Impact of upadacitinib induction and maintenance therapy on health-related quality of life, fatigue, and work productivity in patients with moderately-to-severely active Crohn's disease.

BACKGROUND AND AIMS: Quality of life in patients with active Crohn's disease may be significantly reduced. We evaluated the effects of upadacitinib induction and maintenance therapy on fatigue, quality of life, and work productivity in the phase 3 trials U-EXCEL, U-EXCEED, and U-ENDURE. METHODS: Clinical responders to upadacitinib 45 mg in U-EXCEL and U-EXCEED induction trials were re-randomized 1:1:1 to upadacitinib 30 mg, 15 mg, or placebo for 52 weeks of maintenance in U-ENDURE. Clinically meaningful improvements in Inflammatory Bowel Disease Questionnaire (IBDQ) response, IBDQ remission, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Work Productivity and Activity Impairment were evaluated. Percentages of patients achieving clinically meaningful improvements were assessed at induction Weeks 4 and 12 and maintenance Week 52. RESULTS: Analysis included 1021 and 502 patients assessed at induction and maintenance, respectively. In U-EXCEL, greater improvements (all p≤0.001) in IBDQ response (71.0% vs 50.2%), IBDQ remission (44.2% vs 23.7%), and FACIT-Fatigue (42.0% vs 27.0%) were observed in upadacitinib-treated patients versus placebo at Week 4. Improvements in IBDQ response, IBDQ remission, and FACIT-Fatigue were similar or greater at Week 12. Clinically meaningful improvement in overall work impairment (52.1% vs 38.1%, p≤0.05) was demonstrated at Week 12. Similar results were observed in U-EXCEED. Improvements were sustained through 52 weeks of upadacitinib maintenance treatment. CONCLUSIONS: In patients with active Crohn's disease, upadacitinib treatment relative to placebo significantly improved fatigue, quality of life, and work productivity as early as Week 4. These effects were sustained through 52 weeks of maintenance.

Abscisic Acid Induces DNA Methylation Alteration in Genes Related to Berry Ripening and Stress Response in Grape (Vitis vinifera L).

Abscisic acid (ABA) is a major regulator of nonclimacteric fruit ripening, with its processes involving epigenetic mechanisms. It remains unclear whether DNA methylation is associated with ABA-regulated ripening. In this study, we investigated the patterns of DNA methylation and gene expression following ABA treatment in grape berries by using whole-genome bisulfite sequencing and RNA-sequencing. ABA application changed global DNA methylation in grapes. The hyper-/hypo-differently methylated regions were enriched in defense-related metabolism, degreening processes, or ripening-related metabolic pathways. Many differentially expressed genes showed an alteration in DNA methylation after ABA treatment. Specifically, ten downregulated genes with hypermethylation in promoters were involved in the ripening process, ABA homeostasis/signaling, and stress response. Nine upregulated genes exhibiting hypo-methylation in promoters were related to the ripening process and stress response. These findings demonstrated ABA-induced DNA alteration of ripening related and stress-responsive genes during grape ripening, which provides new insights of the epigenetic regulation of ABA on fruit ripening.

Medication persistence and its impact on type 2 diabetes.

OBJECTIVES: Medication persistence in type 2 diabetes (T2D) is a critical factor for preventing adverse clinical events. We assessed persistence among newly treated patients with T2D and documented the impact of persistence on clinical outcomes and costs. STUDY DESIGN: Retrospective study of Optum Clinformatics Data Mart commercial and Medicare Advantage enrollees from 2007 to 2020. METHODS: We identified adult patients who initiated antidiabetic treatments. Patients were required to have at least 1 treatment-free year prior to their first T2D prescription. Persistence was measured as the duration of continuous therapy until a 60-day gap in drug availability appeared in any antidiabetic therapy. Factors associated with duration were documented, focusing on the initial class(es) of T2D drugs. The impact of treatment duration on the risk of hospitalization and on total health care costs was also examined. RESULTS: A total of 673,265 patients were included, with a median follow-up of 7 years. Only 22% of patients maintained continuous treatment, of whom 10% added a second medication. A 1-month increase in duration was associated with reduced risk of hospitalization due to stroke by 0.54% (95% CI, 0.46%-0.60%), acute myocardial infarction by 0.51% (95% CI, 0.44%-0.57%), and all-cause hospitalization by 0.36% (95% CI, 0.34%-0.37%). A 1-month increase in duration was associated with a year-to-year decrease in medical costs of $51 (95% CI, -$54 to -$48) and an increase in year-to-year drug costs of $14 (95% CI, $13-$14). CONCLUSIONS: Our findings show low persistence among patients with T2D and emphasize the importance of medication persistence, which is associated with cost savings and lower risk of hospitalizations.

Analysis of the influences of social isolation on cognition and the therapeutic potential of deep brain stimulation in a mouse model.

Background: Social interaction is a fundamental human need. Social isolation (SI) can have negative effects on both emotional and cognitive function. However, it is currently unclear how age and the duration of SI affect emotion and recognition function. In addition, there is no specific treatment for the effects of SI. Methods: The adolescence or adult mice were individually housed in cages for 1, 6 or 12 months and for 2 months to estabolish SI mouse model. We investigated the effects of SI on behavior in mice at different ages and under distinct durations of SI, and we explored the possible underlying mechanisms. Then we performed deep brain stimulation (DBS) to evaluate its influences on SI induced behavioral abnormalities. Results: We found that social recognition was affected in the short term, while social preference was damaged by extremely long periods of SI. In addition to affecting social memory, SI also affects emotion, short-term spatial ability and learning willingness in mice. Myelin was decreased significantly in the medial prefrontal cortex (mPFC) and dorsal hippocampus of socially isolated mice. Cellular activity in response to social stimulation in both areas was impaired by social isolation. By stimulating the mPFC using DBS, we found that DBS alleviated cellular activation disorders in the mPFC after long-term SI and improved social preference in mice. Conclusion: Our results suggest that the therapeutic potential of stimulating the mPFC with DBS in individuals with social preference deficits caused by long-term social isolation, as well as the effects of DBS on the cellular activity and density of OPCs.

Transcranial low-intensity ultrasound stimulation for treating central nervous system disorders: A promising therapeutic application.

Transcranial ultrasound stimulation is a neurostimulation technique that has gradually attracted the attention of researchers, especially as a potential therapy for neurological disorders, because of its high spatial resolution, its good penetration depth, and its non-invasiveness. Ultrasound can be categorized as high-intensity and low-intensity based on the intensity of its acoustic wave. High-intensity ultrasound can be used for thermal ablation by taking advantage of its high-energy characteristics. Low-intensity ultrasound, which produces low energy, can be used as a means to regulate the nervous system. The present review describes the current status of research on low-intensity transcranial ultrasound stimulation (LITUS) in the treatment of neurological disorders, such as epilepsy, essential tremor, depression, Parkinson's disease (PD), and Alzheimer's disease (AD). This review summarizes preclinical and clinical studies using LITUS to treat the aforementioned neurological disorders and discusses their underlying mechanisms.

Cangfudaotan decoction inhibits mitochondria-dependent apoptosis of granulosa cells in rats with polycystic ovarian syndrome.

Polycystic ovary syndrome (PCOS) is a universal endocrine and metabolic disorder prevalent in reproductive aged women. PCOS is often accompanied with insulin resistance (IR) which is an essential pathological factor. Although there is no known cure for PCOS, cangfudaotan (CFDT) decoction is widely used for the treatment of PCOS; nevertheless, the underlying mechanism is not clear. In this study, 40 Sprague-Dawley (SD) rats (female) were randomized to 4 groups, namely the control group, PCOS group, PCOS+CFDT group, and PCOS+metformin group. The rats in the control group were fed a normal-fat diet, intraperitoneally injected with 0.5% carboxymethyl cellulose (CMC, 1 mL/kg/d) for 21 days and orally given saline (1 mL/kg/d) for the next 4 weeks. The rats in the PCOS group, PCOS+CFDT group, and PCOS+Metformin group were fed a high-fat diet (HFD) and intraperitoneally injected with letrozole (1.0 mg/kg) for 21 days. During this period, we recorded the body weight, estrous cycles, and rate of pregnancy in all rats. We also observed the ovarian ultrastructure. Blood glucose indices, serum hormones, and inflammatory factors were also recorded. Then, we detected apoptotic and mitochondrial function, and observed mitochondria in ovarian granular cells by transmission electron microscopy. We also detected genes of ASK1/JNK pathway at mRNA and protein levels. The results showed that CFDT alleviated pathohistological damnification and apoptosis in PCOS rat model. In addition, CFDT improved ovarian function, reduced inflammatory response, inhibited apoptosis of granular cells, and inhibited the operation of ASK1/JNK pathway. These findings demonstrate the occurrence of ovary mitochondrial dysfunction and granular cell apoptosis in PCOS. CFDT can relieve mitochondria-dependent apoptosis by inhibiting the ASK1/JNK pathway in PCOS rats.

Genome-Wide Identification and Expression Analysis of Senescence-Associated Genes in Grapevine (Vitis vinifera L.) Reveal Their Potential Functions in Leaf Senescence Order.

Natural leaf senescence is an acclimation strategy that enables plants to reallocate nutrients. In the present study, interestingly, we found that the basal mature leaves of grapevine primary shoots (P) exhibited the earliest senescence, followed by the apical young leaves of secondary shoots (ST), and then the basal mature leaves of secondary shoots (S). The Chl level decreased with the extent of leaf senescence. According to the genome-wide identification and expression analysis, sixteen senescence-associated genes (SAGs) involved in Chl breakdown were identified in the grapevine genome. Their expression patterns showed that the transcript changes in VvSGR, VvPPH2, and VvFtsH6-2 corresponded to the changes in Chl content among P, S, and ST. The changes in the transcription of VvNYC1, VvSGR, VvPAO1, VvPAO2, VvPAO4, VvPPH1, VvPPH3, and VvFtsH6-1 only contributed to low Chl levels in P. The cis-element analysis indicated that these SAGs possessed several light- and hormone-responsive elements in their promoters. Among them, ABA-responsive elements were found in twelve of the sixteen promoters of SAGs. Correspondingly, ABA-signaling components presented various changes in transcription among P, S, and ST. The transcription changes in VvbZIP45 and VvSnRK2.1 were similar to those in VvSGR, VvPPH2, and VvFtsH6-2. The other nine ABA-signaling components, which included VvRCAR2, VvRCAR4, VvRCAR6, VvRCAR7, VvRCAR2, VvPP2C4, VvPP2C9, VvbZIP25, and VvSnRK2.3, were highly expressed in P but there was no difference between S and ST, with similar expression patterns for VvNYC1, VvSGR, VvPAO1, VvPAO2, VvPAO4, VvPPH1, VvPPH3, and VvFtsH6-1. These results suggested that the senescence of P and ST could be regulated by different members of Chl breakdown-related SAGs and ABA-signaling components. These findings provide us with important candidate genes to further study the regulation mechanism of leaf senescence order in grapevine.

Healthcare Resource Use in Patients with Immune-Mediated Conditions Treated with Targeted Immunomodulators During COVID-19 Pandemic: A Retrospective Claims Analysis.

INTRODUCTION: The impact of the COVID-19 pandemic on routine medical care may result in altered healthcare resource use in patients with immune-mediated conditions. The aim of this study was to determine the impact of treatment interruptions in patients with and without COVID-19 infections who were treated with targeted immunomodulators (TIMs) in the USA. METHODS: Data from the IBM® MarketScan® Research Databases were analyzed in patients with immune-mediated conditions from January 1, 2018, through December 31, 2020. Healthcare resource use (HCRU) including hospitalizations, emergency department (ED) visits, in-person outpatient visits, and respiratory outcomes was assessed in a cohort of patients without COVID-19 who had uninterrupted versus interrupted TIM use. The impact of treatment interruption on HCRU and respiratory outcomes was also evaluated in a cohort of patients with COVID-19. Results from adjusted logistic regression were reported as adjusted odds ratios (aORs) with 95% confidence intervals. RESULTS: Approximately 25% of patients in both the COVID-19 (N = 787) and non-COVID-19 cohorts (N = 77,178) experienced interruptions in TIM therapy. In the non-COVID-19 cohort, the likelihood of being hospitalized was 20% less in patients with uninterrupted versus interrupted TIM use (aOR = 0.80, 95% CI 0.71-0.90). Patients with uninterrupted TIM use had a similar likelihood of an ED visit (aOR = 0.99, 95% CI 0.91-1.08) and respiratory outcome (aOR = 0.97, 95% CI 0.71-1.31) versus patients with interrupted TIM use. The likelihood of having an in-person outpatient visit was 87% greater in patients with uninterrupted versus interrupted TIM use (aOR = 1.87, 95% CI 1.81-1.94). Similar findings were observed in the COVID-19 cohort. CONCLUSION: This analysis of real-world claims data showed that uninterrupted TIM use was not associated with an increased likelihood of hospitalizations, ED visits, or negative respiratory outcomes compared to interrupted TIM use among patients with immune-mediated conditions, regardless of COVID-19 diagnosis.

Tanshinone IIA combined with CsA inhibit myocardial cell apoptosis induced by renal ischemia-reperfusion injury in obese rats.

BACKGROUND: Acute myocardial injury (AMI), which is induced by renal ischemia-reperfusion (IR), is a significant cause of acute kidney injury (AKI)-related associated death. Obesity increases the severity and frequency of AMI and AKI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) pretreatment was used to alleviate myocardial cell apoptosis induced by renal IR, and to determine whether TIIA combined with CsA would attenuate myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats. METHODS: Male rates were fed a high fat diet for 8 weeks to generate obesity. AKI was induced by 30 min of kidney ischemia followed 24 h of reperfusion. Obese rats were given TIIA (10 mg/kg·d) for 2 weeks and CsA (5 mg/kg) 30 min before renal IR. After 24 h of reperfusion, the rats were anaesthetized, the blood were fetched from the abdominal aorta and kidney were fetched from abdominal cavity, then related indicators were examined. RESULTS: TIIA combined with CsA can alleviate the pathohistological injury and apoptosis induced by renal IR in myocardial cells. TIIA combined with CsA improved cardiac function after renal ischemia (30 min)-reperfusion (24 h) in obese rats. At the same time, TIIA combined with CsA improved mitochondrial function. Abnormal function of mitochondria was supported by decreases in respiration controlling rate (RCR), intracellular adenosine triphosphate (ATP), oxygen consumption rate, and mitochondrial membrane potential (MMP), and increases in mitochondrial reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA damage, and mitochondrial respiratory chain complex enzymes. The injury of mitochondrial dynamic function was assessed by decrease in dynamin-related protein 1 (Drp1), and increases in mitofusin1/2 (Mfn1/2), and mitochondrial biogenesis injury was assessed by decreases in PPARγ coactivator-1-α (PGC-1), nucleo respiratory factor1 (Nrf1), and transcription factor A of mitochondrial (TFam). CONCLUSION: We used isolated mitochondria from rat myocardial tissues to demonstrate that myocardial mitochondrial dysfunction occurred along with renal IR to induce myocardial cell apoptosis; obesity aggravated apoptosis. TIIA combined with CsA attenuated myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.

Impact of Adding Pharmacists and Comprehensive Medication Management to a Medical Group's Transition of Care Services.

OBJECTIVES: Evaluate the impact of pharmacist-provided transition of care (TOC) services on hospital readmissions. METHODS: Starting March 2014, TOC services were provided to all hospitalized patients from an at-risk medical group. Data covering all inpatient and outpatient services and prescription drugs were retrieved for all adult patients discharged between January 2010 and December 2018. The overall impact of TOC was estimated using a generalized estimating equation with logistic regression. Longitudinal TOC effects were estimated using generalized estimating equation in an interrupted time series model. Parallel analyses were conducted using data from an affiliated medical group in a neighboring county without access to the TOC intervention. RESULTS: The study included 13,256 hospital discharges for adult patients for the 30-day readmission analysis and 10,740 discharges for the 180 days analysis. The TOC program reduced 30-day readmission risk by 34.9% [odds ratio (OR)=0.651 (range, 0.590-0.719)] and 180-day readmissions by 33.4% [OR=0.666 (range, 0.604-0.735)]. The interrupted time series results found the 30-day readmission rate to be stable over the pre-TOC period (OR=0.00; not significant) then to decreased by 1.5% per month in the post-TOC period [OR=0.985 (range, 0.980-0.991)]. For 180-day readmissions, risk decreased by 1% per month after TOC implementation [OR=0.990 (range, 0.984-0.996)]. Referral to the medical group's pre-existing Priority Care clinic also reduced readmission risk. Results from the comparison medical group found 180-day readmission declined by 1% per month after March 2014 [OR=0.990 (0.891-1.00)]. CONCLUSIONS: Adding a pharmacist-led TOC program to the medical group's existing outpatient services reduced 30- and 180-day readmissions by "bending the curve" for readmission risk over time.

Cost-Effectiveness Analysis of Four Common Diagnostic Methods for Clostridioides difficile Infection.

BACKGROUND: No studies have evaluated the cost-effectiveness of single and two-step different diagnostic test strategies for Clostridioides difficile infection (CDI), including direct and indirect costs. OBJECTIVE: To evaluate the cost-effectiveness of commonly available diagnostic tests for CDI including nucleic acid amplification testing (NAAT) alone, glutamate dehydrogenase followed by enzyme immunoassay for toxin (GDH/EIA), GDH then NAAT (GDH/NAAT), and NAAT then EIA (NAAT/EIA). DESIGN: Decision tree model from the US societal perspective with inputs derived from the literature. Willingness-to-pay threshold was set at $150,000 per quality-adjusted life year (QALY) gained. To assess the impact of uncertainty in model inputs on the findings, we performed one-way and probabilistic sensitivity analyses. PARTICIPANTS: We conducted the analysis to represent a population aged 65 years old with diarrhea who received a CDI diagnostic test. MAIN MEASURES: Incremental cost-effectiveness ratios (ICER) and incremental net monetary benefits (INMB). KEY RESULTS: NAAT alone was the most cost-effective approach overall; GDH/NAAT was the most cost-effective two-step option. NAAT alone led to the highest QALYs gained, at an incremental cost of $54,547 (vs. GDH/NAAT), $55,410 (vs. GDH/EIA), and $50,231 (vs. NAAT/EIA) per QALY gained. NAAT/EIA was not cost-effective compared to any other strategy. GDH/NAAT resulted in a higher QALY compared to GDH/EIA, at an incremental cost of $96,841 per QALY gained. Variability in the likelihood of comorbidities, CDI probability, and age at disease onset did not substantially change the results. One-way sensitivity analyses showed that results were most sensitive to likelihood of recurrence, followed by CDI mortality rate and probability of severe CDI. Probabilistic sensitivity analyses explored known uncertainties in the base case and confirmed the robustness of the results. CONCLUSIONS: NAAT alone and GDH/NAAT (among the two-step options) were the most cost-effective diagnostic test approaches for CDI.

Time to hospital arrival among patients with acute myocardial infarction in China: a report from China PEACE prospective study.

Aims: Few contemporary studies have reported the time between acute myocardial infarction (AMI) symptoms onset and hospital arrival, associated factors, and patient perceptions of AMI symptoms and care seeking. We sought to study these issues using data from China, where AMI hospitalizations are increasing. Methods and results: We used data from the China PEACE prospective AMI study of 53 hospitals across 21 provinces in China. Patients were interviewed during index hospitalization for information of symptom onset, and perceived barriers to accessing care. Regression analyses were conducted to explore factors associated with the time between symptom onset and hospital arrival. The final sample included 3434 patients (mean age 61 years). The median time from symptom onset to hospital arrival was 4 h (interquartile range 2-7.5 h). While 94% of patients reported chest pain or chest discomfort, only 43% perceived symptoms as heart-related. In multivariable analyses, time to hospital arrival was longer by 14% and 39% for patients failing to recognize symptoms as cardiac and those with rural medical insurance, respectively (both P < 0.001). Compared with patients with household income over 100 000 RMB, those with income of 10 000-50 000 RMB, and <10 000 RMB had 16% and 23% longer times, respectively (both P = 0.03). Conclusion: We reported an average time to hospital arrival of 4 h for AMI in China, with longer time associated with rural medical insurance, failing to recognize symptoms as cardiac, and low household income. Strategies to improve the timeliness of presentation may be essential to improving outcomes for AMI in China. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT01624909.

Neutrophil-to-lymphocyte Ratio (NLR) as a predictor for recurrence in patients with stage III melanoma.

Neutrophil-to-lymphocyte ratio is a strong predictor for overall survival and disease free survival in many cancers. Our study is the first investigation aiming to determine the predictive value of neutrophil-to-lymphocyte ratio on prognosis of patients with stage III melanoma. This retrospective study utilized a cohort of 107 patients with stage III melanoma treated at Huntsman Cancer Institute, University of Utah, from May 2002 to March 2016. The optimal cutoff of neutrophil-to-lymphocyte ratio was determined by the significance of log-rank tests. A total of 97 log-rank tests were conducted to find the optimal cutoff. Disease free survival was assessed using the Kaplan-Meier method, and univariable and multivariable Cox models were applied to evaluate the predictive value of neutrophil-to-lymphocyte ratio. 2.5 was identified as the optimal cutoff. Kaplan-Meier curve showed that the disease free survival rate of the low value group was significantly higher compared to that of high value group. After adjusting for confounders and other prognostic factors, the neutrophil-to-lymphocyte ratio ≥ 2.5 remained a strong predictor for disease recurrence in patients with stage III melanoma.

Large-Scale Epidemiologic Studies of Cardiovascular Diseases in China: Need for Improved Data Collection, Methods, Transparency, and Documentation.

With the advent of international precision medicine initiatives, it is important to evaluate existing large-scale studies to inform future investigation. This study sought to review, describe, and evaluate all large-scale cardiovascular disease (CVD) studies completed in China. We undertook a review of all large-scale CVD studies completed in China to describe and evaluate their design, implementation, and dissemination in published medical reports. Seventeen studies met the inclusion criteria. There were substantial variations in study design, geographic location, and data collection. Most studies lacked standard study names, did not publish their methods, and provided no publicly available data. Few studies included underdeveloped regions or minority groups. Most published articles contained only descriptions of the average population at risk of CVD, and no study predicted individual CVD risk or identified people at high risk. Future CVD studies in China may need to incorporate stronger systematic data collection methods, increased data transparency, clearer documentation, and standard study names to most gain from China's burgeoning field of CVD research.

Protocol for the China PEACE (Patient-centered Evaluative Assessment of Cardiac Events) Million Persons Project pilot.

INTRODUCTION: Collection of high-quality data from large populations is considered essential to generate knowledge that is critical to an era of precision medicine. Cardiovascular disease (CVD) is a leading cause of mortality in China and is a suitable focus of an initiative to discover factors that would improve our ability to assess and modify individual risk. METHODS AND ANALYSIS: The pilot phase of China PEACE (Patient-centered Evaluative Assessment of Cardiac Events) Million Persons Project is being conducted during 2014-2015 in four provinces across China to demonstrate the feasibility of a population-based assessment. It is designed to screen 0.4 million community-dwelling residents aged 40-75 years with measurements of blood pressure, height and weight, a lipid blood test, and a questionnaire on cardiovascular-related health status. Participants identified at high risk of CVD receive further health assessments, including ECG, ultrasound scan, blood and urine analysis, and a questionnaire on lifestyle and medical history. Collection of blood and urine samples is used to establish a biobank. High-risk subjects are also counselled with suggestions regarding potential lifestyle changes. In addition, high-risk subjects are followed-up either in a return clinic visit or by telephone interview, with measurement of blood pressure, weight, ECG, and a questionnaire on survival status, hospitalisations and lifestyle. The first 0.1 million participants screened were used to conduct a preliminary analysis, with information on baseline characteristics, health-related behaviours, anthropometric variables, medical history, and prevalence of high-risk subjects. ETHICS AND DISSEMINATION: The central ethics committee at the China National Center for Cardiovascular Disease (NCCD) approved the pilot. Written informed consent is obtained from all participants on entry into the project. Findings will be disseminated in future peer-reviewed papers and will inform strategies aimed at developing precise methods of assessing and modifying risk. TRIAL REGISTRATION NUMBER: NCT02536456.