The Fragility of Statistically Significant Results in Gynaecologic Surgery: A Systematic Review.

OBJECTIVE: To use the fragility index (FI) to evaluate the robustness of gynaecologic surgery trials that report statistically significant results. The FI defines the minimum number of patients who must have an alternative outcome to alter statistical significance. DATA SOURCES: We searched MEDLINE, Web of Science, Embase, and ClinicalTrials.gov from 2011 to 2021 to identify gynaecologic surgery randomized controlled trials (RCTs). STUDY SELECTION: A total of 4775 trials were screened for eligibility. All included studies evaluated benign gynaecologic surgery interventions or peri-operative medical interventions. Only 2-arm RCTs with statistically significant dichotomous primary outcomes were included. Ninety-three trials were ultimately included for analysis. DATA EXTRACTION AND SYNTHESIS: Data from the included studies, including sample size, loss to follow-up, and number of events, were recorded. The FI of each study was calculated using a predefined technique. The overall FI and FIs by subgroup (clinical subspecialty, country of origin, and statistical test used) are reported as medians alongside their interquartile ranges (IQRs). The Kruskal-Wallis test was applied to find possible statistically significant relationships between FI and the nominal subgroups. Among this cohort, the median FI was 3 (IQR 1-7). The FI was 0 in 13 trials (14%), and in 39 trials (42%), the number of patients lost to follow-up was greater than the FI. The median FI within clinical subspecialty groups (general gynaecology, anaesthesia, urogynaecology, and fertility) did not differ (P = 0.122). CONCLUSION: Statistically significant results of RCTs in gynaecologic surgery are fragile, suggesting that clinicians should interpret results with caution. This is particularly true when the number of patients lost to follow-up is greater than the FI. The FI serves as a quality metric that can be used to evaluate robustness of results when applying the outcomes of RCTs to clinical practice or guideline development.

Janus Kinase 2 (JAK2) Dissociates Hepatosteatosis from Hepatocellular Carcinoma in Mice.

Hepatocellular carcinoma is an end-stage complication of non-alcoholic fatty liver disease (NAFLD). Inflammation plays a critical role in the progression of non-alcoholic fatty liver disease and the development of hepatocellular carcinoma. However, whether steatosis per se promotes liver cancer, and the molecular mechanisms that control the progression in this disease spectrum remain largely elusive. The Janus kinase signal transducers and activators of transcription (JAK-STAT) pathway mediates signal transduction by numerous cytokines that regulate inflammation and may contribute to hepatocarcinogenesis. Mice with hepatocyte-specific deletion of JAK2 (L-JAK2 KO) develop extensive fatty liver spontaneously. We show here that this simple steatosis was insufficient to drive carcinogenesis. In fact, L-JAK2 KO mice were markedly protected from chemically induced tumor formation. Using the methionine choline-deficient dietary model to induce steatohepatitis, we found that steatohepatitis development was completely arrested in L-JAK2 KO mice despite the presence of steatosis, suggesting that JAK2 is the critical factor required for inflammatory progression in the liver. In line with this, L-JAK2 KO mice exhibited attenuated inflammation after chemical carcinogen challenge. This was associated with increased hepatocyte apoptosis without elevated compensatory proliferation, thus thwarting expansion of transformed hepatocytes. Taken together, our findings identify an indispensable role of JAK2 in hepatocarcinogenesis through regulating critical inflammatory pathways. Targeting the JAK-STAT pathway may provide a novel therapeutic option for the treatment of hepatocellular carcinoma.

Chronic dietary n-6 PUFA deprivation leads to conservation of arachidonic acid and more rapid loss of DHA in rat brain phospholipids.

To determine how the level of dietary n-6 PUFA affects the rate of loss of arachidonic acid (ARA) and DHA in brain phospholipids, male rats were fed either a deprived or adequate n-6 PUFA diet for 15 weeks postweaning, and then subjected to an intracerebroventricular infusion of (3)H-ARA or (3)H-DHA. Brains were collected at fixed times over 128 days to determine half-lives and the rates of loss from brain phospholipids (J out). Compared with the adequate n-6 PUFA rats, the deprived n-6-PUFA rats had a 15% lower concentration of ARA and an 18% higher concentration of DHA in their brain total phospholipids. Loss half-lives of ARA in brain total phospholipids and fractions (except phosphatidylserine) were longer in the deprived n-6 PUFA rats, whereas the J out was decreased. In the deprived versus adequate n-6 PUFA rats, the J out of DHA was higher. In conclusion, chronic n-6 PUFA deprivation decreases the rate of loss of ARA and increases the rate of loss of DHA in brain phospholipids. Thus, a low n-6 PUFA diet can be used to target brain ARA and DHA metabolism.

Momentary emotion regulation strategy use and success: Testing the influences of emotion intensity and habitual strategy use.

Successful emotion regulation (ER) is important for a wide range of psychosocial outcomes. Specific ER strategies have been identified as being more or less likely to be successful. However, recent evidence suggests significant individual differences in the association between strategy implementation and ER success. Indeed, 2 key factors may play an important role in moderating the link between ER strategy use and ER success in the moment: (a) the intensity of the specific emotional experience, and (b) the relative frequency in using a given ER strategy. Experience-sampling across 14-days (N = 304, Mage = 19.14, % female = 87.5) was used to assess whether emotion intensity and trait ER strategy use were differentially associated with perceived regulatory success depending on which ER strategy was used. Multilevel modeling revealed that more intense emotions were associated with lower perceived success for all strategies. Additionally, habitual reappraisal predicted greater success and habitual rumination predicted lower success. We discuss the possibility that results reflected intensity-based ER strategy choices and add to the growing call to abandon the reductive labeling of ER strategies as either "adaptive" or "maladaptive." (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Any time and place? Digital emotional support for digital natives.

Digital natives (i.e., those who have grown up in the digital age) are likely to receive emotional support through digital means, such as texting and video calling. However, virtually all studies assessing the benefits of emotional support have focused on in-person support; the relative efficacy of digital support remains unclear. This study assessed a sample of young adults' negative emotions, digital and in-person support for those emotions, and success in regulating them 3 times per day for 14 days (N = 164; 6,530 collective measurement occasions). Participants' social surroundings at the time of each negative emotion and trait levels of social avoidance were also considered. Digital support was expected to be received more often and perceived as more effective for regulating negative emotions when participants were alone and higher in social avoidance. However, with the exception of those higher in social avoidance receiving less digital (and in-person) support, digital support was received and perceived as effective regardless of these factors, and its perceived effectiveness was on par with that of in-person support. For digital natives, digital support may be just as effective as the "real thing" and its benefits may not be restricted to isolated or socially avoidant users. Findings are discussed in relation to the emotional consequences and social constraints of the COVID-19 pandemic. If transcending the time and space limitations of in-person support with digital support is the new norm, the good news is that it seems to be working. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Nucleation and growth of elastin-like peptide fibril multilayers: an in situ atomic force microscopy study.

Controlling how molecules assemble into complex supramolecular architectures requires careful consideration of the subtle inter- and intra-molecular interactions that control their association. This is particularly crucial in the context of assembly at interfaces, where both surface chemistry and structure can play a role in directing structure formation. We report here the results of a study into the self-assembly of the elastin-like peptide EP I on structurally modified highly ordered pyrolytic graphite, including the role of spatial confinement on fibril nucleation and the growth of oriented fibril multilayers. In situ atomic force microscopy performed in fluid and at elevated temperature provided direct evidence of frustrated fibril nuclei and oriented growth of independent fibril domains. These results portend the application of this in situ strategy for studies of the nucleation and growth mechanisms of other fibril- and amyloid-forming proteins.

Early- and Late-Stage Cancer Diagnosis Under 3 Years of Medicaid Expansion.

INTRODUCTION: Health insurance expansions may increase early detection of cancer and reduce late-stage cancer incidence. The study assesses the effects of the Affordable Care Act Medicaid expansions on rates of early- and late-stage cancer diagnosis up to 3 years after implementation. METHODS: Population-based quasi-experimental analysis of nonelderly adults was conducted in 732 counties from the 2010-2016 Surveillance, Epidemiology, and End Results Program cancer registry data. Multivariate event study regressions were estimated to compare annual changes in county-level rates of cancer diagnoses in states that expanded Medicaid with those that did not. Data analysis was performed from May to October 2019. RESULTS: Medicaid expansion was associated with an increase in early-stage cancer diagnoses of 21.3 per 100,000 population (95% CI=2.9, 35.2) or 9.14% of population in its first year; estimates for Years 2 and 3 were also positive but smaller and not statistically significant. There was a marginally significant reduction in late-stage diagnoses of 8.7 per 100,000 population (95% CI= -25.0, 3.4) or 5.7% of population relative to baseline, 3 years after Medicaid expansion. There was no detectable effect of expansion on total diagnoses. CONCLUSIONS: Medicaid expansions increased early-stage cancer diagnosis in the first year of expansion, but effects dissipated in subsequent years, suggesting a response to pent-up patient demand for screening and diagnostic services immediately after expansion. There was also suggestive evidence of reductions in late-stage diagnosis in the third year of Medicaid expansion, highlighting the potential role of public health insurance in improving cancer outcomes among nonelderly adults.

Direct and Indirect Suppression of Scn5a Gene Expression Mediates Cardiac Na+ Channel Inhibition by Wnt Signalling.

BACKGROUND: Myocardial infarction and heart failure are associated with reduced voltage-gated Na+ current (INa) that promotes arrhythmias and sudden deaths. We have previously shown that the Wnt/ß-catenin signalling (Wnt signalling), which is active in heart disease, reduces cardiac INa, suggesting that Wnt signalling may be a potential therapeutic target. However, because Wnt signalling is required for the homeostasis of many noncardiac tissues, administration of Wnt inhibitors to heart patients would cause significant side effects. The present study aims to elucidate the molecular mechanisms of cardiac INa inhibition by Wnt, which would identify cardiac-specific therapeutic targets. METHODS: Wnt signalling was activated in neonatal rat ventricular myocytes by Wnt3a protein. Adenovirus expressing Wnt3a was injected into the adult rat ventricle. CRISPR/Cas9 and chromatin immunoprecipitation were used for mechanistic studies. RESULTS: Wnt signalling activation in neonatal rat ventricular myocytes reduced Nav1.5 protein and Scn5a mRNA, but increased Tbx3, a known suppressor of Scn5a. Chromatin immunoprecipitation showed that Wnt signalling inhibits Scn5a expression through downstream mediator (TCF4) binding to both Tbx3 and Scn5a promoters. Overexpression or knockdown of Tbx3 directly modified Nav1.5 and INa, whereas CRISPR/Cas9-induced mutations at TCF4 binding sites within the Scn5a promoter attenuated Wnt inhibition of Scn5a and Nav1.5. In adult rat hearts, adenovirus expressing Wnt3a reduced Nav1.5, increased QRS duration in electrocardiogram, and increased the susceptibility to ventricular tachycardia. CONCLUSIONS: Wnt signalling inhibits the Na+ channel by direct and indirect (via Tbx3) suppression of Scn5a transcription. Strategies to block TCF4 binding to the Tbx3 and Scn5a promoters would represent novel strategies for cardiac-specific inhibition of the Wnt pathway to rescue INa and prevent sudden cardiac deaths.

Detection and Quantification Methods for Fibrillar Products of In Vitro Tau Aggregation Assays.

Alzheimer's disease is characterized in part by the intracellular misfolding and aggregation of tau protein. The aggregates, which range in size from small oligomers to large filaments, are markers for disease diagnosis and staging, potential vectors for disease propagation, and candidate sources of neurotoxicity. Here we present protocols for synthesizing large tau aggregates characterized by filamentous morphology and cross-ß-sheet structure from monomeric full-length tau precursors in vitro. We also describe their detection and quantification through thioflavin dye binding, filter trap, and transmission electron microscopy methods. These methods cover applications requiring high-throughput capability as well as those requiring high-resolution analysis of aggregation mechanism.

Plasma non-esterified docosahexaenoic acid is the major pool supplying the brain.

Despite being critical for normal brain function, the pools that supply docosahexaenoic acid (DHA) to the brain are not agreed upon. Using multiple kinetic models in free-living adult rats, we first demonstrate that DHA uptake from the plasma non-esterified fatty acid (NEFA) pool predicts brain uptake of DHA upon oral administration, which enters the plasma NEFA pool as well as multiple plasma esterified pools. The rate of DHA loss by the brain is similar to the uptake from the plasma NEFA pool. Furthermore, upon acute iv administration, although more radiolabeled lysophosphatidylcholine (LPC)-DHA enters the brain than NEFA-DHA, this is due to the longer plasma half-life and exposure to the brain. Direct comparison of the uptake rate of LPC-DHA and NEFA-DHA demonstrates that uptake of NEFA-DHA into the brain is 10-fold greater than LPC-DHA. In conclusion, plasma NEFA-DHA is the major plasma pool supplying the brain.