Real-world evidence on the association between natural medicinal products and the recurrence of sleep disorders is currently limited, particularly when compared to the evidence reported for prescription hypnotics. In a retrospective cohort analysis, we investigated patients with sleep disorders prescribed either the natural medicinal product Neurexan (Nx4), benzodiazepines, or nonbenzodiazepines (Z-drugs) using the IQVIA Disease Analyzer database, which encompasses electronic medical records nationwide in Germany. A 1:1 matching procedure based on age, sex, prevalent depression, anxiety or adjustment disorder, and the number of medical consultations in the past 12 months resulted in four cohorts: patients prescribed Nx4 were matched with those prescribed Z-drugs (two cohorts with 8594 matched patients each), and another cohort of patients prescribed Nx4 were matched with those prescribed benzodiazepines (7779 matched pairs). Results from multivariable-adjusted Cox regression models demonstrated that Nx4 was associated with a significantly lower risk of recurrent sleep disorder diagnosis within 30-365 days after prescription compared to both Z-drugs (HR = 0.65, 95%CI = 0.60-0.70, p < 0.001) and benzodiazepines (HR = 0.85, 95%CI = 0.79-0.93, p < 0.001). Additionally, Nx4 was associated with a lower prevalence of depression compared to Z-drugs (HR = 0.90, 95%CI = 0.83-0.98, p = 0.020) and benzodiazepines (HR = 0.89, 95%CI = 0.82-0.97, p = 0.009). These findings suggest an association between Nx4 and improved sleep and mental health outcomes. However, due to inherent limitations in the study design, the causality of this relationship cannot be stated.

BACKGROUND: Pulmonary hypertension due to interstitial lung disease (PH-ILD) is associated with high rates of respiratory failure and death. Healthcare resource utilization (HCRU) and cost data are needed to characterize PH-ILD disease burden.
METHODS: A retrospective cohort analysis of the Truven Health MarketScan® Commercial Claims and Encounters Database and Medicare Supplemental Database between June 2015 to June 2019 was conducted. Patients with ILD were identified and indexed based on their first claim with a PH diagnosis. Patients were required to be 18 years of age on the index date and continuously enrolled for 12-months pre- and post-index. Patients were excluded for having a PH diagnosis prior to ILD diagnosis or the presence of other non-ILD, PH-associated conditions. Treatment patterns, HCRU, and healthcare costs were compared between the 12 months pre- versus 12 months post-index date.
RESULTS: In total, 122 patients with PH-ILD were included (mean [SD] age, 63.7 [16.6] years; female, 64.8%). The same medication classes were most frequently used both pre- and post-index (corticosteroids: pre-index 43.4%, post-index 53.5%; calcium channel blockers: 25.4%, 36.9%; oxygen: 12.3%, 25.4%). All-cause hospitalizations increased 2-fold, with 29.5% of patients hospitalized pre-index vs. 59.0% post-index (P < 0.0001). Intensive care unit (ICU) utilization increased from 6.6 to 17.2% (P = 0.0433). Mean inpatient visits increased from 0.5 (SD, 0.9) to 1.1 (1.3) (P < 0.0001); length of stay (days) increased from 5.4 (5.9) to 7.5 (11.6) (P < 0.0001); bed days from 2.5 (6.6) to 8.0 (16.3) (P < 0.0001); ICU days from 3.8 (2.3) to 7.0 (13.2) (P = 0.0362); and outpatient visits from 24.5 (16.8) to 32.9 (21.8) (P < 0.0001). Mean (SD) total all-cause healthcare costs increased from $43,201 ($98,604) pre-index to $108,387 ($190,673) post-index (P < 0.0001); this was largely driven by hospitalizations (which increased from a mean [SD] of $13,133 [$28,752] to $63,218 [$75,639] [P < 0.0001]) and outpatient costs ($16,150 [$75,639] to $25,604 [$93,964] [P < 0.0001]).
CONCLUSIONS: PH-ILD contributes to a high HCRU and cost burden. Timely identification, management, and treatment are needed to mitigate the clinical and economic consequences of PH-ILD development and progression.

Dysregulation of the immune system and N6-methyladenosine (m6A) contribute to immune therapy resistance and cancer progression in urothelial carcinoma (UC). This study aims to identify immune-related molecules, that are m6A-modified, and that are associated with tumor progression, poor prognosis, and immunotherapy response.
We identified prognostic immune genes (PIGs) using Cox analysis and random survival forest variable hunting algorithm (RSF-VH) on immune genes retrieved from the Immunology Database and Analysis Portal database (ImmPort). The RM2Target database and MeRIP-seq analysis, combined with a hypergeometric test, assessed m6A methylation in these PIGs. We analyzed the correlation between the immune pattern and prognosis, as well as their association with clinical factors in multiple datasets. Moreover, we explored the interplay between immune patterns, tumor immune cell infiltration, and m6A regulators.
28 PIGs were identified, of which the 10 most significant were termed methylated prognostic immune genes (MPIGs). These MPIGs were used to create an immune pattern score. Kaplan-Meier and Cox analyses indicated this pattern as an independent risk factor for UC. We observed significant associations between the immune pattern, tumor progression, and immune cell infiltration. Differential expression analysis showed correlations with m6A regulators expression. This immune pattern proved effective in predicting immunotherapy response in UC in real-world settings.
The study identified a m6A-modified immune pattern in UC, offering prognostic and therapeutic response predictions. This emphasizes that immune genes may influence tumor immune status and progression through m6A modifications.

UNASSIGNED: Diabetes is a major cause of disease burden with considerable public health significance. While the pancreas plays a significant role in glucose homeostasis, the association between pancreatitis and new onset diabetes is not well understood. The purpose of this study was to examine that association using large real-world data.
UNASSIGNED: Utilizing the IBM® MarketScan® commercial claims database from 2016 to 2019, pancreatitis and diabetes regardless of diagnostic category, were identified using International Classification of Diseases, Tenth Revision [ICD-10] codes. We then performed descriptive analyses characterizing non-pancreatitis (NP), acute pancreatitis (AP), and chronic pancreatitis (CP) cohort subjects. Stratified Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of diabetes across the three clinical categories.
UNASSIGNED: In total, 310,962 individuals were included in the analysis. During 503,274 person-years of follow-up, we identified 15,951 incident diabetes cases. While men and women had higher incidence rates of CP and AP-related diabetes, the rates were significantly greater in men and highest among individuals with CP (91.6 per 1000 persons-years (PY)) followed by AP (75.9 per 1000-PY) as compared to those with NP (27.8 per 1000-PY). After adjustment for diabetes risk factors, relative to the NP group, the HR for future diabetes was 2.59 (95% CI: 2.45-2.74) (P<0.001) for the CP group, and 2.39 (95% CI: 2.30-2.48) (P<0.001) for the AP group.
UNASSIGNED: Pancreatitis was associated with a high risk of diabetes independent of demographic, lifestyle, and comorbid conditions.

UNASSIGNED: Proteinuria is associated with an increased risk of kidney function deterioration, cardiovascular disease, or cancer. Previous reports suggesting an association between kidney dysfunction and bone fracture may be confounded by concomitant proteinuria and were inconsistent regarding the association between proteinuria and bone fracture. Therefore, we aimed to evaluate the association using a large administrative claims database in Japan.
UNASSIGNED: Using the DeSC database, we retrospectively identified individuals with laboratory data including urine dipstick test between August 2014 and February 2021. We evaluated the association between proteinuria and vertebral or hip fracture using multivariable Cox regression analyses adjusted for various background factors including kidney function. We also performed subgroup analyses stratified by sex and kidney function and sensitivity analyses with Fine & Gray models considering death as a competing risk.
UNASSIGNED: We identified 603 766 individuals and observed 21 195 fractures. With reference to the negative proteinuria group, the hazard ratio for hip or vertebral fracture was 1.10 [95% confidence interval (CI), 1.05-1.14] and 1.16 (95%CI, 1.11-1.22) in the trace and positive proteinuria group, respectively, in the Cox regression analysis. The subgroup analyses showed similar trends. The Fine & Gray model showed a subdistribution hazard ratio of 1.09 (95%CI, 1.05-1.14) in the trace proteinuria group and 1.15 (95% CI, 1.10-1.20) in the positive proteinuria group.
UNASSIGNED: Proteinuria was associated with an increased risk of developing hip or vertebral fractures after adjustment for kidney function. Our results highlight the clinical importance of checking proteinuria for predicting bone fractures.

P450nor is a heme-containing enzyme that catalyzes the conversion of nitric oxide (NO) to nitrous oxide (N2O). Its catalytic mechanism has attracted attention in chemistry, biology, and environmental engineering. The catalytic cycle of P450nor is proposed to consist of three major steps. The reaction mechanism for the last step, N2O generation, remains unknown. In this study, the reaction pathway of the N2O generation from the intermediate I was explored with the B3LYP calculations using an active center model after the examination of the validity of the model. In the validation, we compared the heme distortions between P450nor and other oxidoreductases, suggesting a small effect of protein environment on the N2O generation reaction in P450nor. We then evaluated the electrostatic environment effect of P450nor on the hydride affinity to the active site with quantum mechanics/molecular mechanics (QM/MM) calculations, confirming that the affinity was unchanged with or without the protein environment. The active center model for P450nor showed that the N2O generation process in the enzymatic reaction undergoes a reasonable barrier height without protein environment. Consequently, our findings strongly suggest that the N2O generation reaction from the intermediate I depends sorely on the intrinsic reactivity of the heme cofactor bound on cysteine residue.

BACKGROUND: The application of palliative care is limited and challenging in intensive care units (ICUs) because of complex factors such as time constraints and unpredictable disease progression. Although research results and international consensus stress the early use of palliative care, utilization remains low, resulting in increased risks of ineffective medical care and poor quality of death. Improving this situation requires a comprehensive understanding of the palliative condition in ICUs.
OBJECTIVE: This study was designed to investigate the utilization of hospice resources in adult ICUs and to compare this utilization between users and non-users.
METHODS: This retrospective correlation study recruited cases from the adult ICU database of a medical center in northern Taiwan between June and July 2022. Descriptive statistics, independent t-test and chi-square were used to analyze the data.
RESULTS: A total of 1,181 records were analyzed, including 458 (38.8%) females and 723 (61.2%) males. Two hundred and seventeen cases (18.4%) used hospice resources. Although 124 (10.4%) of the 1181 cases were identified as \"in urgent need of hospice resources\" (i.e., died within 30 days of ICU admission), 25 (20.2%) did not use these resources. Significant differences between the urgent-need cases who did and did not use hospice resources were found in terms of age, disease type, degree of frailty, cardiac arrest, infection, state of consciousness, intubation and tracheostomy status, inotropic and vasopressor medication, renal replacement, ECMO placement, delirium, and Acute Physiology and Chronic Health Evaluation III and Sequential Organ Failure Assessment Scores.
CONCLUSIONS: The roughly 20% of ICU patients in urgent needs of palliative care who did not utilize palliative care resources highlight the needs for continued discussion to better assist patients on palliative care decision-making. The findings show multifaceted differences between those who did and did not access palliative care. Future studies should design and test strategies to facilitate the identification of palliative care needs and ensure the effective allocation of palliative care resources in ICUs.
BACKGROUND: 成人加護病房安寧緩和醫療使用—現況調查及其差異比較.
UNASSIGNED: 加護病房運用安寧緩和醫療資源的使用狀況，因受到病人診斷複雜、病況緊急多變等因素影響，一直面臨諸多挑戰。即便研究及國際共識均鼓勵早期運用安寧緩和醫療資源，然而安寧緩和醫療在加護病房之利用率仍偏低，導致末期病人接受無效醫療之機率增加及較差的死亡品質。為改善上述臨床現況，首要須對加護單位安寧緩和醫療資源使用之現況有全面性的了解。.
UNASSIGNED: 調查成人加護病房病人之安寧緩和醫療資源使用現況，並比較使用者與未使用者之差異。.
UNASSIGNED: 本研究為回溯式相關性研究（retrospective correlation study），自北台灣一醫學中心之成人加護病房資料庫選取2022年6月1日到7月31日之個案，運用描述性統計、獨立樣本t檢定及卡方檢定進行分析。.
UNASSIGNED: 本研究共分析1,181人，含458位女性（38.8%）及723位男性（61.2%）。共發現217人（18.4%）有使用安寧緩和醫療資源。其中「急需安寧緩和醫療資源者」，亦即加護病房入院30天內死亡者，共有124人（10.6%）；此族群仍有20.2%（n = 25）未曾使用安寧緩和醫療資源。比較使用與未使用安寧緩和醫療資源者，其在年齡、疾病別、虛弱程度、心搏停止、感染、意識狀態、插管、氣切造口、強心升壓藥物、腎臟替代療法、葉克膜置放、譫妄、Sequential Organ Failure Assessment及Acute Physiology and Chronic Health Evaluation III分數上有顯著差異。.
UNASSIGNED: 約兩成具急迫需要者無法即時使用安寧緩和醫療資源，顯示目前之醫療決策依據，仍有可討論之空間。結果呈現有使用與無使用安寧緩和資源之組間有多面向之差異，顯示醫療團隊廣泛考量各面向因子以判斷安寧緩和醫療需求，但如何選定更精準且具經濟效益之決策輔佐指標，以協助安寧緩和醫療資源啟動與分配之判斷，為未來研究與臨床實踐之要務。.

BACKGROUND: Patients with overactive bladder may cycle through different antimuscarinic medications even though there is limited evidence to support this approach.
OBJECTIVE: To describe treatment patterns and the associated health care resource utilisation (HCRU) according to antimuscarinic cycling groups.
METHODS: The CYCLe AntiMuscarinics in ENgland (CYCLAMEN) study was a retrospective observational investigation that used primary care records from the Clinical Practice Research Datalink GOLD database linked to Hospital Episode Statistics secondary care data. Eligible patients (≥18 yr) were prescribed their first antimuscarinic between January 2014 and December 2017. Patients were categorised into groups prescribed one, two, or three or more (groups 1-3) consecutive unique antimuscarinics over 18 mo.
METHODS: The HCRU rate and costs were calculated for the period of continuous antimuscarinic therapy (first antimuscarinic treatment episode) and the 18-mo follow-up period. Treatment sequence patterns were displayed using sunburst plots and Kaplan-Meier analysis was used to assess time on treatment.
CONCLUSIONS: Overall, 35 369 patients were included, of whom 31 760 (89.8%) received one antimuscarinic (group 1), 3182 (9.0%) received two (group 2), and 427 (1.2%) received three or more (group 3). The most common initial antimuscarinics were solifenacin (13 628 patients, 42.9%) in group 1, and oxybutynin in group 2 (1267 patients, 39.8%) and group 3 (200 patients, 46.8%). The median duration of the first antimuscarinic treatment episode was 57 d and <20% of patients were receiving any antimuscarinic after 18 mo. The number of primary care visits and mean costs increased across groups. The reasons for cycling could not be identified in this study.
CONCLUSIONS: Approximately 10% of patients underwent sequential cycling with two or more antimuscarinics. Furthermore, as the majority discontinued treatment within 18 mo, there is a need to improve the management of these patients in the clinical care setting.
RESULTS: We investigated treatment patterns and health care use for patients with overactive bladder who were prescribed at least one antimuscarinic drug (AMD), which are drugs that reduce some of the impulses passing from the bladder to the brain. Around 10% of patients accessing primary health care in England received more than one sequential AMD. Most patients discontinued treatment, which may indicate inadequate management of their condition. Prescription of a higher number of AMDs was associated with higher health care costs.

UNASSIGNED: Sepsis is a life-threatening disease commonly complicated by activation of coagulation and immune pathways. Sepsis-induced coagulopathy (SIC) is associated with micro- and macrothrombosis, but its relation to other cardiovascular complications remains less clear. In this study we explored associations between SIC and the occurrence of atrial fibrillation (AF) in patients admitted to the Intensive Care Unit (ICU) in sinus rhythm. We also aimed to identify predictive factors for the development of AF in patients with and without SIC.
UNASSIGNED: Data were extracted from the publicly available AmsterdamUMCdb database. Patients with sepsis and documented sinus rhythm on admission to ICU were included. Patients were stratified into those who fulfilled the criteria for SIC and those who did not. Following univariate analysis, logistic regression models were developed to describe the association between routinely documented demographics and blood results and the development of at least one episode of AF. Machine learning methods (gradient boosting machines and random forest) were applied to define the predictive importance of factors contributing to the development of AF.
UNASSIGNED: Age was the strongest predictor for the development of AF in patients with and without SIC. Routine coagulation tests activated Partial Thromboplastin Time (aPTT) and International Normalized Ratio (INR) and C-reactive protein (CRP) as a marker of inflammation were also associated with AF occurrence in SIC-positive and SIC-negative patients. Cardiorespiratory parameters (oxygen requirements and heart rate) showed predictive potential.
UNASSIGNED: Higher INR, elevated CRP, increased heart rate and more severe respiratory failure are risk factors for occurrence of AF in critical illness, suggesting an association between cardiac, respiratory and immune and coagulation pathways. However, age was the most dominant factor to predict the first episodes of AF in patients admitted in sinus rhythm with and without SIC.

The purpose of this study was to systematically review the statistical methods used in pharmacovigilance studies without a priori hypotheses.
A systematic review was performed on studies published in the MEDLINE database between 2012 and 2021. The included studies were analyzed for database name and type, statistical methods, anatomical therapeutic chemical class for the studied drug(s), and SOC MedDRA classification for the studied adverse drug reaction.
Ninety-two studies were included, with pharmacovigilance databases being the most used type. Disproportionality analysis using frequentist or Bayesian methods was the most common statistical method employed. The most studied drug classes were anti-infectives, nervous system drugs, and antineoplastics and immunomodulators. However, no common procedure was implemented to correct for multiple testing.
This review highlights the limited number of statistical methods employed for pharmacovigilance studies without a priori hypotheses, with no established consensus-based method and a lack of interest in multiple testing correction. The establishment of guidelines is recommended to improve the performance of such studies.