction during exercise, despite the greater Wpeak found for HC condition (p < 0.001) compared to placebo. CONCLUSION: Coffee ingestion with high caffeine level (6 mg/kg body weight) significantly enhanced skeletal muscle reactivity at rest. However, the improvement of exercise performance with coffee intake is not accompanied by alterations in muscle oxygen extraction.

Ambient Air Pollution and Hospitalizations for Schizophrenia in China.

Importance: Schizophrenia episodes may be triggered by short-term environmental stimuli. Short-term increases in ambient air pollution levels may elevate the risk of schizophrenia episodes, yet few epidemiologic studies have examined this association. Objective: To investigate whether short-term increases in air pollution levels are associated with an additional risk of schizophrenia episodes, independent of absolute air pollution concentrations, and whether sustained increases in air pollution levels for several days are associated with more pronounced risks of schizophrenia episodes. Design, Setting, and Participants: This nationwide, population-based, time-stratified case-crossover study was performed based on hospitalization records for schizophrenia across 295 administrative divisions of prefecture-level or above cities in China. Records were extracted from 2 major health insurance systems from January 1, 2013, to December 31, 2017. Thirty-six cities with a small number of schizophrenia hospitalizations (n < 50) were excluded. Data analysis for this study was performed from January to March 2024. Exposure: Daily absolute concentrations of fine particulate matter (PM2.5), inhalable particulate matter (PM10), nitrogen dioxide, sulfur dioxide, ozone, and carbon monoxide were collected. Air pollution increases between neighboring days (APINs) were generated as the differences in absolute air pollution concentrations on the current day minus that on the previous day. Sustained increases (APIN ≥5 µg/m3 for PM2.5 and PM10, APIN ≥1 µg/m3 for nitrogen dioxide and sulfur dioxide, and APIN ≥0.05 mg/m3 for carbon monoxide) lasting for 1 or more to 4 or more days were defined for different air pollutants. Main Outcome and Measure: Patients with schizophrenia episodes were identified by principal discharge diagnoses of schizophrenia. A conditional logistic regression model was used to capture the associations of absolute concentrations, APINs, and sustained increase events for different air pollutants with risks of schizophrenia hospitalizations. Results: The study included 817 296 hospitalization records for schizophrenia across 259 Chinese cities (30.6% aged 0-39 years, 56.4% aged 40-64 years, and 13.0% aged ≥65 years; 55.04% male). After adjusting for the absolute concentrations of respective air pollutants, per-IQR increases in 6-day moving average (lag0-5) APINs of PM2.5, PM10, nitrogen dioxide, sulfur dioxide, and carbon monoxide were associated with increases of 2.37% (95% CI, 0.88%-3.88%), 2.95% (95% CI, 1.46%-4.47%), 4.61% (95% CI, 2.93%-6.32%), 2.16% (95% CI, 0.59%-3.76%), and 2.02% (95% CI, 0.39%-3.68%) in schizophrenia hospitalizations, respectively. Greater risks of schizophrenia hospitalizations were associated with sustained increases in air pollutants lasting for longer durations up to 4 or more days. Conclusions and Relevance: This case-crossover study of the association between ambient air pollution increases and schizophrenia hospitalizations provides novel evidence that short-term increases in ambient air pollution levels were positively associated with an elevated risk of schizophrenia episodes. Future schizophrenia prevention practices should pay additional attention to APINs, especially sustained increases in air pollution levels for longer durations, besides the absolute air pollution concentrations.

The interplay of brain neurotransmission and mental fatigue: A research protocol.

INTRODUCTION: Mental fatigue (MF) significantly affects both cognitive and physical performance. However, the precise mechanisms, particularly concerning neurotransmission, require further investigation. An implication of the role of dopamine (DA) and noradrenaline (NA) is stated, but empirical evidence for this theory still needs to be provided. To address this gap, we aim to investigate the role of brain neurotransmission in elucidating if, and how prolonged cognitive activity induces MF and its subsequent impact on cognitive performance. METHODS: This study (registration number: G095422N) will adopt a randomized cross-over design with sixteen healthy participants aged 18-35 years. The sessions include a familiarization, two experimental (DA: 20mg Methylphenidate; NA: 8mg Reboxetine) conditions, and one placebo (lactose tablet: 10mg) condition. A 60-minute individualized Stroop task will be used to investigate whether, and how the onset of MF changes under the influence of reuptake inhibitors. Attention and response inhibition will be assessed before and after the MF-inducing task using a Go/NoGo task. The integration of physiological (electroencephalography, heart rate), behavioral (attention, response inhibition), and subjective indicators (scales and questionnaires) will be used to detect the underlying mechanisms holistically. Data analysis will involve linear mixed models with significance at p<0.05. DISCUSSION: The integration of diverse techniques and analyses offers a comprehensive perspective on the onset and impact of MF, introducing a novel approach. Future research plans involve extending this protocol to explore the connection between brain neurotransmission and physical fatigue. This protocol will further advance our understanding of the complex interplay between the brain and fatigue.

3D printed versus milled stabilization splints for the management of bruxism and temporomandibular disorders: study protocol for a randomized prospective single-blinded crossover trial.

BACKGROUND: Nowadays, stabilization splints for the management of bruxism and temporomandibular disorders (TMD) can be produced utilizing a digital workflow comprising a digital impression of the teeth, digital splint design, and computer-aided manufacturing of the splints. The latter is usually a milling process, however, more recently 3D printing gained popularity due to its better cost and time efficiency. It remains unknown whether 3D printed stabilization splints are inferior to milled splints regarding clinical outcomes. METHODS: This clinical trial assesses the non-inferiority of 3D printed occlusal splints compared to milled occlusal splints in a monocentric prospective randomized single-blinded crossover trial with two cohorts. One cohort includes 20 participants with bruxism, the other 20 participants with pain-related TMD, i.e., myalgia, myofascial pain, or arthralgia of the jaw muscles/the temporomandibular joint(s) diagnosed according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD). Michigan-type stabilization splints are fabricated in a digital workflow by milling or 3D printing using CE-marked materials within their intended purpose. The participants wear a milled and a 3D printed splint in a randomized order for 3 months each, with follow-up visits after 2 weeks and 3 months. Investigated outcome parameters are oral health-related quality of life (OHRQoL) evaluated by the Oral Health Impact Profile (OHIP-G14), participant satisfaction as rated on a visual analog scale, therapeutic efficacy, and technical result of the splints. In this context, therapeutic efficacy means antagonist wear and-in the TMD group-reduction of pain/disability assessed by the Graded Chronic Pain Scale (GCPS v2.0) and clinical assessment following the DC/TMD standard, while technical outcome measures splint fit, wear and fracture rate. DISCUSSION: The trial will provide important information on the clinical outcome of 3D printed stabilization splints in comparison to milled splints and will, therefore, enable an evidence-based decision in favor of or against a manufacturing process. This, in turn, will guarantee for a maximum of the patient's OHRQoL during splint therapy, therapeutic efficacy, and longevity of the splints. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00033904. Registered on March 15, 2024.

Effect of repeated sessions of transcranial direct current stimulation on subjective and objective measures of recovery and performance in soccer players following a soccer match simulation.

We investigated the effect of repeated sessions of anodal transcranial direct current stimulation (a-tDCS) on subjective and objective measures of recovery, cognitive and sport-specific performance in professional soccer players following a soccer match simulation (SMS). Sixteen soccer players participated in this randomized, crossover, and sham-controlled study. They completed baseline assessments of well-being, total quality recovery (TQR), electromyographic activity (EMG) of the thigh muscles, countermovement jump (CMJ), and cognitive and Loughborough soccer passing test (LSPT) skills. Then, the participants engaged in an SMS routine (2 × 45 min, 15-min intervals). There was no significant difference in rating of perceived exertion (RPE) during the SMS in the anodal (17.25 ± 0.85) and sham (16.93 ± 0.92) conditions (p = 0.19). Following the SMS, the participants were randomized to receive three sessions of a-tDCS (2 mA, 20 min, +F3/-F4) targeting the left dorsolateral prefrontal cortex (DLPFC) or sham immediately after, 24 h, and 48 h after the SMS. Finally, the same outcome measures were evaluated 24 and 48 h following the SMS. A two-way repeated-measures ANOVA showed that a-tDCS stimulation improved passing skills (decreased time to perform the LSPT and number of errors; all ps < 0.01; d = 0.56-2.9) and increased the feeling of well-being (p = 0.02; d = 2.8), with no effect on TQR, cognitive performance, CMJ performance, and EMG. Therefore, the results of the present study indicate, for the first time, that repeated a-tDCS could be used as an adjunct method to accelerate soccer players' well-being and technical performance recovery, particularly after congested matches and/or training sessions. These findings may also be applicable to other team sports with characteristics similar to soccer (e.g., futsal, handball, basketball, etc.).

Neuromuscular adaptations to perturbation-based balance training using treadmill belt accelerations do not transfer to an obstacle trip in older people: A cross-over randomised controlled trial.

BACKGROUND: This study examined (i) adaptations in muscle activity following perturbation-based balance training (PBT) using treadmill belt-accelerations or PBT using walkway trips and (ii) whether adaptations during treadmill PBT transfer to a walkway trip. METHODS: Thirty-eight older people (65+ years) undertook two PBT sessions, including 11 treadmill belt-accelerations and 11 walkway trips. Surface electromyography (EMG) was measured bilaterally on the rectus femoris (RF), tibialis anterior (TA), semitendinosus (ST) and gastrocnemius medial head (GM) during the first (T1) and eleventh (T11) perturbations. Adaptations (within-subjects - 1st vs 11th perturbations for treadmill and walkway PBT) and their transfer (between-subjects - 1st walkway trip after treadmill PBT vs 1st walkway trip with no prior training) effects were examined for the EMG parameters. RESULTS: Treadmill PBT reduced post-perturbation peak muscle activation magnitude (left RF, TA, ST, right RF, ST, GM), onset latency (right TA), time to peak (right RF) and co-contraction index (knee muscles) (P < 0.05). Walkway PBT reduced post-trip onset latencies (right TA, ST), peak magnitude (left ST, right GM), time to peak (right RF, ST) and pre-perturbation muscle activity (right TA) (P < 0.05). Those who undertook treadmill PBT were not different to those without prior training during the first walkway trip (P > 0.05). CONCLUSIONS: Both treadmill and walkway PBT induced earlier initiation and peak activation of right limb muscles responsible for the first recovery step. Treadmill PBT also reduced co-contraction of the knee muscles. Adaptations in muscle activity following treadmill PBT did not transfer to a walkway trip.

Acute Effects of Oral Caffeine Intake on Human Global-Flash mfERG Responses: A Placebo-Controlled, Double-Masked, Balanced Crossover Study.

Purpose: To determine the acute effect of caffeine intake on the retinal responses as measured with a global-flash multifocal electroretinogram (gfmERG) protocol at different contrast levels. Methods: Twenty-four young adults (age = 23.3 ± 2.4 years) participated in this placebo-controlled, double-masked, balanced crossover study. On two different days, participants orally ingested caffeine (300 mg) or placebo, and retinal responses were recorded 90 minutes later using a gfmERG at three contrast levels (95%, 50%, and 29%). The amplitude response density and peak time of the direct and induced components (direct component [DC] and induced component [IC], respectively) were extracted for five different eccentricities (1.3°, 5.0°, 9.6°, 15.2°, and 21.9°). Axial length, spherical equivalent refraction, habitual caffeine intake, and body weight were considered as continuous covariates. Results: Increased IC amplitude response density was found after caffeine ingestion in comparison to placebo (P = 0.021, ƞp2 = 0.23), specifically for the 95% and 50% stimulus contrasts (P = 0.024 and 0.018, respectively). This effect of caffeine on IC amplitude response density was independent of the retinal eccentricity (P = 0.556). Caffeine had no effect on DC amplitude response density or DC and IC peak times. Conclusions: Our results show that oral caffeine intake increases the inner electro-retinal activity in young adults when viewing stimuli of high- (95%) to medium-contrast (50%). Given the increasing evidence that the inner retinal function is involved in the emmetropization process, these results may suggest that caffeine or its derivatives could potentially play a role in the mechanisms involved in eye growth.

No Effects of Carbohydrate Ingestion on Muscle Metabolism or Performance During Short-Duration High-Intensity Intermittent Exercise.

Carbohydrates are critical for high-intensity exercise performance. However, the effects of carbohydrate supplementation on muscle metabolism and performance during short-duration high-intensity intermittent exercise remain inadequately explored. Our aim was to address this aspect in a randomized, counterbalanced, double-blinded crossover design. Eleven moderately-to-well-trained males performed high-intensity intermittent cycling receiving carbohydrate (CHO, ~55 g/h) or placebo (PLA) fluid supplementation. Three exercise periods (EX1-EX3) were completed comprising 10 × 45 s at ~105% Wmax interspersed with 135 s rest between bouts and ~20 min between periods. Repeated sprint ability (5 × 6 s sprints with 24 s recovery) was assessed at baseline and after each period. Thigh muscle biopsies were obtained at baseline and before and after EX3 to determine whole-muscle and fiber-type-specific glycogen depletion. No differences were found in muscle glycogen degradation at the whole-muscle (p = 0.683) or fiber-type-specific level (p = 0.763-0.854) with similar post-exercise whole-muscle glycogen concentrations (146 ± 20 and 122 ± 15 mmol·kg-1 dw in CHO and PLA, respectively). Repeated sprint ability declined by ~9% after EX3 with no between-condition differences (p = 0.971) and no overall differences in ratings of perceived exertion (p = 0.550). This was despite distinctions in blood glucose concentrations throughout exercise, reaching post-exercise levels of 5.3 ± 0.2 and 4.1 ± 0.2 mmol·L-1 (p < 0.001) in CHO and PLA, respectively, accompanied by fivefold higher plasma insulin levels in CHO (p < 0.001). In conclusion, we observed no effects of carbohydrate ingestion on net muscle glycogen breakdown or sprint performance during short-duration high-intensity intermittent exercise despite elevated blood glucose and insulin levels. These results therefore question the efficacy of carbohydrate supplementation strategies in high-intensity intermittent sports.

New compact micro-hole zone catheter enables women to achieve effective bladder emptying without flow-stops.

BACKGROUND: Clean intermittent self-catheterisation (CISC) with conventional eyelet catheters (CECs) is associated with urine flow-stops, which require the catheter to be repositioned so flow can resume. Flow-stops often occur because bladder mucosa is sucked into the eyelets. AIMS: This investigation aimed to compare the bladder-emptying performance of the micro-hole zone catheter (MHZC) with the CEC. METHODS: This was a multi-centre, randomised, open-label, controlled cross-over study with 82 women comparing the MHZC to the CEC. The endpoints relating to bladder-emptying performance included the residual volume at first flow-stop, the number of flow-stops and the proportion of successful treatment responses. The women's perception of the catheters was assessed as well as device discomfort. FINDINGS: Catheterisations with MHZC significantly reduced the risk of flow-stops, with relative risk results showing a 2.74 times lower risk of flow-stops with a health professional-led catheterisation and a 2.52 times lower risk during self-catheterisation. There was no statistical difference in residual urine volume at first flow-stop between the two catheters. Catheterisations with the MHZC were significantly more likely to achieve zero flow-stops and a residual urine volume of <10 ml at first flow-stop. The women had a significantly more positive perception of the MHZC than the CEC in areas including handling, confidence, sensation and satisfaction. CONCLUSION: The MHZC enabled effective bladder emptying without catheters needing to be repositioned, supporting the women by simplifying the procedure and making them feel confident that their bladders were empty.

Perturbational complexity index in assessing responsiveness to rTMS treatment in patients with disorders of consciousness: a cross-over randomized controlled trial study.

BACKGROUND: Disorders of Consciousness (DoC) caused by severe brain injuries represent a challenging clinical entity, which is easy to misdiagnosis and lacks effective treatment options. Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive neuroelectric stimulation method that shows promise in improving consciousness for DoC, especially in minimally conscious state (MCS). However, there is little evidence of its effectiveness, especially in RCT studies. METHODS: Twenty MCS patients participated in a double-blind, randomized, crossover, sham-controlled clinical study to evaluate the safety and efficacy of rTMS for MCS. Subjects were randomized into two groups: one group received rTMS-active for 10 consecutive days (n = 10), and the other group received rTMS-sham for 10 consecutive days (n = 10). After a 10-day washout period, the two groups were crossed over and received the opposite treatment. the rTMS protocol consisted of 2,000 pulses per day in the left dorsolateral prefrontal cortex (L-DLPFC), sent at 10 Hz. The stimulation intensity was 90% of the resting motor threshold. Coma Recovery Scale Revised (CRS-R), the main evaluation index, was evaluated before and after each phase in a double-blind manner. Meanwhile RS-EEG and TMS-EEG data were acquired and relative alpha power (RAP), and perturbational complexity index based on state transitions (PCIst) were caculated. RESULTS: One-way ANOVA revealed significantly higher scores in rTMS-active treatment compared to rTMS-sham across various measures, including CRS-R total score, RAP, PCIst (all P < 0.05). Among the 20 MCS patients, 7 (35%) were identified as responders following rTMS treatment. Compared to rTMS-sham, responder scores for CRS-R, RAP, and PCIst (all P < 0.05) were significantly elevated after rTMS-active treatment. Conversely, there was no significant difference observed in non-responders. Furthermore, post-hoc analysis revealed that baseline PCIst was significantly higher in responders than non-responders. Upon a 6-month follow-up, CRS-R scores significantly increased in all 20 patients (P = 0.026). However, the responder group exhibited a more favorable prognosis compared to the non-responder group (P = 0.031). CONCLUSIONS: Applying 10 Hz rTMS to L-DLPFC significantly increased consciousness level in MCS patients. PCIst is a neurophysiological index that has the potential to evaluate and predict therapeutic efficacy. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , identifier: NCT05187000.

Mexiletine versus lamotrigine in non-dystrophic myotonias: a randomised, double-blind, head-to-head, crossover, non-inferiority, phase 3 trial.

BACKGROUND: Non-dystrophic myotonias are skeletal muscle channelopathies caused by ion channel dysfunction. Symptom onset is frequently in the first decade of life, causing disability in a young cohort. Although there is no cure, symptomatic treatments exist. Previous trials provide evidence of the efficacy of mexiletine. More recently, lamotrigine has been shown to be effective. Both treatments have different profiles, including pharmacokinetics and adverse events. This trial aimed to investigate whether lamotrigine is non-inferior to mexiletine to directly inform clinical practice. METHODS: We did a randomised, double-blind, crossover, non-inferiority, phase 3 trial at the National Hospital for Neurology and Neurosurgery (London, UK). Participants (aged ≥18 years) who had genetically confirmed symptomatic non-dystrophic myotonia were randomly assigned (1:1), by means of a block randomisation schedule created by a computer program, to receive either mexiletine for 8 weeks followed by lamotrigine for 8 weeks, or lamotrigine followed by mexiletine, with a 7-day washout period in between. Investigators and participants were masked to treatment allocation. The primary outcome measure was the mean interactive voice response (IVR) diary stiffness score (0-9 scale) over the participant's final 2 weeks of diary reporting in each treatment period. Non-inferiority was assessed using a mixed-effects model with a predefined margin of 0·5 and included all randomly assigned participants who contributed at least 7 days of IVR-diary data in either treatment period. The trial is registered at ClinicalTrials.gov, NCT05017155, and EudraCT, 2020-003375-17. FINDINGS: Between Aug 1, 2021, and Dec 12, 2022, of 60 participants were screened (24 females and 36 males) and randomly assigned between Aug 1, 2021 and Dec 12, 2022, to either the mexiletine-lamotrigine sequence (n=30) or the lamotrigine-mexiletine sequence (n=30). 53 participants contributed data to the primary analysis. The mean IVR stiffness score after treatment with mexiletine was 2·54 (95% CI 1·98 to 3·10) versus 2·77 (2·21 to 3·32) with lamotrigine (mean mexiletine-lamotrigine difference -0·23 [95% CI -0·63 to 0·17]). The most common adverse event with both treatments was indigestion-reflux (eight participants, 208 participant-days receiving mexiletine; seven participants, 130 participant-days receiving lamotrigine). No serious adverse events were reported. INTERPRETATION: We were unable to conclude that lamotrigine is non-inferior to mexiletine; however, improvements in all outcome measures from baseline were similar between lamotrigine and mexiletine. Lamotrigine is an important treatment consideration in non-dystrophic myotonias alongside mexiletine; we propose a treatment algorithm to guide clinical practice. FUNDING: Neuromuscular Study Group, Jon Moulton Charity Trust, UCLH BRC Fast Track Grant.

Bioavailability of a novel sustained-release pellet formulation of 5-flucytosine in healthy-fed participants for use in patients with cryptococcal meningitis.

Cryptococcal meningoencephalitis (CM) is an opportunistic fungal infection and a major cause of death among people living with human immunodeficiency virus in sub-Saharan Africa. 5-flucytosine (5-FC) is a unique, brain-permeable antifungal agent used to reduce mortality from CM and to prevent disease in individuals carrying cryptococcal antigen. 5-FC has a short plasma half-life, requiring 6-hourly oral dosing with an immediate-release (IR) formulation, a significant challenge in hospital and outpatient settings, risking a lack of compliance. We recently reported the relative bioavailability in fasting conditions of a sustained release (SR) oral pellet formulation of 5-FC. In this phase I study, we assessed the safety and pharmacokinetic profiles of the new 5-FC SR formulation in a single dose (2 × 3000 mg), relative to 5-FC IR tablets (Ancotil®; 1500 mg b.i.d.) in healthy participants in fed conditions. This randomized, two-period crossover study was conducted in South Africa to confirm the dose of the identified 5-FC SR formulation for a twice-daily 5-FC regimen in patients. Thirty-six healthy participants were included. All treatments were well tolerated and no serious adverse event was reported. Cmax and AUC(0-t) for the SR formulation (49.2 ± 10.49 µg/mL and 640.4 ± 126.4 h.µg/mL, respectively) were significantly higher than for the IR formulation (36.8 ± 7.61 µg/mL and 456.6 ± 72.8 h.µg/mL, respectively). A physiological based pharmacokinetic model (PBPK) predicted that under fasting conditions, 6000 mg SR pellets would show a good overlap with the IR product (3000 mg b.i.d), thus 6000 mg SR 5-FC b.i.d. in fasting conditions is recommended.

Cocos nucifera and glycerine afterwork moisturizers for secondary prevention of hand dermatitis among fabric worker: a randomized, double-blind, cross over trial.

The use of skin barrier-enhancing topical medication is a favorable approach for the treatment of occupational hand dermatitis (OHD). Cocos nucifera or coconut oil is one of the best sources of lipid enriched with laurate acid, and glycerin is a well-known humectant that improves skin hydration. This study is aimed is to evaluate the effectiveness of C. nucifera and glycerin for secondary prevention of OHD among batik (Indonesian traditional fabric) workers. In a randomized, double-blind, crossover trial, the effect of glycerine-C. nucifera cream versus glycerin-only was considered with multiple afterwork applications of moisturizer over a 2-week period on batik workers with OHD. Assessment of trans-epidermal water loss (TEWL), skin capacitance, and a clinical assessment using the Hand Eczema Severity Index (HECSI) were carried out at day 0 and 14. The results show thirty-two batik dyeing and/or rinsing workers were enrolled in the study with mild to moderate OHD. Clinical improvement was demonstrated by 20% decrease in HECSI and TEWL, and 20% increase in skin capacitance. Both moisturizers were equally effective for the secondary prevention of OHD. As a conclusion, glycerine-C. nucifera and glycerin-only cream are equally effective for secondary prevention for OHD among batik worker to reduce the prevalence of hand dermatitis.

Genetic Variance in Heparan Sulfation Is Associated With Salt Sensitivity.

BACKGROUND: High heritability of salt sensitivity suggests an essential role for genetics in the relationship between sodium intake and blood pressure (BP). The role of glycosaminoglycan genes, which are crucial for salinity tolerance, remains to be elucidated. METHODS: Interactions between 54 126 variants in 130 glycosaminoglycan genes and daily sodium excretion on BP were explored in 20 420 EPIC-Norfolk (European Prospective Investigation Into Cancer in Norfolk) subjects. The UK Biobank (n=414 132) and the multiethnic HELIUS study (Healthy Life in an Urban Setting; n=2239) were used for validation. Afterward, the urinary glycosaminoglycan composition was studied in HELIUS participants (n=57) stratified by genotype and upon dietary sodium loading in a time-controlled crossover intervention study (n=12). RESULTS: rs2892799 in NDST3 (heparan sulfate N-deacetylase/N-sulfotransferase 3) showed the strongest interaction with sodium on mean arterial pressure (false discovery rate 0.03), with higher mean arterial pressure for the C allele in high sodium conditions. Also, rs9654628 in HS3ST5 (heparan sulfate-glucosamine 3-sulfotransferase 5) showed an interaction with sodium on systolic BP (false discovery rate 0.03). These interactions were multiethnically validated. Stratifying for the rs2892799 genotype showed higher urinary expression of N-sulfated heparan sulfate epitope D0S0 for the T allele. Conversely, upon dietary sodium loading, urinary D0S0 expression was higher in participants with stable BP after sodium loading, and sodium-induced effects on this epitope were opposite in individuals with and without BP response to sodium. CONCLUSIONS: The C allele of rs2892799 in NDST3 exhibits higher BP in high sodium conditions when compared with low sodium conditions, whereas no differences were detected for the T allele. Concomitantly, both alleles demonstrate distinct expressions of D0S0, which, in turn, correlates with sodium-mediated BP elevation. These findings underscore the potential significance of genetic glycosaminoglycan variation in human BP regulation.

Exposure to acute ambient temperature extremes and neonatal intensive care unit admissions: A case-crossover study.

BACKGROUND: Extreme in utero temperatures have been associated with adverse birth outcomes, including preterm birth and low birthweight. However, there is limited evidence on associations with neonatal intensive care unit (NICU) admissions, which reflect a range of poor neonatal health outcomes. METHODS: This case-crossover study assesses the associations between ambient temperature changes during the week of delivery and risk of NICU admission. Data from the Consortium on Safe Labor (2002-2008) were linked to ambient temperature at hospital referral regions. Adjusted hazard ratios (HR) and 95 % confidence intervals (CI) estimated NICU admission risk with a 1 °C increase on each day of the week of delivery and of the average weekly temperature, adjusted for particulate matter ≤2.5 µm (PM2.5) and relative humidity. We also estimated associations with 1 °C increases and 1 °C decreases in temperatures during weeks of site-specific extreme heat (>90th and 95th percentiles) and cold (<5th and 10th percentiles), respectively. RESULTS: There were 27,188 NICU admissions with median (25th, 75th) temperature of 16.4 °C (5.8, 23.0) during the week before delivery. A 1 °C increase in temperature during the week of delivery was not associated with risk of NICU admission. However, analyses of extreme temperatures found that a 1 °C decrease in weekly average temperatures below the 10th and 5th percentiles was associated with 30 % (aHR = 1.30, 95 % CI 1.28, 1.31) and 47 % (aHR = 1.47, 95 % CI 1.45, 1.50) increased risk of NICU admissions, while a 1 °C increase in weekly average temperatures above the 90th and 95th percentiles was associated with more than two- (aHR = 2.29, 95 % CI 2.17, 2.42) and four-fold (aHR = 4.30, 95 % CI 3.68, 5.03) higher risk of NICU admission, respectively. CONCLUSIONS: Our study found temperature extremes in the week before delivery increased NICU admission risk, particularly during extreme heat, which may translate to more adverse neonatal outcomes as extreme temperatures persist.