Hourly effect of atmospheric reactive nitrogen species on the onset of acute ischemic stroke: Insight from the Shanghai Stroke Service System Database.

Acute ischemic stroke (AIS) is one of the most predominant causes of mortality and disability in China. Significant uncertainties in stroke diagnosis and time of onset have resulted in inconsistent evidence on the association between ambient air pollution and the risk of AIS. The present study aimed to evaluate the impact of air pollution on AIS onset based on high time-resolution air pollution data and a stroke-specific registry across the past five years. Hourly concentrations of PM2.5, PM10, O3, SO2, CO, NO2 and nitrous acid (HONO) were monitored from 2017 to 2021, with which a distributed lag non-linear model and conditional logistic regression models coupled with a time-stratified case-crossover design were applied to 106,623 AIS cases recorded in the Shanghai Stroke Service (4S) database during the study period. Results from the conditional logistic regression models indicate that acute exposure to PM2.5, PM10, SO2, NO2 and HONO was found to be associated with AIS onset, respectively. The corresponding cumulative excessive risks of AIS onset were 0.8 %, 1 %, 2.4 %, 2.1 % and 1.8 % for each interquartile range increase in the respective concentration. The longest lag-effect (up to 13 h) was observed for reactive nitrogen species (RNS), such as NO2 and HONO, which remained robust in two-pollutant models. Similar important role of RNS in AIS onset were confirmed by the distributed lag non-linear model. By demonstrating the transient effect of ambient air pollution on AIS, especially the relationships between RNS and AIS for the first time, our study provides stringent evidence for future mitigation strategies for pollution emission and public health.

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.

The development of a set of key points to aid clinicians and researchers in designing and conducting n-of-1 trials.

INTRODUCTION: n-of-1 trials are undertaken to optimise the evaluation of health technologies in individual patients. They involve a single patient receiving treatments, both interventional and control, consecutively over set periods of time, the order of which is decided at random. Although n-of-1 trials are undertaken in medical research it could be argued they have the utility to be undertaken more frequently. We undertook the National Institute for Health Research (NIHR) commissioned DIAMOND (Development of generalisable methodology for n-of-1 trials delivery for very low volume treatments) project to develop key points to assist clinicians and researchers in designing and conducting n-of-1 trials. METHODS: The key points were developed by undertaking a stakeholder workshop, followed by a discussion within the study team and then a stakeholder dissemination and feedback event. The stakeholder workshop sought to gain the perspectives of a variety of stakeholders (including clinicians, researchers and patient representatives) on the design and use of n-of-1 trials. A discussion between the study team was held to reflect on the workshop and draft the key points. Lastly, the stakeholders from the workshop were invited to a dissemination and feedback session where the proposed key points were presented and their feedback gained. RESULTS: A set of 22 key points were developed based on the insights from the workshop and subsequent discussions. They provide guidance on when an n-of-1 trial might be a viable or appropriate study design and discuss key decisions involved in the design of n-of-1 trials, including determining an appropriate number of treatment periods and cycles, the choice of comparator, recommended approaches to randomisation and blinding, the use of washout periods and approaches to analysis. CONCLUSIONS: The key points developed in the project will support clinical researchers to understand key considerations when designing n-of-1 trials. It is hoped they will support the wider implementation of the study design.

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.

Tailored Prompting to Improve Adherence to Image-Based Dietary Assessment: Mixed Methods Study.

Background: Accurately assessing an individual's diet is vital in the management of personal nutrition and in the study of the effect of diet on health. Despite its importance, the tools available for dietary assessment remain either too imprecise, expensive, or burdensome for clinical or research use. Image-based methods offer a potential new tool to improve the reliability and accessibility of dietary assessment. Though promising, image-based methods are sensitive to adherence, as images cannot be captured from meals that have already been consumed. Adherence to image-based methods may be improved with appropriately timed prompting via text message. Objective: This study aimed to quantitatively examine the effect of prompt timing on adherence to an image-based dietary record and qualitatively explore the participant experience of dietary assessment in order to inform the design of a novel image-based dietary assessment tool. Methods: This study used a randomized crossover design to examine the intraindividual effect of 3 prompt settings on the number of images captured in an image-based dietary record. The prompt settings were control, where no prompts were sent; standard, where prompts were sent at 7:15 AM, 11:15 AM, and 5:15 PM for every participant; and tailored, where prompt timing was tailored to habitual meal times for each participant. Participants completed a text-based dietary record at baseline to determine the timing of tailored prompts. Participants were randomized to 1 of 6 study sequences, each with a unique order of the 3 prompt settings, with each 3-day image-based dietary record separated by a washout period of at least 7 days. The qualitative component comprised semistructured interviews and questionnaires exploring the experience of dietary assessment. Results: A total of 37 people were recruited, and 30 participants (11 male, 19 female; mean age 30, SD 10.8 years), completed all image-based dietary records. The image rate increased by 0.83 images per day in the standard setting compared to control (P=.23) and increased by 1.78 images per day in the tailored setting compared to control (P≤.001). We found that 13/21 (62%) of participants preferred to use the image-based dietary record versus the text-based dietary record but reported method-specific challenges with each method, particularly the inability to record via an image after a meal had been consumed. Conclusions: Tailored prompting improves adherence to image-based dietary assessment. Future image-based dietary assessment tools should use tailored prompting and offer both image-based and written input options to improve record completeness.

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.

Strategies for knee stabilising and pivot-shift avoidance in a step-down and cross-over task observed sub-acutely after anterior cruciate ligament reconstruction.

BACKGROUND: Individuals with a recent anterior cruciate ligament reconstruction may demonstrate an altered movement strategy for protecting the knee and maintaining stability. Altered knee movement might lead to abnormal intra-articular load, potentially contributing to early knee osteoarthritis onset. A protective strategy may be particularly evident during active tasks that induce a pivot-shift manoeuvre, such as a step-down and cross-over task. In this study, we investigated whether knee joint mechanics and muscle activity differed between participants early (∼3 months) following reconstruction (n = 35) to uninjured controls (n = 35) during a step-down and cross-over task with a 45° change-of-direction. METHODS: We used motion capture, force plates and surface electromyography to compare time-normalised curves of sagittal and transverse-plane knee mechanics and muscle activity during the cross-over phase between groups using functional t-tests. We also compared knee mechanics between sides within the injured group and compared discrete outcomes describing the cross-over phase between groups. FINDINGS: Compared to controls, the injured participants had greater knee flexion angle and moment, lower internal rotation moment, more preparatory foot rotation of the pivoting leg, a smaller cross-over angle, and a longer cross-over phase for both the injured and uninjured sides. The injured leg also had greater biceps femoris and vastus medialis muscle activity compared to controls and different knee mechanics than the uninjured leg. INTERPRETATION: Individuals with anterior cruciate ligament reconstruction showed a knee-stabilising and pivot-shift avoidance strategy for both legs early in rehabilitation. These results may reflect an altered motor representation and motivate considerations early in rehabilitation.

A Review of Capacity Decay Studies of All-vanadium Redox Flow Batteries: Mechanism and State Estimation.

As a promising large-scale energy storage technology, all-vanadium redox flow battery has garnered considerable attention. However, the issue of capacity decay significantly hinders its further development, and thus the problem remains to be systematically sorted out and further explored. This review provides comprehensive insights into the multiple factors contributing to capacity decay, encompassing vanadium cross-over, self-discharge reactions, water molecules migration, gas evolution reactions, and vanadium precipitation. Subsequently, it analyzes the impact of various battery parameters on capacity. Based on this foundation, the article expounds upon the significance of battery internal state estimation technology. Additionally, the review also summarizes domestic and international mathematical models utilized for simulating capacity decay, serving as a valuable reference for future research endeavors. Finally, through the comparison of traditional experimental methods and mathematical modeling methods, this article offers effective guidance for the future development direction of battery state monitoring. This review generally overview the problems related to the capacity attenuation of all-vanadium flow batteries, which is of great significance for understanding the mechanism behind capacity decay and state monitoring technology of all-vanadium redox flow battery.

Practical and methodological challenges when conducting a cluster randomized trial: Examples and recommendations.

The use of cluster randomized trial design to answer research questions is increasing. This design and associated variants such as the cluster randomized crossover and stepped wedge are useful to assess complex interventions in a pragmatic way but when adopting such designs, one may face specific implementation challenges. This article summarizes common challenges faced when conducting cluster randomized trials, cluster randomized crossover trials, and stepped wedge trials, and provides recommendations.

Aerodynamic/Hydrodynamic Investigation of Water Cross-Over for a Bionic Unmanned Aquatic-Aerial Amphibious Vehicle.

An aerodynamic/hydrodynamic investigation of water cross-over is performed for a bionic unmanned aquatic-aerial amphibious vehicle (bionic UAAV). According to flying fish features and UAAV flight requirements of water cross-over, the bionic conceptual design of crossing over water is described and planned in multiple stages and modes of motion. A solution procedure for the numerical simulation method, based on a modified SST turbulence model and the VOF model, is expressed, and a verification study is presented using a typical case. Longitudinal-lateral numerical simulation analysis investigates the cruise performance underwater and in the air. The numerical simulation and principal experiment verification are conducted for crossing over water and water surface acceleration. The results indicate that the bionic UAAV has an excellent aerodynamic/hydrodynamic performance and variant configuration to adapt to water cross-over. The bionic UAAV has good water and air navigation stability, and the cruise flying lift-drag ratio is greater than 15 at a low Reynolds number. Its pitching moment has the phenomenon of a "water mound" forming and breaking at the water cross-over process. The present method and the bionic variant configuration provide a feasible water cross-over design and analysis strategy for bionic UAAVs.

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.

Non-Local Muscle Fatigue Impairs Mean Propulsive Velocity During Strength Loading in Strength-Trained Men.

Purpose: This study examined the acute influence of a bench press (BP) loading on the explosive squat (SQ) performance and vice versa. Methods: Nineteen strength-trained men completed 2 experimental sessions consisting of either a SQ+BP loading or a BP+SQ loading with 3 × 5 + 3 × 3 repetitions at 80% of the 1-repetition maximum in a randomized order. SQ and BP mean propulsive velocity (MPV) were assessed during both loadings, at baseline (T0) as well as immediately after the first (T1) and second strength loading (T2). Results: Both BP and SQ MPV decreased between T0 and T1 in SQ+BP (-6.13 ± 6.13%, p = .014, g = 0.485 and -9.11 ± 7.23%, p < .001, g = 0.905, respectively) and BP+SQ (-15.15 ± 7.69%, p < .001, g = 1.316 and -7.18 ± 6.16%, p < .001, g = 0.724, respectively). Mean BP MPV was lower in set 2 to set 6 in SQ+BP when compared to BP+SQ (-7.90% - 9.88%, all p < .05, g = 0.523-0.808). Mean SQ MPV was lower in set 1 and set 4 in BP+SQ when compared to SQ+BP (-4.94% - 5.22%, all p < .001, g = 0.329-0.362). Conclusions: These results demonstrate that the presence of non-local muscle fatigue affects the movement velocity. Therefore, if a training program aims to perform strength training exercises with maximal movement velocity, it is essential to carefully evaluate whether upper and lower body exercises should be carried out within close proximity.

When there is no justice, we need an old HERO. The trickle-down effect of psychological capital: the moderating role of organizational justice and leaders' age.

The objective of the study was to explore the impact of leaders' ages and followers' perceptions of organizational justice (POJ) on the transfer of psychological capital (PsyCap) from leaders to followers, particularly examining how employees' resilience is influenced by leaders' PsyCap. While some evidence exists regarding PsyCap's trickle-down effect, the specific circumstances triggering this phenomenon remain unclear. This study investigates the relationship between followers' and leaders' PsyCap, employing the Social Cognitive Theory and considering the moderating effects of leaders' age and POJ. The study focused on leader-follower dyads within a randomly selected sample of 406 businesses, encompassing 812 respondents. The survey investigation utilized the CAPI approach. The hypothesized model underwent testing through multilevel dyadic regression analysis, employing an actor-partner interdependence model. The findings support two moderators -employees' POJ and managers' age - and highlight the cross-over effect of PsyCap. Specifically, a stronger trickle-down link is observed when a leader is older and operating within a low POJ environment. Additionally, the study revealed a positive correlation between employees' PsyCap and POJ. The development of POJ enhances employees' PsyCap and resilience, while leaders' PsyCap may compensate for organizational POJ deficiencies. This study is among the first to explore PsyCap's moderators, specifically analyzing leaders' ages and POJ as factors influencing the cross-over effect of PsyCap. By identifying previously unrecognized moderators affecting the cross-over PsyCap effect, this research contributes significantly to the PsyCap literature.

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).

Blood flow restriction augments the cross-education effect of isometric handgrip training.

INTRODUCTION: The application of blood flow restriction (BFR) to low-intensity exercise may be able to increase strength not only in the trained limb but also in the homologous untrained limb. Whether this effect is repeatable and how that change compares to that observed with higher intensity exercise is unknown. PURPOSE: Examine whether low-intensity training with BFR enhances the cross-education of strength compared to exercise without BFR and maximal efforts. METHODS: A total of 179 participants completed the 6-week study, with 135 individuals performing isometric handgrip training over 18 sessions. Participants were randomly assigned to one of four groups: 1) low-intensity (4 × 2 min of 30% MVC; LI, n = 47), 2) low-intensity with blood flow restriction (LI + 50% arterial occlusion pressure; LI-BFR, n = 41), 3) maximal effort (4 × 5 s of 100% MVC; MAX, n = 47), and 4) non-exercise control (CON, n = 44). RESULTS: LI-BFR was the only group that observed a cross-education in strength (CON: 0.64 SD 2.9 kg, LI: 0.95 SD 3.6 kg, BFR-LI: 2.7 SD 3.3 kg, MAX: 0.80 SD 3.1 kg). In the trained hand, MAX observed the greatest change in strength (4.8 SD 3.3 kg) followed by LI-BFR (2.8 SD 4.0 kg). LI was not different from CON. Muscle thickness did not change in the untrained arm, but ulna muscle thickness was increased within the trained arm of the LI-BFR group (0.06 SD 0.11 cm). CONCLUSION: Incorporating BFR into low-intensity isometric training led to a cross-education effect on strength that was greater than all other groups (including high-intensity training).

Feedback Intervention for the Control of Glucocorticoid Prescription in Primary Care Institutions: A Cluster Randomized Cross-Over Controlled Trial in Southwest China.

Purpose: The purpose of this study is to assess the effect of glucocorticoid prescription feedback intervention in complex primary care institutions for regulating its inappropriate use. Design Setting and Interventions: A six-month cluster randomized cross-over controlled trial was conducted in primary care institutions. A total of 347 physicians from 69 participating institutions were randomly allocated to either group A or group B. Both groups were given feedback interventions or serve as control. The feedback intervention comprised two components: a real-time pop-up warning of inappropriate glucocorticoid prescriptions based on the Hospital Information System and a high-proportion prescription feedback intervention warning system. Outcome Measures: The primary outcome measure was the 10-day inappropriate glucocorticoid prescription rate, while the 10-day glucocorticoid prescription rate served as secondary outcome measure. Results: At baseline, the 10-day inappropriate glucocorticoid prescription rates were 66.63% and 66.57% in group A and group B, respectively, showing no significant difference (p = 0.140). Following the intervention, group A exhibited a significant reduction in 10-day inappropriate glucocorticoid prescription rate at the crossing point by 13.69% (p < 0.001). In contrast, group B, which served as the control group, experienced an increase of 5.93% (p = 0.037) at the same crossover point. After the crossover point, there was a decrease in 10-day inappropriate glucocorticoid prescription rate for both groups. Group B as the intervention group demonstrated a reduction of 28.22% compared to the crossing point (p < 0.001), whereas group A showed a decrease of 12.20% (p = 0.339). The characteristics of physicians did not significantly influence the inappropriate glucocorticoid prescription rate. Conclusion: The real-time pop-up warning of inappropriate glucocorticoid prescriptions based on the Hospital Information System and high-proportion prescription feedback intervention warning system can effectively regulate the inappropriate glucocorticoid prescribing behavior of physicians. Trial Registration: ISRCTN11747547.

Octreotide improves human lymphatic fluid transport a translational trial.

OBJECTIVES: Chylothorax is a complex condition and many different pharmacological agents have been tried as treatment. Octreotide is used off-label to treat chylothorax, but the efficacy of octreotide remains unclear. A decrease in lymph production is suggested as the mechanism. In this cross-over study, we explore the direct effect of octreotide on human lymphatic drainage. METHODS: Pre-clinical: the effect of octreotide on force generation was assessed during acute and prolonged drug incubation on human lymphatic vessels mounted in a myograph. Clinical: in a double-blinded, randomized, cross-over trial including 16 healthy adults, we administered either octreotide or saline as an intravenous infusion for 2.5 h. Near-infrared fluorescence imaging was used to examine spontaneous lymphatic contractions and lymph pressure in peripheral lymphatic vessels and plethysmography was performed to assess the capillary filtration rate, capillary filtration coefficient and isovolumetric pressures of the lower leg. RESULTS: Pre-clinical: human thoracic duct (n = 12) contraction rate was concentration-dependently stimulated by octreotide with a maximum effect at 10 and 100 nmol/l in the myograph chamber. Clinical: spontaneous lymphatic contractions and lymph pressure evaluated by near-infrared fluorescence did not differ between octreotide or placebo (P = 0.36). Plethysmography revealed similar capillary filtration coefficients (P = 0.057), but almost a doubling of the isovolumetric pressures (P = 0.005) during octreotide infusion. CONCLUSIONS: Octreotide stimulated lymphatic contractility in the pre-clinical setup but did not affect the spontaneous lymphatic contractions or lymph pressure in healthy individuals. Plethysmography revealed a doubling in the isovolumetric pressure. These results suggest that octreotide increases lymphatic drainage capacity in situations with high lymphatic afterload.

Evaluation of a flexible piecewise linear mixed-effects model in the analysis of randomized cross-over trials.

Cross-over designs are commonly used in randomized clinical trials to estimate efficacy of a new treatment. They have received a lot of attention, particularly in connection with regulatory requirements for new drugs. The main advantage of using cross-over designs over conventional parallel designs is increased precision, thanks to within-subject comparisons. In the statistical literature, more recent developments are discussed in the analysis of cross-over trials, in particular regarding repeated measures. A piecewise linear model within the framework of mixed effects has been proposed in the analysis of cross-over trials. In this article, we report on a simulation study comparing performance of a piecewise linear mixed-effects (PLME) model against two commonly cited models-Grizzle's mixed-effects (GME) and Jones & Kenward's mixed-effects (JKME) models-used in the analysis of cross-over trials. Our simulation study tried to mirror real-life situation by deriving true underlying parameters from empirical data. The findings from real-life data confirmed the original hypothesis that high-dose iodine salt have significantly lowering effect on diastolic blood pressure (DBP). We further sought to evaluate the performance of PLME model against GME and JKME models, within univariate modeling framework through a simulation study mimicking a 2 × 2 cross-over design. The fixed-effects, random-effects and residual error parameters used in the simulation process were estimated from DBP data, using a PLME model. The initial results with full specification of random intercept and slope(s), showed that the univariate PLME model performed better than the GME and JKME models in estimation of variance-covariance matrix (G) governing the random effects, allowing satisfactory model convergence during estimation. When a hierarchical view-point is adopted, in the sense that outcomes are specified conditionally upon random effects, the variance-covariance matrix of the random effects must be positive-definite. The PLME model is preferred especially in modeling an increased number of random effects, compared to the GME and JKME models that work equally well with random intercepts only. In some cases, additional random effects could explain much variability in the data, thus improving precision in estimation of the estimands (effect size) parameters.

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.