The OCT2/MATE1 Interaction Between Trifluridine, Metformin and Cimetidine: A Crossover Pharmacokinetic Study.

BACKGROUND AND OBJECTIVES: Trifluridine/tipiracil, registered for the treatment of patients with metastatic gastric and colorectal cancer, is a substrate and inhibitor for the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1), which raises the potential for drug-drug interactions with other OCT2/MATE1 modulators. Therefore, we prospectively examined the effect of an OCT2/MATE1 inhibitor (cimetidine) and substrate (metformin) on the pharmacokinetics of trifluridine. METHODS: In this three-phase crossover study, patients with metastatic colorectal or gastric cancer were sequentially treated with trifluridine/tipiracil alone (phase A), trifluridine/tipiracil concomitant with metformin (phase B) and trifluridine/tipiracil concomitant with cimetidine (phase C). The primary endpoint was the relative difference in exposure of trifluridine assessed by the area under the curve from timepoint zero to infinity. A > 30% change in exposure was considered clinically relevant. A p-value of < 0.025 was considered significant because of a Bonferroni correction. RESULTS: Eighteen patients were included in the analysis. Metformin did not significantly alter the exposure to trifluridine (- 12.6%; 97.5% confidence interval - 25.0, 1.8; p = 0.045). Cimetidine did alter the exposure to trifluridine significantly (+ 18.0%; 97.5% confidence interval 4.5, 33.3; p = 0.004), but this increase did not meet our threshold for clinical relevance. Metformin trough concentrations were not influenced by trifluridine/tipiracil. CONCLUSIONS: Our result suggests that the OCT2/MATE1 modulators cimetidine and metformin can be co-administered with trifluridine/tipiracil without clinically relevant effects on drug exposure. CLINICAL TRIAL REGISTRATION: NL8067 (registered 04-10-2019).

Translation of culturally and contextually informed diabetes training for Aboriginal primary health care providers on Aboriginal client outcomes: Protocol of a cluster randomized crossover trial of effectiveness.

BACKGROUND: Indigenous populations globally have significantly high rates of type 2 diabetes compared to their non-Indigenous counterparts. This study aims to implement and evaluate the effectiveness of a culturally and contextually informed Aboriginal Diabetes Workforce Training Program on Aboriginal primary health care workforce knowledge, attitude, confidence, skill and practice relating to diabetes care. METHODS: A Cluster Randomised Crossover Control Trial with two arms (Group A and Group B) will be conducted with Aboriginal primary health care services in South Australia. These services primarily provide primary health care to Aboriginal and Torres Strait Islander people. All healthcare service sites will be randomised into groups A and B to receive the training program. The training program consists of three components: 1) Peer support network, 2) E-Learning modules and 3) onsite support. Aboriginal Health Workers of participating sites will be invited to participate in the monthly online peer support network and all chronic disease staff are eligible to participate in the E-Learning modules and onsite support. The Peer Support Network runs for the entirety of the study, 17 months. Training components 2 and 3 occur simultaneously and are 2.5 months in length, with a six-month washout period between the two randomised groups undertaking the training. All primary outcomes of the study relate to diabetes management in a primary health care settings and measure participants' knowledge, attitude, confidence, practice and skills. These will be collected at seven time points across the entire study. Secondary outcomes measure satisfaction of the peer support network using a survey, interviews to understand enablers and barriers to participation, health service systems characteristics through focus groups, and medical record review to ascertain diabetes patients' care received and their clinical outcomes up to 12 months post training intervention. DISCUSSION: The findings will explore the effectiveness of the training program on Aboriginal primary health care provider knowledge, attitude, confidence, skill and practice relating to diabetes care. The final findings will be published in 2027. TRIAL REGISTRATION: The study was prospectively registered in The Australian New Zealand Clinical Trials Registry (ANZCTR), with registration number ACTRN12623000749606 at ANZCTR - Registration. Universal Trial Number (UTN) U1111-1283-5257.

Bioequivalence study of low dose drospirenone/ethinyl estradiol 3 mg/0.03 mg film tablets under fasting conditions in Turkish healthy female subjects.

This bioequivalence research aims to evaluate the relative bioavailability and pharmacokinetic characteristics of ethinyl estradiol and drospirenone in the test preparation in comparison to the reference preparation during fasting conditions. A liquid chromatography method with tandem mass spectrometry was used to determine the concentrations of drospirenone and ethinyl estradiol in plasma. The pharmacokinetic parameters that were analyzed were the maximum plasma concentration (Cmax), time to achieve Cmax (tmax), elimination half life, and area under the concentration time curve of plasma (AUC0-t, AUC0-∞ for ethinyl estradiol, and AUC0-72h for drospirenone). Both the AUC and Cmax parameters were determined to be between 80.00% and 125.00% (90% confidence intervals), which is the acceptable range. Based on the study findings, it was concluded that the test formulation, which includes 3 mg of drospirenone and 0.03 mg of ethinyl estradiol, demonstrated bioequivalence when compared to the reference formulation.

Evaluation of plaque removal by a single-headed versus a triple-headed manual toothbrush using different plaque assessment tools.

Background: Dental plaque is a common issue that can be effectively managed with proper oral hygiene practices and regular oral health care. The aim of this crossover study was to assess dental plaque using different methods (digital and clinical plaque scores) and evaluate the effectiveness of toothbrushing with a triple-headed manual toothbrush compared to a single-headed manual toothbrush in removing dental plaque. Methods: Plaque staining was performed to assess dental plaque amounts before and after brushing with the triple-headed (test) and single-headed (control) manual toothbrush in 21 study participants after plaque was allowed to accumulate for 48 hours. Dental plaque was scored both clinically as well as digitally. Results: Toothbrushing with a manual single-headed toothbrush and a triple-headed toothbrush was found to be equally effective when comparing plaque removal ability. Brushing time was shorter when using a triple-headed toothbrush, compared to a single-headed toothbrush. Conclusion: The triple-headed manual toothbrush may be a good alternative to the single-headed manual toothbrush for certain patient groups.

Contexte: La plaque dentaire est un problème courant qui peut être géré efficacement en adoptant de bonnes pratiques d'hygiène buccale et en obtenant régulièrement des soins buccodentaires. L'objectif de cette étude croisée était d'évaluer l'état de la plaque dentaire à l'aide de différentes méthodes (cotes de plaque numériques et cliniques) et d'évaluer l'efficacité du brossage à l'aide d'une brosse à dents manuelle à 3 côtés comparativement au brossage avec une brosse à dents manuelle à 1 côté pour éliminer la plaque dentaire. Méthodes: On a coloré la plaque dentaire pour en évaluer la quantité avant et après le brossage avec une brosse à dents manuelle à 3 côtés (essai) et à 1 côté (contrôle) parmi les 21 participants à l'étude après avoir laissé la plaque s'accumuler pendant 48 heures. On a attribué une cote clinique et numérique à la plaque dentaire. Résultats: Le brossage avec une brosse à dents manuelle à 3 côtés s'est révélé tout aussi efficace que le brossage avec une brosse manuelle à 1 côté sur le plan de l'élimination de la plaque. Le temps de brossage était plus court avec une brosse à dents à 3 côtés qu'avec une brosse à dents à 1 côté. Conclusion: Pour certains groupes de patients, la brosse à dents à 3 côtés peut être une bonne alternative à la brosse à dents ordinaire.

Pharmacokinetics of isavuconazonium sulfate and its active metabolite isavuconazole in healthy dogs.

Invasive fungal infections (IFIs) are growing in importance in veterinary and human medicine. IFIs such as aspergillosis, blastomycosis, coccidioidomycosis and histoplasmosis remain challenging to treat in dogs. Isavuconazole is a novel antifungal medication that, when compared to currently used azoles, has an expanded spectrum of antifungal activity Rudramurthy (2011), Pfaller (2013), Spec (2018), has more predictable pharmacokinetics in humans Desai (2016), Cojutti (2021) and may cause fewer side effects such as liver and renal toxicity Maertens (2016), DiPippo (2018). The pharmacokinetic profile and safety of isavuconazole in dogs has not yet been characterized. The purpose of this study was to evaluate the pharmacokinetics of isavuconazole in healthy dogs that received a single dose of the prodrug isavuconazonium sulfate. Using full crossover design, six healthy beagle dogs received isavuconazonium sulfate at a mean (+/- SD) dose of 20.6 (+/- 2.8) mg/kg orally and 21.8 (+/- 4.2) mg/kg intravenously. Plasma was collected for batched pharmacokinetic analysis of prodrug and metabolite, isavuconazole, by ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The median (Q1-Q3) maximum isavuconazole peak plasma concentration was estimated at 3,876.5 (2,811.0-4,800.0) ng/mL following oral administration, with a median (Q1-Q3) peak level at 1.3 (1.0-2.0) hours. Following intravenous administration, the median (Q1-Q3) isavuconazole peak plasma concentration was estimated at 3,221.5 (2,241.5-3,609.0) ng/mL, with a median (Q1-Q3) peak level at 0.4 (0.3-0.6) hours. The median (Q1-Q3) half-life of isavuconazole was 9.4 (7.0-12.2) hours and 14.0 (8.1-21.7) hours for oral and intravenous routes, respectively. One dog received inadvertent subcutaneous drug administration without any apparent adverse effects. Another dog experienced an anaphylactic reaction following accidental rapid drug infusion. No other drug-related adverse events were observed. At dosages used in this study, healthy dogs achieved isavuconazole plasma levels comparable to human therapeutic targets, and when properly administered the drug was well-tolerated.

Enhancing circulatory myokines and extracellular vesicle uptake with targeted exercise in patients with prostate cancer (the MYEX trial): a single-group crossover study.

INTRODUCTION: Physical activity is associated with improved disease progression and cancer-specific survival in patients with prostate cancer (PCa). However, the mechanisms underlying these associations remain unclear, while the relative impact of exercise modes is unknown. This study aims to examine the differential impact of exercise mode on tumour-suppressive skeletal muscle-associated systemic molecules as well as their delivery mechanism. This study will compare the effects of the two main exercise modes, aerobic and resistance, on (1) circulatory myokine levels, (2) skeletal muscle-induced extracellular vesicle abundance and cargo contents, and (3) uptake of extracellular vesicles (EVs) in PCa cells in patients with localised or advanced PCa. METHODS: A single-group cross-over design will be used for patients at opposite ends of the disease spectrum. A total of 32 patients (localised PCa, n = 16; metastatic castrate-resistant PCa, n = 16) will be recruited while capitalising on two ongoing studies. Ethics amendment has been approved for two ongoing trials to share data, implement the acute exercise sessions, and collect additional blood samples from patients. The patients will undertake two exercise sessions (aerobic only and resistance only) in random order one week apart. Blood will be collected before, after, and 30 min post-exercise. Circulating/EV-contained myokine levels (irisin, IL-6, IL-15, FGF-21, and SPARC) and plasma skeletal muscle-induced EVs will be measured using ELISA and flow cytometry. PCa cell line growth with or without collected plasma will be examined using PCa cell lines (LNCaP, DU-145, and PC-3), while evaluating cellular uptake of EVs. Ethics amendments have been approved for two capitalising studies to share data, implement acute exercise sessions and collect additional samples from the patients. DISCUSSION: If findings show a differential impact of exercise mode on the establishment of an anti-cancer systemic environment, this will provide fundamental knowledge for developing targeted exercise prescriptions for patients with PCa across different disease stages. Findings will be reported in peer-reviewed publications and scientific conferences, in addition to working with national support groups to translate findings for the broader community. TRIAL REGISTRATION: The registration for the two capitalising studies are NCT02730338 and ACTRN12618000225213.

Effects of a mattress cover with special airflow technology on the structure and function of the sacral and heel skin during loading: A two-arm exploratory crossover trial.

Prolonged mechanical loading of the skin and underlying soft tissue cause pressure ulceration. The use of special support surfaces are key interventions in pressure ulcer prevention. They modify the degree and duration of soft tissue deformation and have an impact on the skin microclimate. The objective of this randomized cross-over trial was to compare skin responses and comfort after lying for 2.5 h supine on a support surface with and without a coverlet that was intended to assist with heat and moisture removal at the patient/surface interface. In addition, physiological saline solution was administered to simulate an incontinence episode on the mattress next to the participants' skin surface. In total, 12 volunteers (mean age 69 years) with diabetes mellitus participated. After loading, skin surface temperature, stratum corneum hydration and skin surface pH increased, whereas erythema and structural stiffness decreased at the sacral area. At the heel skin area, temperature, erythema, and stratum corneum hydration increased. These results indicate occlusion and soft tissue deformation which was aggravated by the saline solution. The differences in skin response showed only minor differences between the support surface with or without the coverlet.

Cardiac Cine MRI Using a Commercially Available 0.55-T Scanner.

Purpose To compare parameters of left ventricular (LV) and right ventricular (RV) volume and function between a commercially available 0.55-T low-field-strength cardiac cine MRI scanner and a 1.5-T scanner. Materials and Methods In this prospective study, healthy volunteers (May 2022 to July 2022) underwent same-day cine imaging using both scanners (0.55 T, 1.5 T). Volumetric and functional parameters were assessed by two experts. After analyzing the results of a blinded crossover reader study of the healthy volunteers, 20 participants with clinically indicated cardiac MRI were prospectively included (November 2022 to February 2023). In a second blinded expert reading, parameters from clinical 1.5-T scans in these participants were compared with those same-day 0.55-T scans. Results are displayed as Bland-Altman plots. Results Eleven healthy volunteers (mean age: 33 years [95% CI: 27, 40]; four of 11 [36%] female, seven of 11 [64%] male) were included. Very strong mean correlation was observed (r = 0.98 [95% CI: 0.97, 0.98]). Average deviation between MRI systems was 1.6% (95% CI: 0.3, 2.9) for both readers. Twenty participants with clinically indicated cardiac MRI were included (mean age: 55 years [95% CI: 48, 62], six of 20 [30%] female, 14 of 20 [70%] male). Mean correlation was very strong (r = 0.98 [95% CI: 0.97, 0.98]). LV and RV parameters demonstrated an average deviation of 1.1% (95% CI: 0.1, 2.1) between MRI systems. Conclusion Cardiac cine MRI at 0.55 T yielded comparable results for quantitative biventricular volumetric and functional parameters compared with routine imaging at 1.5 T, if acquisition time is doubled. Keywords: Cardiac, Comparative Studies, Heart, Cardiovascular MRI, Cine, Myocardium Supplemental material is available for this article. ©RSNA, 2024.

Evaluation of the Effects of Punica granatum Flower Tablets on Pain and Healing of Minor Recurrent Aphthous Stomatitis: A Randomized Clinical Trial.

OBJECTIVES: The purpose of this study was to determine the therapeutic effect of the Punica granatum (PG) flower on recurrent aphthous stomatitis in comparison with corticosteroid therapy. MATERIALS AND METHODS: This cross-over randomized clinical trial was conducted on the patients who had been referred to Shiraz Dental School for their RAS in 2021. All the participants used both P. granatum flower tablets and Triadent a month apart for wash-out time and all compared themselves. In the experimental group, 30 patients received pomegranate flower tablets, three tablets daily, for 6 days. In the control group, oral paste Triadent has been prescribed three times a day for 6 days. The visual analog scale (VAS) and the size of RAS were evaluated on Days 0-6. Data were analyzed by SPSS version 21. The Wilcoxon test was used. RESULTS: The mean age of participants was 27.8 ± 14.77 years old. In this study, 15 patients (50%) were men and 15 patients (50%) were women. The mean value of VAS after using prescribed treatment in both evaluated groups on all days was significantly different such that the VAS values were lower for PG flower tablets than Triadent (p value < 0.05). The size of oral lesions in participants who used PG flower tablets was significantly less than those who used Triadent on all evaluation days (p value < 0.05) except on Day 1 (p value = 0.29). The descending slope of VAS from Days 1 to 6 for both Triadent and PG flower tablet users was significant and noticeable. (p value < 0.05). CONCLUSION: According to the result of this study, both P. granatum flower tablet and Triadent are useful in reducing the size, period of healing, and VAS of patients with RAS, but the PG flower tablet is more effective.

Performance and safety of the PRICO closed-loop oxygen saturation targeting system in neonates: pragmatic multicentre cross-over study (TarOx Study).

OBJECTIVE: This study aims to evaluate the performance of the fabian-Predictive-Intelligent-Control-of-Oxygenation (PRICO) system for automated control of the fraction of inspired oxygen (FiO2). DESIGN: Multicentre randomised cross-over study. SETTING: Five neonatal intensive care units experienced with automated control of FiO2 and the fabian ventilator. PATIENTS: 39 infants: median gestational age of 27 weeks (IQR: 26-30), postnatal age 7 days (IQR: 2-17), weight 1120 g (IQR: 915-1588), FiO2 0.32 (IQR: 0.22-0.43) receiving both non-invasive (27) and invasive (12) respiratory support. INTERVENTION: Randomised sequential 24-hour periods of automated and manual FiO2 control. MAIN OUTCOME MEASURES: Proportion (%) of time in normoxaemia (90%-95% with FiO2>0.21 and 90%-100% when FiO2=0.21) was the primary endpoint. Secondary endpoints were severe hypoxaemia (<80%) and severe hyperoxaemia (>98% with FiO2>0.21) and prevalence of episodes ≥60 s at these two SpO2 extremes. RESULTS: During automated control, subjects spent more time in normoxaemia (74%±22% vs 51%±22%, p<0.001) with less time above and below (<90% (9%±8% vs 12%±11%, p<0.001) and >95% with FiO2>0.21 (16%±19% vs 35%±24%) p<0.001). They spent less time in severe hyperoxaemia (1% (0%-3.5%) vs 5% (1%-10%), p<0.001) but exposure to severe hypoxaemia was low in both arms and not different. The differences in prolonged episodes of SpO2 were consistent with the times at extremes. CONCLUSIONS: This study demonstrates the ability of the PRICO automated oxygen control algorithm to improve the maintenance of SpO2 in normoxaemia and to avoid hyperoxaemia without increasing hypoxaemia.

Pharmacokinetics and Safety of Estradiol Valerate Tablet and Its Generic: A Phase 1 Bioequivalence Study in Healthy Chinese Postmenopausal Female Subjects.

Purpose: Estradiol valerate (Progynova®) is used as hormone therapy to supplement estrogen deficiency. This study aimed to assess the bioequivalence of an estradiol valerate tablet and its generic form, under fasting and fed conditions. Methods: A randomized, open-label, single-dose, 2-period crossover study was conducted on healthy postmenopausal Chinese female volunteers under fasting and fed conditions. For each period, the subjects received either a 1 mg tablet of estradiol valerate or its generic. Blood samples were collected before dosing and up to 72 hours after administration. Plasma levels of total estrone, estradiol, and unconjugated estrone were quantified using a validated liquid chromatography-tandem mass spectrometry method. Results: A total of 54 volunteers were enrolled in this study. The primary pharmacokinetic parameters, including Cmax, AUC0-t, and AUC0-∞, were similar for the two drugs under both fasting and fed conditions, with 90% confidence intervals for the geometric mean ratios of these parameters, all meeting the bioequivalence criterion of 80-125%. A total of 48 adverse events (AEs) were reported in the fed study compared with 24 AEs in the fasting study. Conclusion: Estradiol valerate and its generic form were bioequivalent and well tolerated under both fasting and fed conditions.

Kavalactones support motivation to move during intensive training in males preparing for military special operations forces.

BACKGROUND: Military special operators, elite athletes, and others requiring uninterrupted optimal performance currently lack options for sleep and mood support without performance-inhibiting effects. Kavalactones, derived from the root of the kava plant (Piper methysticum Forst), have been shown to elevate mood and wellbeing by producing a feeling of relaxation without addiction or cognitive impairment. METHODS: In this placebo-controlled, crossover study (NCT05381025), we investigated the effects of 2 weeks of kavalactones use on cortisol (diurnal salivary), sleep (RSQ-W; Restorative Sleep Questionnaire, Weekly), mood (DASS-21; Depression Anxiety Stress Scale-21), and motivation state to expend (Move) or conserve (Rest) energy (CRAVE; Cravings for Rest and Volitional Energy Expenditure, Right Now) in a cohort of 15 healthy, physically fit young males engaged in a rigorous, two-a-day preparation class for special operations forces qualification. RESULTS: Cortisol, sleep, and mood were within normal, healthy parameters in this cohort at baseline. This remained unchanged with kavalactones use with no significant findings of clinical interest. However, a statistically similar, positive slope for within-group Move scores was seen in both groups during kavalactones loading (first group Move slope 2.25, second group Move slope 3.29, p = 0.299). This trend was seen regardless of order and with no apparent effects on the Rest metric (all p ≥ 0.05). Moreover, a significant between-group difference appeared after 1 week of kavalactones use in the first phase (p = 0.044) and persisted through the end of the first loading period (p = 0.022). Following the 10-day washout, this between-groups divergence remained significant (p = 0.038) but was reversed by 1 week after the crossover (p = 0.072), with Move scores once again statistically similar between groups and compared to baseline at study end. Furthermore, the group taking kavalactones first never experienced a significant decrease in Move motivation state (lowest mean score 21.0, highest 28.6, all p ≥ 0.05), while the group receiving kavalactones in the last 2 weeks of the study had Move scores that were statistically lower than baseline (lowest mean score 8.6, highest 25.9, all p ≤ 0.05) at all time points but the last (p = 0.063) after 2 weeks of kavalactones exposure. CONCLUSIONS: We report a novel finding that kavalactones may support performance by maintaining or rescuing the desire to expend energy in the context of significant physical and mental strain in well-conditioned individuals, even in a context of already normal cortisol, sleep, and mood.

Investigating the Bioavailability and Insulin-like Growth Factor-I Release of Two Different Strengths of Somapacitan: A Randomised, Double-Blind Crossover Trial.

STUDY DESIGN AND OBJECTIVE: Randomised, double-blind, crossover trial to confirm bioequivalence of somapacitan, a long-acting growth hormone (GH), in 5 mg/1.5 mL and 10 mg/1.5 mL strengths in equimolar doses. METHODS: Healthy participants were randomised (1:1:1) to subcutaneous somapacitan treatment in one dosing period with 5 mg/1.5 mL and two periods with 10 mg/1.5 mL. Eligibility criteria included age 18-45 years and body mass index 18.5-24.9 kg/m2. Exclusion criteria included history of GH deficiency, previous GH treatment, weight > 100.0 kg and participation in any clinical trial of an investigational medicinal product within 45 days or five times the half-life of the previous investigational product before screening. Area under the curve from time 0 until last quantifiable observation (AUC0-t), maximum serum concentration (Cmax), time to Cmax and terminal half-life of somapacitan and safety were assessed. RESULTS: In total, 33 participants were randomised. For AUC0-t, estimated treatment ratio (ETR) (5 mg/1.5 mL versus 10 mg/1.5 mL) was 0.95 (90% confidence interval [CI] 0.89-1.01). Point estimate and 90% CIs were within the acceptance range (0.80-1.25). For Cmax, ETR was 0.77 (90% CI 0.68-0.89). Point estimate and 90% CIs were outside the acceptance range (0.80-1.25). Mean insulin-like growth factor-I (IGF-I) and IGF-I standard deviation score concentration-time curves for each strength were almost identical. No new safety issues were identified. CONCLUSIONS: Bioequivalence criterion for somapacitan 5 mg/1.5 mL and 10 mg/1.5 mL was met for AUC0-t but not for Cmax. The two strengths had equivalent IGF-I responses. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03905850 (3 April 2019).

Somapacitan is a long-acting growth hormone used to treat people with growth hormone deficiency. Somapacitan is injected under the skin with an injection pen. The dose is based on a person's body weight and how they respond to treatment. We compared two strengths of injection pen, containing either 5 or 10 mg of somapacitan per 1.5 mL. For both strengths, participants were given the same dose. We wanted to understand whether the body absorbs these different strengths into the bloodstream in the same way. We also measured levels of insulin-like growth factor-I (IGF-I), a hormone formed when growth hormone is present in the blood, to see the effect of different strengths of somapacitan on the body. In our study, 33 healthy adults received one round of injection using the somapacitan 5 mg pen and two rounds using the somapacitan 10 mg pen, all at least 3 weeks apart. We found no differences in the amount of somapacitan being absorbed into the bloodstream, nor how fast it was absorbed. The peak amount of somapacitan in the bloodstream was higher in people using the 10 mg pen. There were no differences in IGF-I levels following use of either injection pen. Overall, our results show both strengths of somapacitan lead to similar responses in the body. Having different strength options could allow doctors to adjust the dose of somapacitan more easily, depending on a patient's response to treatment.

Distal Ventricular Pacing for Drug-Refractory Mid-Cavity Obstructive Hypertrophic Cardiomyopathy: A Randomized, Placebo-Controlled Trial of Personalized Pacing.

BACKGROUND: Patients with refractory, symptomatic left ventricular (LV) mid-cavity obstructive (LVMCO) hypertrophic cardiomyopathy have few therapeutic options. Right ventricular pacing is associated with modest hemodynamic and symptomatic improvement, and LV pacing pilot data suggest therapeutic potential. We hypothesized that site-specific pacing would reduce LVMCO gradients and improve symptoms. METHODS: Patients with symptomatic-drug-refractory LVMCO were recruited for a randomized, blinded trial of personalized prescription of pacing (PPoP). Multiple LV and apical right ventricular pacing sites were assessed during an invasive hemodynamic study of multisite pacing. Patient-specific pacing-site and atrioventricular delays, defining PPoP, were selected on the basis of LVMCO gradient reduction and acceptable pacing parameters. Patients were randomized to 6 months of active PPoP or backup pacing in a crossover design. The primary outcome examined invasive gradient change with best-site pacing. Secondary outcomes assessed quality of life and exercise following randomization to PPoP. RESULTS: A total of 17 patients were recruited; 16 of whom met primary end points. Baseline New York Heart Association was 3±0.6, despite optimal medical therapy. Hemodynamic effects were assessed during pacing at the right ventricular apex and at a mean of 8 LV sites. The gradients in all 16 patients fell with pacing, with maximum gradient reduction achieved via LV pacing in 14 (88%) patients and right ventricular apex in 2. The mean baseline gradient of 80±29 mm Hg fell to 31±21 mm Hg with best-site pacing, a 60% reduction (P<0.0001). One cardiac vein perforation occurred in 1 case, and 15 subjects entered crossover; 2 withdrawals occurred during crossover. Of the 13 completing crossover, 9 (69%) chose active pacing in PPoP configuration as preferred setting. PPoP was associated with improved 6-minute walking test performance (328.5±99.9 versus 285.8±105.5 m; P=0.018); other outcome measures also indicated benefit with PPoP. CONCLUSIONS: In a randomized placebo-controlled trial, PPoP reduces obstruction and improves exercise performance in severely symptomatic patients with LVMCO. REGISTRATION: URL: https://clinicaltrials.gov/study; Unique Identifier: NCT03450252.

Effectiveness and satisfaction with virtual and donor dissections: A randomized controlled trial.

In recent years, human anatomy education has faced challenges with traditional donor dissection, leading to the emergence of virtual dissection as an alternative. This study aims to investigate the academic performance and satisfaction of medical students by comparing the virtual and donor dissections. An open-labeled crossover randomized controlled trial was conducted with 154 first-year medical students in Human Anatomy and Neuroanatomy laboratories, which were divided into three classes. Students were randomly assigned to either the virtual (virtual dissection followed by donor dissection) or donor (donor dissection followed by virtual dissection) groups in each class. A curriculum, incorporating head-mounted displays (HMDs), a life-sized touchscreen, and tablets, was developed. Data was evaluated through quizzes and surveys. In the Human Anatomy laboratory, each class of the donor group conducted heart extraction, dissection and observation. In observation class, the virtual group had a significantly higher mean quiz score than the donor group (p < 0.05). Compared to the donor, satisfaction was significantly higher for the HMD (understanding of concept and immersion), life-size touchscreen (esthetics, understanding of the concept, and spatial ability), and tablet (esthetics, understanding of the concept, spatial ability, and continuous use intention). In the Neuroanatomy laboratory, the virtual group showed significantly higher mean quiz scores than the donor group (p < 0.05), and tablet showed a significantly higher satisfaction than donor in terms of esthetics, understanding of the concept, and spatial ability. These results suggest that virtual dissection has the potential to supplement or replace donor dissection in anatomy education. This study is innovative in that it successfully delivered scenario-based virtual content and validated the efficacy in academic performance and satisfaction when using virtual devices compared to donor.Trial registration: This research has been registered in the Clinical Research Information Service (CRIS, https://cris.nih.go.kr/cris/search/detailSearch.do?search_lang=E&focus=reset_12&search_page=L&pageSize=10&page=undefined&seq=26002&status=5&seq_group=26002 ) with registration number "KCT0009075" and registration date "27/12/2023".

What the Fika? Implementation of Swedish Coffee Breaks During Emergency Medicine Conference.

Introduction: In this study we aimed to investigate the effects of incorporating Swedish-style fika (coffee) breaks into the didactic schedule of emergency medicine residents on their sleepiness levels during didactic sessions. Fika is a Swedish tradition that involves a deliberate decision to take a break during the workday and usually involves pastries and coffee. We used the Karolinska Sleepiness Scale to assess changes in sleepiness levels before and after the implementation of fika breaks. Methods: The study design involved a randomized crossover trial approach, with data collected from emergency medicine residents over a specific period. This approach was done to minimize confounding and to be statistically efficient. Results: Results revealed the average sleepiness scale was 4.6 and 5.5 on fika and control days, respectively (P = 0.004). Conclusion: Integration of fika breaks positively influenced sleepiness levels, thus potentially enhancing the educational experience during residency didactics.

Diagnosing Solid Lesions in the Pancreas With Multimodal Artificial Intelligence: A Randomized Crossover Trial.

Importance: Diagnosing solid lesions in the pancreas via endoscopic ultrasonographic (EUS) images is challenging. Artificial intelligence (AI) has the potential to help with such diagnosis, but existing AI models focus solely on a single modality. Objective: To advance the clinical diagnosis of solid lesions in the pancreas through developing a multimodal AI model integrating both clinical information and EUS images. Design, Setting, and Participants: In this randomized crossover trial conducted from January 1 to June 30, 2023, from 4 centers across China, 12 endoscopists of varying levels of expertise were randomly assigned to diagnose solid lesions in the pancreas with or without AI assistance. Endoscopic ultrasonographic images and clinical information of 439 patients from 1 institution who had solid lesions in the pancreas between January 1, 2014, and December 31, 2022, were collected to train and validate the joint-AI model, while 189 patients from 3 external institutions were used to evaluate the robustness and generalizability of the model. Intervention: Conventional or AI-assisted diagnosis of solid lesions in the pancreas. Main Outcomes and Measures: In the retrospective dataset, the performance of the joint-AI model was evaluated internally and externally. In the prospective dataset, diagnostic performance of the endoscopists with or without the AI assistance was compared. Results: The retrospective dataset included 628 patients (400 men [63.7%]; mean [SD] age, 57.7 [27.4] years) who underwent EUS procedures. A total of 130 patients (81 men [62.3%]; mean [SD] age, 58.4 [11.7] years) were prospectively recruited for the crossover trial. The area under the curve of the joint-AI model ranged from 0.996 (95% CI, 0.993-0.998) in the internal test dataset to 0.955 (95% CI, 0.940-0.968), 0.924 (95% CI, 0.888-0.955), and 0.976 (95% CI, 0.942-0.995) in the 3 external test datasets, respectively. The diagnostic accuracy of novice endoscopists was significantly enhanced with AI assistance (0.69 [95% CI, 0.61-0.76] vs 0.90 [95% CI, 0.83-0.94]; P < .001), and the supplementary interpretability information alleviated the skepticism of the experienced endoscopists. Conclusions and Relevance: In this randomized crossover trial of diagnosing solid lesions in the pancreas with or without AI assistance, the joint-AI model demonstrated positive human-AI interaction, which suggested its potential to facilitate a clinical diagnosis. Nevertheless, future randomized clinical trials are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT05476978.

Comparative study of optimal compression pressure between conventional Barton's dressing and prefabricate garment in parotidectomy patients.

Excessive compression after parotidectomy can lead to flap necrosis, while inadequate pressure can cause fluid accumulation. This study aimed to determine the optimal pressure and compression properties of different types of dressings. Initially, pressure measurements were taken for conventional Barton's dressing and a pre-fabricated facial garment. In the subsequent phase, patients were randomly assigned to receive one of three types of pressure dressings: conforming bandage Barton's dressing, elastic bandage Barton's dressing or pre-fabricated facial garment. The dressing types were randomly crossed over the following day. The mean pressure exerted by conventional Barton's dressing and the pre-fabricated facial garment was 15.86 and 14.81 mmHg, respectively. There was no significant difference in the proportion of optimal pressure among the three types of pressure dressing (p-values of 0.195, 0.555 and 0.089 at pre-auricular, angle of mandible and post-auricular sites, respectively). The pre-auricular area demonstrated the highest proportion of optimal pressure, while suboptimal pressure was noted at the angle of the mandible and post-auricular area. Dressing types had no effect on pressure stability (p = 0.37), and there was no significant difference in patient preference (p = 0.91). Conforming bandage Barton's dressing, elastic bandage Barton's dressing and pre-fabricated facial garment exhibit comparable compressive properties, with no significant difference in patient preference and pressure stability.

Effect of coffee intake on appetite parameters in woman with overweight or obesity: A pilot crossover randomized trial.

INTRODUCTION: Coffee consumption has demonstrated an effect on the regulation of appetite, causing less hunger and/or greater satiety; however, its effects are not well known in woman with overweight or obesity. Therefore, this study aimed to evaluate the effect of coffee consumption on hunger, satiety, sensory specific desire (SSD), and dietary intake in women with overweight or obesity. METHODOLOGY: A randomized crossover clinical trial was realized in 3 sessions: in the first session a clinical history, anthropometric measurements and body composition analysis were performed; in sessions 2 and 3 the participants randomly consumed 240mL of coffee with 6mg/caffeine/kg of weight or 240mL of water along with a standardized breakfast. At fasting and every 30min after breakfast for the next 3h, appetite sensations and SSD were recorded using visual analog scales. Blood samples were taken at fasting, 30 and 180min after breakfast. Dietary intake was recorded in the rest of the intervention days. RESULTS: In the coffee intervention there was an increased desire for sweet foods, higher fructose intake during the rest of the day, and higher triglyceride levels than with the water intervention. No differences were detected in ghrelin or cholecystokinin. CONCLUSIONS: Coffee consumption may lead to higher triglycerides and higher intake of simple sugars, mainly fructose, through changes in the SSD. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/NCT05774119.

The interactive walkway provides fit-for-purpose fall-risk biomarkers in the elderly: Comparison of zolpidem and suvorexant.

Dynamic balance assessments such as walking adaptability may yield a more realistic prediction of drug-induced falls compared with postural stability measurements, as falls often result from limited gait adjustments when walking. The Interactive Walkway (IWW) measures walking adaptability but sensitivity to medication effects is unknown. If proven sensitive and specific, IWW could serve as a biomarker for targeted fall-risk assessments in early clinical drug development. In this three-way crossover study, 18 healthy elderly (age: 65-80 years) subjects received 5 mg zolpidem, 10 mg suvorexant, or placebo in the morning. Assessments were performed pre-dose and approximately hourly until 9 h post-dose. IWW assessments included an 8-meter walking test, goal-directed stepping, obstacle-avoidance, and tandem-walking. Other pharmacodynamic measurements were the Timed-Up-and-Go (TUG) test at a comfortable and fast pace, adaptive tracking, and body sway. A decline in performance was observed for zolpidem compared with placebo for 3 h post-dose in IWW walking adaptability outcome measures, TUG, adaptive tracking, and body sway. For the IWW tasks, a decrease in walking speed (among others) was observed. IWW parameters were not affected by suvorexant compared with placebo at any timepoint. However, an increase of 9.8% (95%CI: 1.8%, 18.5%) in body sway was observed for suvorexant compared with placebo up to 3 h post-dose. The IWW successfully quantified drug effects of two hypnotic drugs and distinguished between zolpidem and suvorexant regarding their effects on walking. As a biomarker, the IWW demonstrated sensitivity in assessing dynamic balance and potential fall risk in early phase clinical drug development.