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.

Acupuncture for hot flashes in hormone receptor-positive breast cancer: A pooled analysis of individual patient data from parallel randomized trials.

BACKGROUND: Hot flashes are a common side effect of endocrine therapy (ET) that contribute to poor quality of life and decreased treatment adherence. METHODS: Patients with breast cancer wo were receiving ET and experiencing hot flashes were enrolled through three parallel, randomized trials conducted in the United States, China, and South Korea. Participants were randomized to either immediate acupuncture (IA) or delayed acupuncture control (DAC). IA participants received 20 acupuncture sessions over 10 weeks, whereas DAC participants received usual care, then crossed over to acupuncture with a reduced intensity. The primary end point was a change in score on the endocrine symptom subscale of the Functional Assessment of Cancer Therapy (FACT)-Endocrine Symptoms between baseline and week 10. Secondary end points included the hot flash score and the FACT-Breast score. A planned pooled analysis of individual patient data was performed using longitudinal mixed models. RESULTS: In total, 158 women with stage 0-III breast cancer were randomized (United States, n = 78; China, n = 40; South Korea, n = 40). At week 10, IA participants reported statistically significant improvements in the endocrine symptom subscale score (mean change ± standard error: 5.1 ± 0.9 vs. 0.2 ± 1.0; p = .0003), the hot flash score (-5.3 ± 0.9 vs. -1.4 ± 0.9; p < .003), and the FACT-Breast total score (8.0 ± 1.6 vs. -0.01 ± 1.6; p = .0005) compared with DAC participants. The effect of the acupuncture intervention differed by site (p = .005). CONCLUSIONS: Acupuncture led to statistically and clinically meaningful improvements in hot flashes, endocrine symptoms, and breast cancer-specific quality of life in women undergoing ET for breast cancer in the United States, China, and South Korea.

3D printing vs traditional workflow for the fabrication of mandibular implant overdentures: study protocol for a mixed-methods cross-over RCT.

BACKGROUND: Complete tooth loss is a significant global oral health issue, particularly impacting older individuals with lower socioeconomic status. Computer-assisted technologies enhance oral healthcare access by the elderly. Despite promising in vitro reports on digital denture materials, evidence from randomized clinical trials (RCTs) is lacking to verify their performance. This cross-over RCT will investigate whether 3D-printed implant-retained mandibular overdentures (IMO) are more satisfactory for edentulous seniors than those made through traditional methods. METHODS/DESIGN: We will recruit 26 completely edentulous participants (any sex/gender) based on the following eligibility criteria: age ≥ 60 years, no tooth extraction in the past 12 months, two implants in the lower jaw, and need for new dentures in both jaws. Each participant will receive two denture pairs, either manufactured by 3D printing or traditionally, to be worn in a random order. A timeline of 3 months with each denture pair will be considered for outcome assessment (total: 6 months). Patient satisfaction with dentures will be measured by the McGill Denture Satisfaction Questionnaire. We will evaluate other patient-reported outcomes (including oral health-related quality of life) as well as clinician-assessed quality and cost. At the end of the trial, participants will choose which denture pair they wish to keep and interviewed about their experiences with the 3D-printed IMO. The quantitative and qualitative data will be incorporated through an explanatory mixed-methods strategy. A final quantitative assessment will happen after 12 months with the preferred IMO to assess the long-term performance and maintenance needs. DISCUSSION: This mixed-methods RCT will explore patient experiences with 3D-printed IMOs, aiming to assess the potential for altering clinical practice and dental public health policies. Our results will inform policies by showing whether 3D printing offers comparable outcomes at lower costs, facilitating greater access to oral care for the elderly. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06155630, Registered on 04 December 2023. https://classic. CLINICALTRIALS: gov/ct2/show/NCT06155630.

Knowledge of cytology results affects the performance of colposcopy: a crossover study.

OBJECTIVE: To determine whether knowledge of cytology affects the colposcopist's diagnostic accuracy in the identification of cervical intraepithelial neoplasia grade 2 and worse (≥ CIN2). METHOD: In this cross-over study, healthcare professionals interpreted colposcopy images from 80 patient cases with known histological diagnoses. For each case, 2 images taken with a colposcope were provided (native and after acetic acid application). Inclusion criteria consisted of women with a transformation zone type 1 or 2, who had both a cytological and histological diagnosis. Cases were distributed across two online surveys, one including and one omitting the cytology. A wash-out period of six weeks between surveys was implemented. Colposcopists were asked to give their diagnosis for each case as < CIN2 or ≥ CIN2 on both assessments. Statistical analysis was conducted to compare the two interpretations. RESULTS: Knowledge of cytology significantly improved the sensitivity when interpreting colposcopic images, from 51.1% [95%CI: 39.3 to 62.8] to 63.7% [95%CI: 52.1 to 73.9] and improved the specificity from 63.5% [95%CI: 52.3 to 73.5] to 76.6% [95%CI: 67.2 to 84.0]. Sensitivity was higher by 38.6% when a high-grade cytology (ASC-H, HSIL, AGC) was communicated compared to a low-grade cytology (inflammation, ASC-US, LSIL). Specificity was higher by 31% when a low-grade cytology was communicated compared to a high-grade. CONCLUSIONS: Our data suggests that knowledge of cytology increases sensitivity and specificity for diagnosis of ≥ CIN2 lesions at colposcopy. Association between cytology and histology may have contributed to the findings.

A crossover randomized controlled trial examining the effects of black seed (Nigella sativa) supplementation on IL-1ß, IL-6 and leptin, and insulin parameters in overweight and obese women.

BACKGROUND: Nigella sativa (NS) oil has been found to have advantageous benefits in the management of inflammation and obesity. This study investigated the effect of NS supplementation on blood mRNA expressions and serum levels of IL-1ß, IL-6, leptin, and insulin concentrations in overweight/obese women. METHODS: In a crossover design, participants were randomized to receive either NS supplements(2000 mg/day) or placebo for 2 durations(8 weeks). With between-subject and within-subject components and interactions, a repeated-measure ANOVA model was used considering the treatment, time, and the carryover effects. Cohen's d(d) was used to measure the magnitude of the effects. RESULTS: Forty-six eligible participants were included. NS supplementation significantly reduced the mRNA expressions(d=-0.68, P = 0.03) and serum levels of IL-1ß with medium-high effect sizes(d=-1.6, P < 0.001). Significant reductions with large effect sizes were observed in the gene expression and serum levels of IL-6(d=-1.8, d=-0.78, respectively; P < 0.01) and Leptin(d=-1.9, d=-0.89, respectively; P < 0.01, serum leptin P carryover < 0.001). Despite the meaningful carryover effect for serum leptin, results remained significant following the first intervention period analysis(P < 0.001). A significant but low effect size decrease in serum insulin was observed(d=-0.3, P = 0.02). CONCLUSIONS: The clinical significance of present findings regarding improvements in obesity-related pro-inflammatory markers must be interpreted with caution due to some observed medium-low effect sizes. TRIAL REGISTRATION: IRCT20180430039475N1 (Date:25/6/2018).

Electroencephalography microstates as novel functional biomarkers for insomnia disorder.

Background: Insomnia disorder (ID) is one of the most common mental disorders. Research on ID focuses on exploring its mechanism of disease, novel treatments and treatment outcome prediction. An emerging technique in this field is the use of electroencephalography (EEG) microstates, which offer a new method of EEG feature extraction that incorporates information from both temporal and spatial dimensions. Aims: To explore the electrophysiological mechanisms of repetitive transcranial magnetic stimulation (rTMS) for ID treatment and use baseline microstate metrics for the prediction of its efficacy. Methods: This study included 60 patients with ID and 40 age-matched and gender-matched good sleep controls (GSC). Their resting-state EEG microstates were analysed, and the Pittsburgh Sleep Quality Index (PSQI) and polysomnography (PSG) were collected to assess sleep quality. The 60 patients with ID were equally divided into active and sham groups to receive rTMS for 20 days to test whether rTMS had a moderating effect on abnormal microstates in patients with ID. Furthermore, in an independent group of 90 patients with ID who received rTMS treatment, patients were divided into optimal and suboptimal groups based on their median PSQI reduction rate. Baseline EEG microstates were used to build a machine-learning predictive model for the effects of rTMS treatment. Results: The class D microstate was less frequent and contribute in patients with ID, and these abnormalities were associated with sleep onset latency as measured by PSG. Additionally, the abnormalities were partially reversed to the levels observed in the GSC group following rTMS treatment. The baseline microstate characteristics could predict the therapeutic effect of ID after 20 days of rTMS, with an accuracy of 80.13%. Conclusions: Our study highlights the value of EEG microstates as functional biomarkers of ID and provides a new perspective for studying the neurophysiological mechanisms of ID. In addition, we predicted the therapeutic effect of rTMS on ID based on the baseline microstates of patients with ID. This finding carries great practical significance for the selection of therapeutic options for patients with ID.

IMproving facial PRosthesis construction with contactlESs Scanning and Digital workflow (IMPRESSeD): study protocol for a feasibility crossover randomised controlled trial of digital versus conventional manufacture of facial prostheses in patients with orbital or nasal facial defects.

BACKGROUND: Facial prostheses can have a profound impact on patients' appearance, function and quality of life. There has been increasing interest in the digital manufacturing of facial prostheses which may offer many benefits to patients and healthcare services compared with conventional manufacturing processes. Most facial prosthesis research has adopted observational study designs with very few randomised controlled trials (RCTs) documented. There is a clear need for a well-designed RCT to compare the clinical and cost-effectiveness of digitally manufactured facial prostheses versus conventionally manufactured facial prostheses. This study protocol describes the planned conduct of a feasibility RCT which aims to address this knowledge gap and determine whether it is feasible to conduct a future definitive RCT. METHODS: The IMPRESSeD study is a multi-centre, 2-arm, crossover, feasibility RCT with early health technology assessment and qualitative research. Up to 30 participants with acquired orbital or nasal defects will be recruited from the Maxillofacial Prosthetic Departments of participating NHS hospitals. All trial participants will receive 2 new facial prostheses manufactured using digital and conventional manufacturing methods. The order of receiving the facial prostheses will be allocated centrally using minimisation. The 2 prostheses will be made in tandem and marked with a colour label to mask the manufacturing method to the participants. Participants will be reviewed 4 weeks following the delivery of the first prosthesis and 4 weeks following the delivery of the second prosthesis. Primary feasibility outcomes include eligibility, recruitment, conversion, and attrition rates. Data will also be collected on patient preference, quality of life and resource use from the healthcare perspective. A qualitative sub-study will evaluate patients' perception, lived experience and preference of the different manufacturing methods. DISCUSSION: There is uncertainty regarding the best method of manufacturing facial prostheses in terms of clinical effectiveness, cost-effectiveness and patient acceptability. There is a need for a well-designed RCT to compare digital and conventional manufacturing of facial prostheses to better inform clinical practice. The feasibility study will evaluate key parameters needed to design a definitive trial and will incorporate early health technology assessment and a qualitative sub-study to identify the potential benefits of further research. TRIAL REGISTRATION: ISRCTN ISRCTN10516986). Prospectively registered on 08 June 2021,  https://www.isrctn.com/ISRCTN10516986 .

Effects of Melatonin on Glycemic Variability in Type 2 Diabetes Mellitus: Protocol for a Crossover, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Glycemic variability is recognized as a significant factor contributing to the development of micro- and macrovascular complications in individuals with type 2 diabetes mellitus (T2DM). Numerous studies have shown that melatonin, a hormone involved in regulating various biological rhythms, including those related to glucose regulation, such as hunger, satiety, sleep, and circadian hormone secretion (ie, cortisol, growth hormone, catecholamines, and insulin), is deficient in individuals with T2DM. This raises an important question: Could melatonin replacement potentially reduce glycemic variability in these patients? This warrants investigation as a novel approach to improving glycemic control and reducing the risk of complications associated with T2DM. OBJECTIVE: We aimed to investigate whether melatonin replacement in individuals with T2DM who supposedly have melatonin deficiency can positively impact the regulation of insulin secretion rhythms and improve insulin sensitivity, ultimately resulting in a reduction in glycemic variability. METHODS: This study will use a crossover, randomized, double-blind, placebo-controlled trial design. Patients with T2DM in group 1 will receive 3 mg of melatonin at 9:00 PM in the first week, undergo a washout period in the second week, and receive a placebo in the third week (melatonin-washout-placebo). Group 2 will be randomized to receive a placebo-washout-melatonin sequence (3 mg). Capillary blood glucose levels will be measured at 6 different times before and after meals during the last 3 days of the first and third weeks. The study aims to compare the mean differences in blood glucose levels and the coefficient of glycemic variability in patients receiving melatonin and placebo during the first and third weeks. After analyzing the initial results, the number of needed patients will be recalculated. If the recalculated number is higher than 30, new participants will be recruited. Thirty patients with T2DM will be randomized into the 2 groups: melatonin-washout-placebo or placebo-washout-melatonin. RESULTS: Participant recruitment took place between March 2023 to April 2023. In all, 30 participants were eligible and completed the study. We expect that patients will show different glycemic variability on the days they receive placebo or melatonin. Studies on melatonin and glycemic control have shown both positive and negative results. We hope that there will be a positive outcome regarding glycemic variability (ie, a reduction in glycemic variability), as melatonin has a well-described chronobiotic effect in the literature. CONCLUSIONS: This study aims to determine whether melatonin supplementation can effectively reduce glycemic variability in patients with T2DM. The crossover design is necessary due to the multiple variables involved in the circadian variations of glucose, including diet, physical activity, sleep parameters, and pharmacological treatments. The relatively low cost of melatonin and its potential role in reducing the severe complications associated with T2DM have motivated this research effort. Furthermore, the indiscriminate use of melatonin in current times makes conducting this study essential to evaluate the effect of this substance in patients with T2DM. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials RBR-6wg54rb; https://ensaiosclinicos.gov.br/rg/RBR-6wg54rb. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47887.

Effects of dietary salt intake restriction on blood glucose levels: a meta-analysis of crossover study.

BACKGROUND/OBJECTIVES: To identify modifiable risk factors for type 2 diabetes mellitus and explore the relationship between diet sodium intake and blood glucose levels. MATERIALS/METHODS: Based on inclusion and exclusion criteria, we extracted, analyzed, and assessed the available crossover studies of dietary salt intake restriction and insulin resistance in PubMed, Web of Science, MEDLINE, Embase, Wanfang, and CNKI databases. RESULTS: We included 6 studies with 8 sets of data, covering 485 subjects. I2 statistics results showed insignificant heterogeneity among all data (I2 = 39.2% < 50%). Thus, a fixed-effect model was adopted for the final pooled effect size. Weighted mean difference and its 95% confidence interval (CI) value was 0.193 (95% CI, 0.129-0.257), and the test of the overall effect showed P < 0.001. The results revealed that the blood glucose levels in the subjects in the low-salt intake group were significantly higher than those in the normal or high-salt intake groups. We also found no significant change occurred after the removal of any study through sensitivity analysis, which confirmed that the outcome we calculated was prudent and credible. The quantitative Egger's test (P = 0.109 > 0.05) indicated that insignificant publication bias existed. CONCLUSION: This meta-analysis highlights the relationship between dietary sodium intake and blood glucose levels. Our findings show that higher blood glucose levels might be expected in hypertensive or normal people with low-salt consumption compared to those with normal or high-salt consumption, although these differences were not clinically significant. Trial Registration: PROSPERO Identifier: CRD42021256998.

Comparison between digital and conventional impression techniques in children on preference, time and comfort: A crossover randomized controlled trial.

OBJECTIVE: To compare the conventional alginate impression and the digital impression taken with an intraoral scanner of both dental arches in children, using a randomized crossover design. TRIAL DESIGN: This is a monocentric, controlled, superiority, randomized, crossover, open study. METHODS: Twenty-four orthodontic patients between 6 and 11 years of age underwent intraoral scanning (TRIOS 3; 3Shape) and alginate impression of both dental arches with an interval of 1 week between the two procedures. Participants were recruited from September 2021 to March 2022 and the study was completed in April 2022. Impression time for the two procedures was compared. Patients were asked which one of the two impression procedures they preferred. A questionnaire including Visual Analogue Scale (VAS) for comfort, pain, gag reflex and difficulty in breathing, was administered to the patients. RESULTS: Eighteen out of 24 patients preferred digital impression (75%, 95% confidence interval [CI]: 55% to 88%; P = .014). Scanning time was significantly shorter than alginate impression time (difference -118 seconds; 95% CI: -138 to -99; P < .001). Comfort was significantly higher for digital impression (difference 1.7; 95% CI: 0.5 to 2.8; P = .007). There was no difference in pain (difference -0.2; 95% CI: -1.5 to 1.0; P = .686) while gag reflex and breathing difficulties were smaller for digital impression (gag reflex difference -2.5; 95% CI: -4.0 to -0.9; P = .004 and breathing difficulties difference -1.5; 95% CI: -2.5 to -0.5; P = -.004). CONCLUSIONS: Digital impression is preferred by children aged 6-11 years and it is significantly faster in acquisition time than conventional alginate impression. REGISTRATION: The study was registered on ClinicalTrials.gov with registration number NCT04220957 on January 7th, 2020 (https://clinicaltrials.gov/ct2/show/NCT04220957).

Association between air temperature and emergency admission for esophagogastric variceal bleeding: a case-crossover study in Beijing, China.

BACKGROUND AND AIMS: Studies concerning the impact of air temperature on esophagogastric variceal bleeding (EGVB) have yielded conflicting results. Our study aimed to evaluate the correlation between air temperature and EGVB. METHODS: A time-stratified case-crossover study design was performed. Patients received emergency gastroscopic hemostasis for upper gastrointestinal bleeding between Jan 1, 2014, and Dec 31, 2018 in the Fifth Medical Center of PLA General Hospital were enrolled. Conditional logistic regression analysis was applied to determine the association between air temperature and EGVB for different lag structures. RESULTS: A total of 4204 cirrhotic patients diagnosed with EGVB and received emergency gastroscopic hemostasis were enrolled. The mean number of daily EGVB cases peaked in October (2.65 ± 1.69) and fell to the lowest level in July (1.86 ± 1.38), and was 2.38 ± 1.58 in spring, 2.00 ± 1.46 in summer, 2.37 ± 1.58 in autumn, and 2.45 ± 1.58 in winter, respectively (P < 0.0001). In conditional logistic regression analysis, no significant correlations between air temperature and EGVB were observed and no significant difference were found when stratified by age, sex, etiology, liver cancer status, and grade of varices. CONCLUSION: Emergency admission for EGVB showed significant monthly and seasonal fluctuations, while in conditional logistic regression analysis, no association between minimum temperature and emergency admission for EGVB were observed.

Cross-lagged analysis of upward social comparison and online aggressive behavior among college students / 中国学校卫生

Objective@#To explore the longitudinal relationship between upward social comparison and online aggressive behavior among college students, in order to provide an empirical evidence for educators to carry out mental health promotion for college students.@*Methods@#From December 2021 to March 2022, 539 college students from one university in Inner Mongolia were recruited to complete the Upward Social Comparison Questionnaire (USCQ) and Online Aggressive Behavior Scale (OABS) in a 4 month follow-up study. The structural equation model was used to conduct cross-lagged analysis.@*Results@#The mean scores of upward social comparison for college students tracked at baseline (T1) and 4 months follow-up (T2) were (2.77±0.93, 2.70±1.00) points, and the mean scores of online aggressive behavior were (1.06±0.13, 1.05±0.11) points. There were positive relations between upward social comparison and online aggressive behavior of college students at both cross-sectional levels ( r=0.14-0.19, P <0.05). In the autoregression, T1 upward social comparison could positively predict T2 upward social comparison ( β =0.66), and T1 online aggressive behavior could positively predict T2 online aggressive behavior ( β =0.47)( P <0.01); In the cross-lagged regression, T1 upward social comparison could positively predict T2 online aggressive behavior ( β=0.10, P <0.01), whereas T1 online aggressive behavior could not predict T2 upward social comparison ( β=0.04, P >0.05).@*Conclusion@#Upward social comparison is the cause of online aggressive behavior among college students. The probability of online aggressive behavior among college students should be reduced by guiding students to correctly view the gap between themselves and others.

Efficacy of short duration versus conventional electroacupuncture in the treatment of obesity: a randomized crossover study.

OBJECTIVE: To compare the efficacy of short duration electroacupuncture (EA) with conventional EA to reduce weight and other parameters in obese Thai women. METHODS: A randomized crossover study was conducted in 76 simple obese women. Participants were randomized to undergo either eight weeks of 30-minute EA (EA30) followed by an eight-week washout period, then eight weeks of five-minute EA (EA5), or EA5 followed by a washout period, then EA30. Electro-acupuncture was performed at 14 acupoints for two sessions per week. Participants were randomized to undergo either eight weeks of EA30 followed by an eight-week washout period, then eight weeks of EA5, or EA5 followed by a washout period, then EA30. Electro-acupuncture was performed using a stainless silver needle at 14 acupoints for two sessions per week. The needle was connected to an electric stimulator that delivered a constant current, 40 Hz and 3 mA, for 30 or five minutes according to the assigned treatment period. The primary outcome was the difference in weight reduction between the short-duration and the conventional EA while differences in other anth-ropometric parameters and biochemical parameters were considered as secondary outcomes. RESULTS: After each treatment period, all anthro-pometric characteristics of both groups decreased from the baseline regardless of the treatment sequence, including body weight (1.4-1.8 kg; 0.01), body mass index (0.56-0.70 kg/m ; 0.01), waist and hip circumference, skinfold thickness and body fat percentage as well as the improvement in fasting blood glucose and lipid profiles. There were no significant differences of the treatment effects on anthropometric parameters and biomedical chemistries between conventional and short-duration EA. No adverse effects were reported. CONCLUSION: Short duration EA at 14 acupuncture points had comparable efficacy to conventional EA in reduction of weight and other anthropometric parameters as well as to improve biochemistry parameters in obese women.

The acute effects of milk intake on calcium homeostasis and cardiovascular outcome: A randomized crossover trial in postmenopausal women.

OBJECTIVE: The importance of calcium intake from dairy in regard to cardiovascular health has been investigated in several studies with discrepant results. Hence, we aim to investigate the immediate effects of milk intake on cardiovascular function. DESIGN: A randomized crossover study with at least 10 days for washout between the two interventions, 500 ml of water with 200 µg of cholecalciferol or 500 ml of semi-skimmed milk containing approximately 600 mg of calcium with 200 µg of cholecalciferol. PATIENTS: Twenty community-based postmenopausal women aged 60-80 years. MEASUREMENTS: Parathyroid hormone and ionized calcium were measured at baseline and after 2 and 4 h on each study day. Pulse wave analysis and velocity were measured at baseline and after 4 h on each study day. RESULTS: Compared to water, milk intake increased ionized calcium levels by 0.02 mmol/L (p = .029) and decreased parathyroid hormone levels by 1.78 pmol/L (p < .001). The two interventions caused no changes as measured 4 h after the intervention in the following indices of cardiovascular health; pulse wave velocity, brachial diastolic or systolic blood pressure, central diastolic or systolic blood pressure, mean arterial pressure, pulse pressure, augmentation pressure, augmentation index, heart rate or pulse transit time. CONCLUSIONS: Despite significant changes in calcium homeostasis with increased levels of ionized calcium following milk intake, no acute effects seem to occur on measures of cardiovascular health.

Exemption from informed consent: When it is possible in investigational product and drug trials?

One of the most important ethical step in conducting investigational product trials or drug trials is obtaining informed consent from the participants. Although consent from the participants regarding participation is of prime importance but is not always practical or feasible. There may be several instances where it is practically impossible to obtain informed consent, whereas in some cases, obtaining informed consent from the trial participants adversely affects the quality and validity of the study data. Obtaining informed consent is a highly complex and technical process if the participants are not literate or suffering from a terminal illness, Also in some instances obtaining informed consent regarding the washout of prior prescribed medicine which may affect the trial outcomes. Although many guidelines exist for obtaining proper informed consent while very scarce literature exists on the instances where it can be waived off. Therefore, this brief narrative review aims to provide insight into currently available knowledge about when to obtain informed consent during testing of investigational product trials and drug trials and other possible scenarios where it can be waived off considering the effects of the washout period.

Do ball-type attachment systems for overdenture result in better patient-satisfaction? A systematic review of randomized crossover clinical trial.

OBJECTIVE: This review is to compare patient-satisfaction with ball-type overdenture attachment systems with others attachment systems. MATERIAL AND METHODS: This study was registered in PROSPERO (CRD42018097234) and adheres the PRISMA guidelines. Electronic searches on PubMed/MEDLINE, Scopus, Cochrane, and Web of Science databases for published articles were performed before October 2020. The PICO question was: "Do patients with a ball-type overdenture retention system have greater satisfaction, when compared to other attachment systems?" The evaluation of risk of bias was performed using the Cochrane risk of bias tool. RESULTS: After searching the databases, seven articles were selected out of a total of 2583. A total of 312 implants were placed in 139 patients, with a mean age of 65.9 years. The risk of bias in the included studies varied according to the different domains in a risk of uncertain bias or low bias risk. No difference was found between the ball attachment systems and the others systems, with respect to patient-satisfaction. The meta-analysis revealed no statistically significant difference between the ball systems and another systems (P = 0.11; MD: 10.90; 95% CI: -2.55 to 24.35). CONCLUSIONS: Regarding patient general satisfaction, it was not possible to determine differences between the ball system and another types of attachment system for overdenture. The ball-type system was statistically superior only to the magnet system.

Machine Learning Approach for Active Vaccine Safety Monitoring.

BACKGROUND: Vaccine safety surveillance is important because it is related to vaccine hesitancy, which affects vaccination rate. To increase confidence in vaccination, the active monitoring of vaccine adverse events is important. For effective active surveillance, we developed and verified a machine learning-based active surveillance system using national claim data. METHODS: We used two databases, one from the Korea Disease Control and Prevention Agency, which contains flu vaccination records for the elderly, and another from the National Health Insurance Service, which contains the claim data of vaccinated people. We developed a case-crossover design based machine learning model to predict the health outcome of interest events (anaphylaxis and agranulocytosis) using a random forest. Feature importance values were evaluated to determine candidate associations with each outcome. We investigated the relationship of the features to each event via a literature review, comparison with the Side Effect Resource, and using the Local Interpretable Model-agnostic Explanation method. RESULTS: The trained model predicted each health outcome of interest with a high accuracy (approximately 70%). We found literature supporting our results, and most of the important drug-related features were listed in the Side Effect Resource database as inducing the health outcome of interest. For anaphylaxis, flu vaccination ranked high in our feature importance analysis and had a positive association in Local Interpretable Model-Agnostic Explanation analysis. Although the feature importance of vaccination was lower for agranulocytosis, it also had a positive relationship in the Local Interpretable Model-Agnostic Explanation analysis. CONCLUSION: We developed a machine learning-based active surveillance system for detecting possible factors that can induce adverse events using health claim and vaccination databases. The results of the study demonstrated a potentially useful application of two linked national health record databases. Our model can contribute to the establishment of a system for conducting active surveillance on vaccination.

Active School Breaks and Students' Attention: A Systematic Review with Meta-Analysis.

School physical activity breaks are currently being proposed as a way to improve students' learning. However, there is no clear evidence of the effects of active school breaks on academic-related cognitive outcomes. The present systematic review with meta-analysis scrutinized and synthesized the literature related to the effects of active breaks on students' attention. On January 12th, 2021, PubMed, PsycINFO, Scopus, SPORTDiscus, and Web of Science were searched for published interventions with counterbalanced cross-over or parallel-groups designs with a control group, including school-based active breaks, objective attentional outcomes, and healthy students of any age. Studies' results were qualitatively synthesized, and meta-analyses were performed if at least three study groups provided pre-post data for the same measure. Results showed some positive acute and chronic effects of active breaks on attentional outcomes (i.e., accuracy, concentration, inhibition, and sustained attention), especially on selective attention. However, most of the results were not significant. The small number of included studies and their heterogeneous design are the primary limitations of the present study. Although the results do not clearly point out the positive effects of active breaks, they do not compromise students' attention. The key roles of intensity and the leader of the active break are discussed. INPLASY registration number: 202110054.

Treatment of Barth Syndrome by Cardiolipin Manipulation (CARDIOMAN) With Bezafibrate: Protocol for a Randomized Placebo-Controlled Pilot Trial Conducted in the Nationally Commissioned Barth Syndrome Service.

BACKGROUND: Barth syndrome is a rare, life-threatening, X-linked recessive genetic disease that predominantly affects young males and is caused by abnormal mitochondrial lipid metabolism. Currently, there is no definitive treatment for Barth syndrome other than interventions to ameliorate acute symptoms, such as heart failure, cardiac arrhythmias, neutropenia, and severe muscle fatigue. Previous mechanistic studies have identified the lipid-lowering drug bezafibrate as a promising potential treatment; however, to date, no human trials have been performed in this population. OBJECTIVE: The aim of this study is to determine whether bezafibrate (and resveratrol in vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin (MLCL) to tetralinoleoyl-cardiolipin (L4-CL), ameliorating the disease phenotype in those living with the disease. METHODS: The CARDIOMAN (Cardiolipin Manipulation) study is a UK single-center, double-blinded, randomized, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was administered in two 15-week phases with a minimum washout period of 1 month between the phases where no treatment was administered. The primary outcome is peak oxygen consumption (VO2 peak). Secondary outcomes include MLCL/L4-CL ratio and CL profile in blood cells, amino acid expression, phosphocreatine to adenosine triphosphate ratio in cardiac muscle and skeletal muscle oxidative function on phosphorus-31 magnetic resonance spectroscopy, quality of life using the Pediatric Quality of Life Inventory questionnaire, absolute neutrophil count, cardiac function and rhythm profiles at rest and during exercise, and mitochondrial organization and function assessments. Outcomes were assessed at baseline and during the final week of each treatment phase. RESULTS: A total of 12 patients were scheduled to participate across three consecutive research clinics between March and April 2019. In total, 11 participants were recruited, and the follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in 2021. CONCLUSIONS: This trial was approved by the United Kingdom National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform the future conduct of randomized controlled trials in rare disease populations as well as testing the efficacy of bezafibrate as a potential treatment for the disease and advancing the mechanistic understanding of Barth syndrome. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 58006579; https://www.isrctn.com/ISRCTN58006579. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/22533.