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The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.
This is an update of a Cochrane review published in 2012 of initiation of antihypertensive monotherapy or step-up therapy in people with untreated mild hypertension (systolic blood pressure 140 to 159 mmHg or diastolic blood pressure 90 to 99 mmHg, or both) and no pre-existing cardiovascular disease. The original review demonstrated no difference in the incidence of all-cause mortality, total cardiovascular events (stroke, myocardial infarction, and congestive heart failure), stroke incidence, coronary heart disease, or withdrawal due to adverse effects (WDAEs). Evidence for antihypertensive pharmacotherapy in people with mild hypertension for primary prevention remains uncertain in the literature with conflicting studies. We therefore performed an update of the original Cochrane review to reassess whether initiation of antihypertensive pharmacotherapy compared to placebo or no treatment in people with untreated mild hypertension and no pre-existing cardiovascular disease reduces the risk of all-cause mortality, total cardiovascular events, stroke, coronary heart disease, or WDAEs. To reassess the efficacy and risks of initiating antihypertensive pharmacotherapy in adults with untreated mild hypertension and no pre-existing cardiovascular disease. The primary objective was to reassess the risk of all-cause mortality and total cardiovascular events (defined as fatal and non-fatal strokes, myocardial infarction, and congestive heart failure). The secondary objectives were to reassess the risk of stroke (fatal and non-fatal), coronary heart disease (fatal and non-fatal myocardial infarction and sudden cardiac death), and WDAEs. We searched the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from inception to June 2024. We included randomized controlled trials (RCTs) of at least one-year duration comparing initiation on antihypertensive monotherapy or step-up therapy, or both, versus placebo or no treatment in participants with mild hypertension and no pre-existing cardiovascular disease. Our critical outcomes were all-cause mortality and total cardiovascular events. Important outcomes were stroke, coronary heart disease (fatal and non-fatal myocardial infarction and sudden cardiac death), and WDAEs. Two review authors assessed risk of bias independently and in duplicate using Cochrane's RoB 1 tool. Two review authors performed title and abstract screening, full-text review, and data extraction independently and in duplicate. We calculated risk ratio (RR) along with 95% confidence interval (CI) for all-cause mortality, total cardiovascular events, stroke events, coronary heart disease events, and WDAEs with the Mantel-Haenszel test and a fixed-effect model. We assessed the certainty of the evidence using the GRADE approach. We included individual patient data from five trials involving a total of 9124 participants, of whom 4593 received antihypertensives and 4531 received placebo or no treatment. All five trials reported all-cause mortality; four trials reported total cardiovascular events and strokes; three trials reported coronary heart disease; and one trial reported WDAEs. There may be little to no reduction in all-cause mortality (RR 0.85, 95% CI 0.64 to 1.14; 5 trials, 9124 participants; low-certainty evidence), total cardiovascular events (RR 0.93, 95% CI 0.69 to 1.24; 4 trials, 7292 participants; low-certainty evidence), or coronary heart disease (RR 1.12, 95% CI 0.80 to 1.57; 3 trials, 7080 participants; low-certainty evidence). There may be a decreased risk of stroke (RR 0.41, 95% CI 0.20 to 0.84; 4 trials, 7292 participants; low-certainty evidence) and an increase in WDAEs (RR 4.80, 95% CI 4.14 to 5.57; 1 trial, 17,354 participants [aggregate trial-level data; individual patient data unavailable]; low-certainty evidence) with antihypertensives. We downgraded the certainty of evidence for all outcomes due to imprecision, indirectness, and risk of bias. In people with untreated mild hypertension and no pre-existing cardiovascular disease, initiation of antihypertensive monotherapy or step-up therapy may not reduce all-cause mortality, total cardiovascular events, or coronary heart disease compared to those who received placebo or no treatment. There may be a reduction in stroke, but possibly also an increase in WDAEs. CIHR Grant to the Hypertension Review Group and British Columbia Ministry of Health Grant to the Therapeutics Initiative. Protocol (2007): doi.org/10.1002/14651858.CD006742. Original review (2012): doi.org/10.1002/14651858.CD006742.pub2.
While epilepsy research has largely focused on medical management and clinical outcomes, less attention has been given to the unmet psychosocial and everyday needs of people with epilepsy (PWE), particularly in low- and middle-income countries. The Global Epilepsy Needs Study (GENS) aims to explore these needs, which are integral to the quality of life, by capturing both shared and context-specific experiences. The GENS employed a patient-centered approach and mixed-methods design, integrating a cross-sectional survey and semi-structured interviews in 15 countries. The survey, available in 12 languages, captured experiences across 10 life domains (n = 5296 participants). Interviews were analyzed thematically using a phenomenological approach and Colaizzi's method, exploring lived experiences in depth (n = 75 participants). To ensure meaningful involvement and diverse representation, national patient associations, healthcare professionals, researchers, and people with lived experience guided each stage of the research process, from study design to manuscript development. Quantitative and qualitative data were integrated using a joint display method. This analysis generated five Generalized Themes across all life domains: (1) managing uncertainty and redefining daily life; (2) living with risk, social exclusion, and misunderstanding; (3) challenges in navigating inaccessible systems; (4) consequences of inaccessible or inadequate information; and (5) complex epilepsy needs demand more than standard approaches. This first-of-its-kind global study offers a comprehensive picture of the psychosocial and everyday challenges faced by PWE. It establishes a critical evidence base for epilepsy organizations, highlights the need for healthcare systems to adopt holistic, multidisciplinary approaches, and calls on policymakers to invest in systemic reforms that safeguard dignity, inclusion, and life opportunities. Future research should explore the needs of underserved groups, including caregivers, individuals with complex epilepsy, women, and those in low-income or rural settings. This study examined the everyday challenges faced by people with epilepsy in different parts of the world. It showed that many people struggle with fear, stigma, poor access to services, and a lack of clear information and support. Women, people in rural areas, and those in low-income settings often face the greatest challenges. The study calls for better education, more support for caregivers, and improvements across health, work, school, and transport systems. It also shows the need for more research to understand and respond to the real-life needs of people most impacted by epilepsy.
Gastrointestinal symptoms in Parkinson's disease (PD), in particular chronic constipation, are common and are treated in China using the traditional Chinese medicine (Jia-Wei-Ji-Chuan-Jian decoction) (JWJCJ)). However, information on therapeutic targets and the underlying mechanism is limited. A total of 72 PD patients with constipation attending Departments of Neurology in Shanghai, China (Shanghai Pudong New Area Gongli Hospital and Shuguang Hospital Affiliated to Shanghai University) were recruited into the study and allocated to a Treatment group (n = 36) and a Control group (n = 36). Patients in the Control group received a combination treatment comprising anti-Parkinson agents (Western drug regimen) with the addition of a traditional Chinese patent medicine (Huang-Xing Run-Chang Tablets*) over a period of 5 weeks, whereas patients in the Treatment group received the same anti-PD Western drug regimen together with the JWJCJ decoction, also for a period of 5 weeks. An evaluation using clinical efficacy scores was carried out together with network pharmacology analysis. Identified drug targets for JWJCJ using the traditional Chinese medicine Swiss Target Prediction database (TCMSP) and disease targets for chronic constipation in PD were obtained from Genecards and the OMIM database. Therapeutic targets for JWJCJ in the treatment of chronic constipation were identified by intersecting drug targets and disease targets. GO functional enrichment analysis, KEGG pathway analysis, and disease association analysis were carried out using the DAVID database and visualized using Cytoscape 3.9.1 software. CSS efficacy scores in the Treatment group were higher than that in the Control group (88.57 vs. 52.94%, p < 0.001). No significant differences were seen prior to treatment in the CSS, PDQ-39 and MDS-UPDRS scores and the corresponding total scores for the two groups. After treatment, CSS values for patients in the Treatment group were higher than values before treatment (p < 0.01). Network pharmacology analysis identified 172 active components, 9,542 drug targets, and 421 intersecting target genes for JWJCJ. PPI analysis identified 10 main and possibly key targets for JWJCJ in the treatment of chronic constipation. KEGG analysis identified 198 signaling pathways, where pathways in cancer, specific cancer pathways such as prostate cancer and non-small cell lung cancer, lipid and atherosclerosis, hepatitis B, and the AGE-RAGE signaling pathway in diabetic complications were among the pathways most significantly enriched. These findings are evidence that the active ingredients in JWJCJ in the treatment of chronic constipation in PD mainly target TP53, SRC, AKT1, PIK3R1, and PIK3CA. The efficacy of JWJCJ in treating chronic constipation in PD involves the targets SRC, PIK3R1, JUN, TP53, STAT3, PIK3CA, EGFR, ESR1, MAPK1, and AKT1 domains. These findings provide theoretical basis for the clinical application of JWJCJ decoction in the treatment of chronic constipation in PD.
An increasing number of older adults living with frailty are undergoing surgery, yet scarce data on postoperative functional recovery, care needs after surgery, and extent of caregiver supports exist. To characterize older adults' and caregivers' recovery experiences in the first 6 months after surgery. This mixed-methods, multicenter, prospective nested cohort study included 17 hospitals in Canada. Participants included adults aged 65 years or older with a Clinical Frailty Scale score of 4 or more, who were recovering after major elective noncardiac surgery between March 16, 2021, and June 13, 2023, and their caregivers. Surveys included functional status via basic and instrumental activities of daily living, care needs, and care received or provided. A subset of patients and caregivers were invited to participate in semistructured interviews about their experiences and were analyzed using interpretive descriptive qualitative analysis. There were 289 individuals, including 204 older adults (mean [SD] age, 72.8 [5.6] years; 108 males [52.9%]) and 85 caregivers (mean [SD] age, 68.2 [12.2] years; 50 females [59.5%]), who participated in surveys, and 63 individuals (43 older adults and 20 caregivers) who participated in interviews. Older adults had a median (range) Clinical Frailty Score of 4 (3-6), indicating mild frailty, and 190 (93.1%) had 1 or more chronic diseases. Caregivers had a median (range) of 2 (0-8) chronic diseases, and 69 (82%) were spouses. Two months postoperatively, 129 of 203 older adults (64%) had more than 1 instrumental activities of daily living impairment, decreasing to 84 of 198 (42%) at 6 months after surgery; 68 of 203 (33%) had more than 1 activities of daily living impairment 2 months postoperatively, and this decreased to 38 of 198 (19%) at 6 months after surgery. Themes related to the recovery experiences were: (1) inadequate patient and caregiver education, preparation for surgery, and discharge; (2) the association of reduced independence with patient and caregivers; (3) the association of surgery with mental health; and (4) postoperative support from the health care team. All participants indicated that they wanted to be better prepared for surgery and discharge. In this mixed-methods cohort study, functional recovery in the first 6 months after noncardiac major elective surgery was associated with daily living impairment for older adults and their caregivers. Targeted interventions including preoperative education, caregiver-inclusive discharge planning (eg, wound-care teaching, how to recognize complications and what to do for support, and more rehabilitation), and early follow-up after discharge may optimize recovery experiences.
To examine the effects of the oral uremic toxin absorbent AST-120 on the concentration of free and protein-bound indoxyl sulphate (IS) and to assess the effects of serum albumin in end-stage kidney disease (ESKD) patients undergoing hemodialysis. The study enrolled 37 ESKD patients who initiated hemodialysis at the Shirasagi Hospital. Serum free and bound IS concentrations were measured before the first of 4 hemodialysis sessions and after the last hemodialysis 7 days later. The cohort contained a subgroup of patients in whom AST-120 treatment (6 g/day) was discontinued immediately prior to the first hemodialysis and a subgroup not treated with AST-120. Clinical characteristics were obtained from electronic medical records. Discontinuation in AST-120 treatment prior to dialysis resulted in marked but highly variable increases in IS concentrations, measured 7 days later, where the efficiency of dialysis of IS was dependent on the serum albumin concentration. The observation that the percentage change in IS concentration was significantly higher after discontinuation of AST-120 compared to those not receiving AST-120 was unexpected as was the finding of a high inter-patient variability in IS concentrations before and after hemodialysis. The effects of a discontinuation in AST-120 administration can be interpreted as a rebound in the systemic absorption of indole precursors, but the source of variability in IS concentrations was unclear. Although there are important limitations in this investigation, the report presents valid and valuable data on free and albumin-bound IS concentrations during hemodialysis and AST-120 treatment as well as measurements of serum albumin concentrations in the group of largely elderly subjects. AST-120 in ESKD patients has profound effects on the disposition of IS. There are important sources of variability having a possible marked effect on the concentration of IS in patients with chronic kidney disease. Discontinuing AST-120 treatment before hemodialysis, a practice in Japan to avoid the "off-label" administrations of the agent, will result in high and variable concentrations of uremic toxins such as IS. The consequences of this effect will include progression of the disease and the occurrence of cardiovascular and neurological degeneration.
BACKGROUND: Cisplatin chemoresistance is a critical challenge in treating head and neck squamous cell carcinoma (HNSCC). Previous research from Manyanga et al. (2021) suggested that e-cigarette (e-cig) aerosol, including formulations with and without nicotine, might increase cisplatin resistance in oral cancer cells. This multicenter replication study aimed to validate the findings and evaluate the oncologic impacts of e-cigarette use during chemotherapy. METHODS: This in vitro study utilized standardized and harmonized protocols across international laboratories to examine the effects of cigarette smoke (1R6F) and e-cig aerosols with different concentrations of nicotine (0, 12, and 20 mg/ml nicotine) on cisplatin sensitivity in HNSCC cell lines (SCC-25, FaDu, and UM-SCC-1). Aqueous extracts from 1R6F smoke and e-cig vapor were collected using a smoking and a vaping machine, respectively, following ISO20778:2018 and ISO20768:2018 puffing regimes. The smoke and vapor were collected in PBS and diluted to 10 puffs/5L for HNSCC cell treatment. Chemosensitivity, clonogenicity, DNA repair gene expression related to cisplatin-induced damage, and gene/protein expression of cisplatin transporters, were assessed by MTS, NRU, trypan blue exclusion, qRT-PCR, and Western blot assays, respectively. RESULTS: Contrary to previous findings, exposure to e-cig aerosols did not significantly modulate cisplatin sensitivity in all cell lines. IC50 values, cytotoxicity assays, and clonogenic survival rates remained similar between cells treated with e-cig aerosols and those exposed to cisplatin alone. Analysis of gene and protein expression revealed occasional variations in the levels of cisplatin transporters and DNA repair mechanisms, but these changes were inconsistent. CONCLUSIONS: This study did not fully substantiate previous claims that aerosols generated from e-cigarette, with and without nicotine, increase cisplatin resistance. The variability in gene and protein expression among different cell lines underscores the need for cautious interpretation and further investigation of the role of e-cigarette components in cancer treatment. These findings provide a critical perspective for shaping public health policies and clinical practices regarding e-cigarette use during chemotherapy.
Information on childhood cancer burden is crucial for effective cancer policy planning. Unfortunately, observed paediatric cancer data are not available in every country, and previous global burden estimates have not discretely reported several common cancers of childhood. We aimed to inform efforts to address childhood cancer burden globally by analysing results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, which now include nine additional cancer causes compared with previous GBD analyses. GBD 2023 data sources for cancer estimation included population-based cancer registries, vital registration systems, and verbal autopsies. For childhood cancers (defined as those occurring at ages 0-19 years), mortality was estimated using cancer-specific ensemble models and incidence was estimated using mortality estimates and modelled mortality-to-incidence ratios (MIRs). Years of life lost (YLLs) were estimated by multiplying age-specific cancer deaths by the standard life expectancy at the age of death. Prevalence was estimated using survival estimates modelled from MIRs and multiplied by sequelae-specific disability weights to estimate years lived with disability (YLDs). Disability-adjusted life-years (DALYs) were estimated as the sum of YLLs and YLDs. Estimates are presented globally and by geographical and resource groupings, and all estimates are presented with 95% uncertainty intervals (UIs). Globally, in 2023, there were an estimated 377 000 incident childhood cancer cases (95% UI 288 000-489 000), 144 000 deaths (131 000-162 000), and 11·7 million (10·7-13·2) DALYs due to childhood cancer. Deaths due to childhood cancer decreased by 27·0% (15·5-36·1) globally, from 197 000 (173 000-218 000) in 1990, but increased in the WHO African region by 55·6% (25·5-92·4), from 31 500 (24 900-38 500) to 49 000 (42 600-58 200) between 1990 and 2023. In 2023, age-standardised YLLs due to childhood cancer were inversely correlated with country-level Socio-demographic Index. Childhood cancer was the eighth-leading cause of childhood deaths and the ninth-leading cause of DALYs among all cancers in 2023. The percentage of DALYs due to uncategorised childhood cancers was reduced from 26·5% (26·5-26·5) in GBD 2017 to 10·5% (8·1-13·1) with the addition of the nine new cancer causes. Target cancers for the WHO Global Initiative for Childhood Cancer (GICC) comprised 47·3% (42·2-52·0) of global childhood cancer deaths in 2023. Global childhood cancer burden remains a substantial contributor to global childhood disease and cancer burden and is disproportionately weighted towards resource-limited settings. The estimation of additional cancer types relevant in childhood provides a step towards alignment with WHO GICC targets. Efforts to decrease global childhood cancer burden should focus on addressing the inequities in burden worldwide and support comprehensive improvements along the childhood cancer diagnosis and care continuum. St Jude Children's Research Hospital, Gates Foundation, and St Baldrick's Foundation.
Chronic urticaria (CU) is a refractory, long-course skin disorder involving multifactorial and complex pathophysiology. Although Shengma Gegen decoction (SMGG) shows clinical benefit, its mechanistic basis remains unclear. To elucidate the multitarget, multipathway mechanisms of SMGG in CU and to prioritize key targets and pathways for subsequent experimental validation. We integrated network pharmacology and bioinformatics using TCMSP, UniProt, GeneCards, and OMIM. A total of 126 bioactive compounds and 216 putative targets were identified. Enrichment analyses (including KEGG) were performed, immune-infiltration patterns were assessed, and molecular docking plus molecular-dynamics simulations evaluated ligand-target interactions. Key regulatory targets were highlighted - MMP9, IL6, AKT1, IL1B and TNF - with strong associations to inflammatory and immune regulation. KEGG analysis prioritized AGE-RAGE, TNF, and IL-17 pathways. Immune-infiltration analysis suggested that SMGG may modulate the Th1/Th2 balance. Docking and dynamics demonstrated stable binding and plausible dynamic interactions between representative active components and the prioritized targets. These findings support a multi-target, multi-pathway mode of action for SMGG in CU, aligning inflammatory signaling and immune modulation. As an in-silico study, the results provide hypotheses that warrant rigorous in-vitro and in-vivo validation. SMGG may ameliorate CU by coordinately regulating inflammatory pathways (AGE-RAGE, TNF, IL-17) and immune balance via core targets (MMP9, IL6, AKT1, IL1B, TNF). The study offers a mechanistic basis and target/pathway prioritization to guide future experimental work and the modernization of traditional formulations.
This study was conducted to compare the single-dose pharmacokinetic and safety profiles of JLP-1401 (fixed-dose combination (FDC) of telmisartan/amlodipine/rosuvastatin) to those of each constituent co-administered in healthy Korean male volunteers. A total of 40 healthy Korean subjects participated in an open-label, randomized, single-dose, 4-period crossover study. During each treatment period, the subjects received the test drug (FDC tablet of telmisartan/amlodipine/rosuvastatin 80 mg/10 mg/20 mg) or reference drug (co-administration of telmisartan/amlodipine FDC tablet and rosuvastatin tablet). Plasma samples were collected pre dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours post dose to evaluate pharmacokinetic profiles. Safety was assessed by the evaluation of adverse events (AEs), laboratory assessments, 12-lead electrocardiograms, physical examinations, and vital sign measurements. The geometric least-square mean ratios and their 90% confidence intervals of AUClast and Cmax were 1.01 (0.94 - 1.07) and 0.83 (0.72 - 0.95) for telmisartan, 1.01 (0.99 - 1.04) and 1.03 (1.01 - 1.06) for amlodipine, and 1.03 (0.98 - 1.08) and 0.94 (0.85 - 1.04) for rosuvastatin, respectively. All AEs were of mild or moderate intensity, and there were no significant differences in the incidence of AEs between the treatments. The pharmacokinetic profiles of the test and reference drugs were within the bioequivalent criteria, and both drugs were safe and well tolerated.
To evaluate the effects of anesthesia with dexmedetomidine (DEX) and closed-loop target-controlled inhalation of sevoflurane on the intestinal flora and levels of serum pain mediators in patients undergoing abdominal surgery. A cohort of 100 patients who had received abdominal surgery in the period February 2022 to March 2024 were recruited in this retrospective study. The observational group (n = 50) received anesthesia with DEX plus closed-loop target-controlled inhalation of sevoflurane, and the control group (n = 50) received anesthesia with DEX alone. Inter-group comparisons were made for sex, age, etiology, and educational level and for the quality of anesthesia (anesthesia recovery time and induction time), changes in the intestinal flora (Shannon index and Simpson index) and levels of serum pain mediators (prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and 5-hydroxytryptamine (5-HT)) before anesthesia and 5 minutes after anesthesia induction. The anesthesia recovery and induction time were significantly shorter in the observational group than in the control group (p < 0.05). At 5 minutes after anesthesia induction, both the Shannon index and Simpson index were significantly lower in the control group than in the observation group (p < 0.05), and the levels of PGE2, TNF-α, and 5-HT were also significantly lower in the observation group (p < 0.05). Evidence was provided showing that anesthesia with DEX plus closed-loop target-controlled inhalation with sevoflurane improves the quality of the anesthesia, reduces the levels of serum pain mediators, and has potentially beneficial effects on the intestinal flora in patients undergoing abdominal surgery.
The mucosal protective agent, bismuth potassium citrate, is used for treatment of chronic gastritis and gastric stress conditions, including heartburn and acid reflux. 1) To establish and validate a new inductively coupled mass spectrometry (ICP-MS) analytical method for the determination of bismuth metal in human plasma; and 2) to determine the systemic absorption and safety characteristics of bismuth following the administration of bismuth potassium citrate granules (test drug) and bismuth potassium citrate tablets (reference drug) in healthy Chinese subjects. A single-center, randomized, open-label, two-drug, single-dose, two-cycle, double-crossover pharmacokinetics study was carried out in a cohort of 24 healthy adult subjects in the fasting state. Subjects meeting the inclusion criteria were randomly assigned to the first cycle in ascending order of screening number obtained prior to dosing. The randomization table assigned subject either to the TR-group (test-reference cycle) or the RT group (reference-test cycle) where each group contained a total of 12 subjects. Subjects recruited but not completing the study, or in whom the data sets were incomplete, were not replaced. Using this study design, all subjects received a single dose of both preparations in the fasting state whereby 12 subjects received the drugs in the order RT and 12 subjects in the order TR, with a washout period of 7 days between each drug administration cycle, respectively. Pharmacokinetic parameters (concentration maximum (Cmax), AUC0-t, and area under the concentration-time curve to infinity (AUC0-∞) were analyzed using a linear mixed-effects model after natural log transformation. The lower limit of the 90% confidence intervals for the geometric mean ratio (test preparation/reference preparation) were below 100%, and the bioavailability of the test formulation (granules) was markedly superior to that for the reference formulation (tablets) where values for Cmax, AUC0-t, and AUC0-∞ after natural log transformation were 5.44, 12.82, 10.86, 22.44, and 13.79%, 27.42%, respectively. The systemic absorption of bismuth metal from the granules was not greater than that for the tablets. Although the bioavailability of the granules was markedly superior to tablets, the systemic absorption of bismuth metal from the two formulations was similar, and there was no evidence for a difference in the safety characteristics.
ABBV-368 is a humanized monoclonal antibody that targets the costimulatory receptor OX40. Here, we investigate a treatment strategy with ABBV-368 combined with the investigational toll-like receptor 9 agonist tilsotolimod, the programmed cell death 1 inhibitor budigalimab, and nab-paclitaxel in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). To our knowledge, this is the first clinical study in this setting to investigate chemotherapy combined with three immunotherapy agents, aiming to overcome failure of prior immune checkpoint inhibition and chemotherapy. This phase 1b, multicenter, open-label study (NCT04196283) enrolled adult patients with R/M HNSCC into one of three treatment arms: ABBV-368 with tilsotolimod, ABBV-368 with tilsotolimod and nab-paclitaxel, or ABBV-368 with tilsotolimod, nab-paclitaxel, and budigalimab. Patients were treated in 28-day cycles. ABBV-368, nab-paclitaxel, and budigalimab were administered intravenously and tilsotolimod via intratumoral injection. Study objectives included safety, tolerability, pharmacokinetics, and preliminary antitumor activity. In addition, biomarker analyses were performed. Overall, 30 patients were enrolled; 16 received ABBV-368 plus tilsotolimod, 7 ABBV-368 plus tilsotolimod and nab-paclitaxel, and 7 ABBV-368 plus tilsotolimod, nab-paclitaxel, and budigalimab. In total, 80% of patients experienced any-grade adverse events related to ABBV-368. ABBV-368 and tilsotolimod induced peripheral interferon-gamma pathway upregulation, Th1 cytokine production, and T-cell activation that was not negatively impacted by nab-paclitaxel. There were no responses in the ABBV-368 plus tilsotolimod arm; one partial response was demonstrated in both the ABBV-368 plus tilsotolimod and nab-paclitaxel, and ABBV-368 plus tilsotolimod, nab-paclitaxel, and budigalimab arms, corresponding to an overall response rate of 14.3%. The quadruple combination of ABBV-368, tilsotolimod, nab-paclitaxel, and budigalimab was well tolerated and demonstrated pharmacodynamic activity. Several patients had disease stabilization, but clinical responses were limited. Initial priming and T-cell immune activation were inadequate to overcome prior therapy resistance mechanisms including a hypothesized unfavorable tumor microenvironment. Future work investigating strategies to target this inhibitory tumor microenvironment with optimally scheduled immunotherapy combinations in selected patients and indications is urgently needed to improve patient outcomes. NCT04196283.
To investigate safety signals associated with recombinant human growth hormone (rhGH) using the FDA Adverse Event Reporting System (FAERS) and make recommendations for its application. rhGH is widely used in the management of pediatric growth disorders, but a comprehensive evaluation of its safety in pediatric populations is limited. Adverse event (AE) reports involving patients under 18 years of age where rhGH was the primary suspect (PS) drug were retrieved from the FAERS database for the period beginning the first quarter of 2004 to the end of the third quarter of 2024. The reports were standardized and duplicate reports removed. Disproportionality analysis of AE signals was conducted using four complementary methods, namely i) reporting odds ratio (ROR), ii) proportional reporting ratio (PRR), iii) Bayesian confidence propagation neural network (BCPNN), and iv) empirical Bayesian geometric mean (EBGM). A total of 33,888 AE reports were retrieved and analyzed. Disproportionality analysis identified 167 positive signals across 19 System Organ Classes (SOCs), the most frequently of which was "Investigations," and the most common preferred term (PT) was "Arthralgia". In addition to confirmed AEs, several endocrine-related signals were also recognized including a) fluctuations in thyroid-stimulating hormone, b) increase in unbound concentrations of thyroxine, c) type 1 diabetes mellitus, d) low concentrations of high-density lipoprotein, and e) abnormal body odor. A comprehensive safety profile was established for rhGH when used in pediatric populations and comprising several newly identified potential AE signals. The findings underscore the importance of surveillance to mitigate risks and ensure the safe clinical use of rhGH.
To evaluate the efficacy and safety of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in chronic kidney disease (CKD). Dyslipidemia is common in patients with CKD and contributes to their elevated cardiovascular risk. However, evidence regarding the lipid-lowering efficacy and renal safety of PCSK9 inhibitors in CKD stages 3 - 4 is limited. A cohort of 200 patients with stage 3 - 4 CKD and hyperlipidemia were administered evolocumab in a single-center retrospective study. Lipid parameters including low-density lipoprotein cholesterol (LDL-C), renal function (estimated glomerular filtration rate, serum creatinine, blood urea nitrogen), and liver enzymes were assessed at baseline and at 3, 6, and 12 months follow-up. Subgroup and multivariate analyses were performed to determine factors associated with LDL-C reduction. Publicly available transcriptomic resources were consulted to provide biological parameters regarding tissue-specific PCSK9 expression. After 12 months, LDL-C was significantly decreased (-56.3 ± 10.5%) compared to baseline where the reduction in stages 3 and stage 4 CKD were similar. Non-high-density lipoprotein (HDL-C) and total cholesterol also declined significantly, but here were no significant changes in HDL-C and triglycerides. Renal function showed no significant deterioration, and no hepatotoxicity or clinically significant adverse events occurred. Baseline LDL-C and age were independent predictors of LDL-C reduction. Public transcriptomic data indicated that PCSK9 expression is predominantly enriched in liver tissue but remains minimal in renal tissues and across major renal cell types, providing biological evidence to explain the preserved renal function observed in this cohort. Evolocumab is an effective agent for lowering LDL-C levels and has a satisfactory short-term renal and hepatic safety in this cohort with similar effects across CKD subgroups. The low renal expression of PCSK9 may partly explain its renal safety. These results support the use of evolocumab as a practical and well-tolerated lipid-lowering option for CKD patients who need intensive LDL-C control.
To retrospectively analyze the clinical safety and adverse drug reactions (ADRs) of sintilimab, to evaluate risk factors for ADR occurrence, and to develop a predictive model to support individualized treatment strategies. Medical records of patients who received sintilimab treatment in the period January 2021 to December 2022 were examined. Clinical data, including demographic characteristics, medication details, and ADRs were recorded and evaluated using univariate and multivariate logistic regression analyses to identify independent risk factors for sintilimab-induced ADRs. Variables such as gender, age, comorbidities, and treatment regimens were included. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive accuracy of individual and combined risk factors, enabling the safety profile of sintilimab to be established. A total of 337 cases were retrieved of which 208 (61.72%) referred to patients who experienced ADRs. Multivariate analysis identified combination drug therapy (OR = 25.670, 95% CI: 11.319 - 58.218, p < 0.001) and pretreatment baseline assessment (OR = 0.388, 95% CI: 0.191 - 0.789, p = 0.009) as two independent risk factors. The logistic model indicated that the combined prediction ability of these factors gave an area under the curve (AUC) of 0.800 (p < 0.001), which indicated prediction superiority compared to using the factors alone. Cross-validation using 115 cases demonstrated an accuracy of ~ 80.87% for the model. Combination therapy and pretreatment baseline assessment are independent risk factors for ADRs occurring during therapy with sintilimab. The combined predictive model derived shows high accuracy and may have value in predicting treatment risks and managing personalized medication.
To assess the use of laboratory monitoring, folic acid supplementation, and folinate calcium therapy in patients with rheumatoid arthritis (RA) receiving first-line methotrexate (MTX) according to the 2019 Japan College of Rheumatology safety updates and using a large Japanese claims database (DeSC). Patient data for the period 2015 - 2020 were retrieved from the database, and patients were identified who had presented with active disease. The number of patients commencing with MTX treatment and receiving concomitant disease-modifying antirheumatic drug and folic acid supplementation were determined together with information on recommended laboratory testing (blood tests, serum creatinine, chest radiography, and KL-6) in the year prior to MTX initiation. The impact of the 2019 Japan College of Rheumatology guidelines was assessed by comparing the extent of folic acid supplementation before and after publication of the guidelines. Of the 1,574 patients identified with active RA, 919 (58.4%) started MTX. Folic acid was co-administered in 85.1% of MTX users, with no significant change in supplementation rates before and after the introduction of the 2019 guidelines (81.8 vs. 82.2%, p = 0.56), indicating that these safety protocols were already well-established. Baseline blood tests were carried out in 99.8% and chest radiography in 69.2% of patients. After commencing MTX treatment, the monitoring of serum creatinine (87.2 vs. 93.7%, p < 0.05) and KL-6 (15.2 vs. 28.4%, p < 0.05) increased significantly. The frequency of chest radiography decreased to 56.0% (p < 0.05), reflecting a shift toward more sensitive diagnostic tools in clinical practice. No patients required folinate calcium rescue therapy. MTX prescribing and monitoring in RA is generally carried out in accordance with clinical guidelines. Although folic acid supplementation is recommended and widely implemented, ~ 20% of patients do not receive it. Monitoring is generally carried out rigorously, but safety data indicate that these measures should receive more attention in high-risk elderly populations who were probably under-represented in this study.
This study was conceived to compare the clinical efficacy of Tripterygium wilfordii Hook F (TWHF) medical wine and Tripterygium glycoside tablets (TGTs) in patients with primary Sjögren's syndrome (pSS), mainly focusing on inflammatory markers, autoantibody profiles, and salivary gland function. In this prospective, randomized controlled trial, 90 pSS patients were enrolled and randomly assigned into a TWHF medical wine group (Observation) or TGTs group (Control), receiving either TWHF medical wine (8 mL, twice daily) or TGTs (10 mg, 3 times daily) for 12 weeks. Primary outcomes included unstimulated whole saliva (UWS) flow rate, EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), and positivity rates of anti-SSA/SSB antibodies. Secondary outcomes included subjective symptom scores (EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI)), serum IgG levels, and safety profiles. Baseline characteristics were comparable between the two groups. After 12 weeks, the Observation group showed significantly greater improvements in UWS and ESSDAI scores. The positive rates of anti-SSA and anti-SSB had decreased in both groups, with a more pronounced decline observed in the observation group, though between-group differences were not statistically significant. ESSPRI scores and IgG levels were significantly reduced in both groups, with more pronounced changes in the Observation group. No severe adverse events occurred, and both treatments were well tolerated with comparable safety profiles. TWHF medical wine is more effective than TGTs in improving salivary gland function, systemic disease activity, and immunological profiles in pSS patients, with comparable safety. These results suggest that TWHF medical wine is a suitable alternative treatment for primary Sjögren's syndrome.
Apremilast is a pioneering oral selective phosphodiesterase-4 inhibitor for the treatment of psoriasis. To evaluate and compare the pharmacokinetic properties and bioavailability of apremilast tablets manufactured by Nanjing Haijing Pharmaceutical Company (Nanjing, China) with apremilast tablets certified by Celgene Europe B.V. (Utrecht, The Netherlands), we conducted a randomized, open-label, single-dose, two-period, crossover study in healthy Chinese subjects under fasted and fed conditions. Eligible subjects were randomly assigned to receive reference or test apremilast tablets in the first treatment period and the other formulation in the second period. Serial blood samples were collected for pharmacokinetic analysis. Adverse events were recorded. A total of 28 healthy subjects were enrolled in the fasting cohort and 36 subjects in the fed cohort. The 90% confidence intervals of the geometric mean ratios of the test to reference formulations were 91.56 - 106.18% for Cmax, 96.08 - 108.18% for AUC0-t, and 96.02 - 107.67% for AUC0-∞ in the fasting cohort, and 95.15 - 107.05% for Cmax, 105.13 - 113.45% for AUC0-t, and 104.80 - 111.91% for AUC0-∞in the fed cohort, all of which were within the bioequivalence range of 80.00 - 125.00%. There were no serious adverse events. The results showed that the test and reference apremilast tablets were bioequivalent and well tolerated in healthy Chinese subjects under fasting and fed conditions.
To investigate differences in drug-induced dysphagia profiles among causative drugs, with a focus on reporting risk, patient age, and time to onset. Drug-induced dysphagia is one of several causes of dysphagia. However, its detailed profile, including differences among drugs and age groups, has not yet been thoroughly examined. Data were obtained from the Japanese Adverse Drug Event Report Database. Reports submitted between April 2004 and October 2021 were analyzed. The 10 drugs with the highest number of reports of drug-induced dysphagia were selected as the target drugs. Reporting odds ratios were calculated to evaluate the association between each drug and dysphagia. The primary endpoint was the reporting odds ratio, while age distribution and time to onset were secondary outcomes. A total of 756,965 reports were analyzed. All target drugs were associated with drug-induced dysphagia. Cevimeline was identified as a novel finding because dysphagia was not observed during clinical trials. For most drugs, dysphagia occurred within approximately 25 days of administration. In contrast, paroxetine and milnacipran were associated with dysphagia even after long-term use. The age distribution of reported cases differed by drug, suggesting drug-specific differences in susceptible age groups. Drug-induced dysphagia profiles differ among drugs, particularly in terms of timing of onset and patient age distribution. Therefore, clinicians should consider both the causative drug and the patient's age when monitoring for dysphagia.