OBJECTIVES:To evaluate the safety and efficacy across rifapentine doses ranging from 10 to 20 mg/kg for pulmonary drug-susceptible tuberculosis population. METHODS:The stage 1 of this seamless phase 2/3 randomized controlled trial recruited enrolled adults with drug-susceptible tuberculosis at 16 sites in China between 1 February 2023 and 29 September 2024 (NCT05401071). Participants were randomly divided (1:1:1:1) to receive one of three 4-month regimens containing rifapentine 10, 15, or 20 mg/kg daily plus isoniazid, moxifloxacin, and pyrazinamide, or a standard 6-month regimen consisting of isoniazid, rifampicin, pyrazinamide, and ethambutol. In the stage 1, the primary endpoint was the incidence of permanent regimen discontinuation for safety reasons by week 8. Key secondary endpoints included culture conversion before week 8, adverse events during treatment, and favourable outcomes at the end of treatment. RESULTS:A total of 400 participants underwent randomization in stage 1. The incidences of primary endpoint were 9.3% (9/97), 8.9% (9/101), and 14.6% (14/96) in the rifapentine 10, 15, and 20 mg/kg groups, and 3.0% (3/99) in the control group, respectively. Culture conversion before week 8 occurred in 73.8% (45/61), 84.8% (56/66), and 87.9% (51/58) of participants in the rifapentine 10, 15, and 20 mg/kg groups, and 78.0% (46/59) in the control group. Favourable outcomes at the end of treatment were similar across the groups: 81.4% (79/97) in the control group, 80.9% in the rifapentine 10 mg/kg group (relative risk [RR], 0.99; 95% CI, 0.87-1.14), 87.1% in the rifapentine 15 mg/kg group (RR, 1.07; 95% CI, 0.95-1.21), and 82.6% in the rifapentine 20 mg/kg group (RR, 1.01; 95% CI, 0.89-1.16). CONCLUSIONS:Both rifapentine 15 and 20 mg/kg yielded higher culture conversion rates. However, safety-related discontinuation, particularly in the 20 mg/kg group, was more frequent, highlighting the need for careful benefit-risk assessment and enhanced safety monitoring.

AIMS:Etrasimod is an oral sphingosine-1-phosphate receptor modulator approved for moderate-to-severe ulcerative colitis. The impact of CYP2C9 polymorphisms and hepatic impairment on etrasimod exposure remains unclear. This study aimed to characterize their effects and identify clinically relevant dose adjustment strategies in Chinese patients. METHODS:A physiologically based pharmacokinetic model was developed and verified using in vitro metabolism and single-dose, multiple-dose and drug-drug interaction clinical pharmacokinetic data. The validated model was extrapolated to Chinese populations with different CYP2C9 genotypes and hepatic impairment severity to characterize exposure changes and optimize dosing. RESULTS:Most predicted pharmacokinetic parameters are within a twofold error range. At the approved dose of 2 mg once daily, the predicted median steady-state AUC0-24 and Cmax were 1976.95 ng·h/mL (95% prediction interval [PI]: 975.78-4144.29 ng·h/mL) and 98.40 ng/mL (95% PI: 52.9-190.51 ng/mL) in Caucasian subjects and 1988.82 ng·h/mL (95% PI: 814.91-4244.10 ng·h/mL) and 105.18 ng/mL (95% PI: 51.30-198.03 ng/mL) in Chinese subjects, respectively. In Chinese populations, hepatic impairment and CYP2C9 polymorphisms increased etrasimod exposure, with the greatest increase observed in CYP2C9 poor metabolizers with Child-Pugh C hepatic impairment (67% increase in AUCss). CONCLUSIONS:CYP2C9 polymorphisms and hepatic impairment increased etrasimod exposure, particularly when combined. Model-based exposure matching supported dose reduction to 1.5 mg once daily for most affected subgroups and to 1 mg once daily for CYP2C9 poor metabolizers with Child-Pugh C hepatic impairment, providing quantitative support for individualized dosing.

BackgroundAtherosclerotic cardiovascular disease (ASCVD) imposes a substantial clinical and economic burden in China. Despite maximally tolerated statin therapy, many patients fail to achieve recommended low-density lipoprotein cholesterol (LDL-C) targets. Inclisiran, a novel small interfering ribonucleic acid (siRNA) therapy, provides sustained LDL-C reduction, but its economic value under the Chinese healthcare system remains uncertain.ObjectiveTo evaluate the cost-effectiveness of inclisiran when added to standard lipid-lowering therapy for patients with ASCVD in China.MethodsA Markov cohort multistate-transition model was developed from the perspective of the Chinese healthcare system, using a one-year cycle length and a lifetime horizon. Clinical inputs, costs, and utilities were derived from published literature and clinical trials. Both costs and outcomes were discounted at 4.5% annually. The primary result of the economic evaluation was the incremental cost-effectiveness ratio (ICER), with inclisiran considered cost-effective if the ICER was below the willingness-to-pay (WTP) threshold of CNY 191,498 per quality-adjusted life year (QALY), equivalent to two times China's per capita gross domestic product in 2024. One-way and probabilistic sensitivity analyses were conducted to assess model uncertainty.ResultsCompared with statin therapy alone, inclisiran added to statin therapy yielded an additional 0.41 QALYs and incurred incremental costs of CNY 58,321.35, resulting in an ICER of CNY 143,044.57/QALY, which is well below the WTP threshold. One-way sensitivity analyses showed that the mortality reduction effect, discount rate, and inclisiran price were the main drivers of model outcomes; however, inclisiran remained cost-effective across all tested scenarios. Probabilistic sensitivity analysis showed a 95.1% probability that inclisiran is cost-effective at the current price.ConclusionsAt its current negotiated price of CNY 2,790 per dose, inclisiran added to standard therapy is cost-effective for patients with ASCVD in China.

IntroductionAsymptomatic tuberculosis (TB) is increasingly recognised through active case finding and prevalence surveys. However, treatment strategies for this patient group remain poorly defined, and there is no consensus on optimal regimens, duration, or outcomes.Methods and analysisWe will conduct a systematic review of observational and interventional studies reporting anti-TB treatment in patients with asymptomatic TB. Databases including MEDLINE, Embase, Scopus, Web of Science, CINAHL, and the Cochrane Library will be searched without language restrictions. Outcomes of interest include favourable outcome rate, treatment coverage, success rate, relapse, mortality, loss to follow-up, adverse events, and patient-reported outcomes such as pill burden and treatment discontinuation. Study selection, data extraction, and quality assessment will be performed independently by two reviewers, following PRISMA guidelines. Where appropriate, meta-analyses will be conducted using a random-effects model.DiscussionThis review will provide a comprehensive synthesis of current evidence on the treatment of asymptomatic TB. It aims to inform future clinical and public health strategies, including the potential for simplified or shortened treatment regimens tailored to this population. By identifying gaps and inconsistencies in current practice, the findings will support evidence-based decision-making and contribute to global TB control efforts.

Tacrolimus (TAC) is an essential immunosuppressant for preventing graft failure after liver transplantation, but its narrow therapeutic window, high cost, and metabolism by CYP3A4/3A5 create challenges for individualized dosing. Diltiazem (DTZ), a CYP3A4 inhibitor commonly co-administered for comorbid hypertension, may increase TAC exposure and thereby reduce the TAC dose required to achieve target concentrations, potentially lowering treatment costs. This study evaluated the cost-effectiveness of potential TAC/DTZ dosing regimens in liver transplant recipients with hypertension using a linked pharmacometrics-pharmacoeconomics (PMPE) framework. Clinical data from 483 liver transplant cases at a specialist hospital were used to develop a physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model that quantified the relationship between TAC trough concentrations and graft failure risk and supported regimen optimization. A Markov model was then applied to estimate annual costs and graft failure outcomes across candidate regimens. Among the evaluated strategies, the TAC/DTZ 1/30mg regimen was identified as the most cost-effective option. Cost-effectiveness acceptability curve (CEAC) analysis showed that the optimized regimen had a 70.0% probability of being cost-effective at a willingness-to-pay (WTP) threshold of $38,201. These findings suggest that TAC/DTZ combination regimens may be cost-effective in hypertensive liver transplant recipients and demonstrate the feasibility of a linked PMPE model for generating pharmacoeconomic (PE) evidence to support clinical and policy decision-making.

Individuals with asymptomatic tuberculosis (TB) are considered a significant risk to the disease burden and transmission. However, the progression and treatment for asymptomatic TB remain incompletely described. This prospective cohort study was embedded within a prevalence survey conducted in 2021 and 2022 in Lanxi County, China. All patients with pulmonary TB who consented to participate would be included in the study and were categorized as asymptomatic or symptomatic. For the primary analysis, asymptomatic TB was defined as the absence of current cough, fever, night sweats, weight loss, or hemoptysis. Patients were followed up until 10 November 2024. Among 109 345 individuals screened, 193 were included, of whom 101 (52.3%) were symptomatic and 92 (47.7%) were asymptomatic. The proportion of asymptomatic TB varied from 32.5% to 62.7% depending on varying symptom negative threshold. Fewer asymptomatic patients were bacteriologically confirmed compared to symptomatic patients (71.7% [66/92] vs 90.1% [91/101], P = .001). The median time for asymptomatic patients at screening to develop symptoms was 102 days. Most patients in both groups received treatment for active TB (97.8% vs 99.0%, P = .606). The treatment success rate among asymptomatic patients was comparable to that of symptomatic patients (93.3% vs 96.0%, P = .521), but their treatment duration was significantly shorter (196 vs 273 days, P < .001). In the community setting, a significant number of TB cases were asymptomatic and remained so for months. These cases demonstrated satisfactory treatment coverage and outcomes, with shorter durations compared to symptomatic TB, suggesting the potential for developing shorter regimens for asymptomatic TB.

Effective tuberculosis (TB) management relies on prompt diagnosis of Mycobacterium tuberculosis complex (MTBC) and associated drug resistance. The Sanity 2.0 assay is a high-resolution melting assay designed for direct respiratory sample testing, enabling simultaneous detection of MTBC and resistance to rifampicin (RIF), isoniazid (INH), and fluoroquinolones (FQ) in a single step. This study evaluated its diagnostic performance in two registered multicenter trials among bacteriologically confirmed TB patients. Diagnostic performance was evaluated for MTBC detection, as well as for the identification of resistance to RIF, INH, and FQ, using phenotypic drug susceptibility testing, whole-genome sequencing, and a composite reference standard. Agreement analyses were conducted between the Sanity 2.0 assay and Xpert MTB/RIF and Xpert MTB/XDR. Among 611 patients, the Sanity 2.0 assay detected MTBC in 563 patients, exhibiting a sensitivity of 92.1% (95% CI: 89.7-94.0). For detecting resistance to RIF, INH, and FQ, sensitivities exceeded 90%, with specificities of 95.8% (95% CI: 88.5-98.6), 100.0% (95% CI: 96.4-100.0), and 97.8% (95% CI: 93.8-99.3) against the composite reference standard, respectively. The agreement with Xpert MTB/RIF for RIF detection was 98.6% (95% CI: 96.9-99.3). For INH and FQ resistance, the agreement with Xpert MTB/XDR was 92.0% (95% CI: 88.5-94.5) and 94.3% (95% CI: 91.2-96.3), respectively. The Sanity 2.0 assay is a rapid and user-friendly platform capable of detecting both MTBC and key drug resistance. It demonstrated good diagnostic performance and could potentially be an effective alternative to guide individualized anti-TB treatment, especially in resource-limited settings. IMPORTANCE:Rapid and accurate detection of both Mycobacterium tuberculosis complex (MTBC) and key drug resistance is critical to improving tuberculosis treatment outcomes and reducing transmission. However, current molecular diagnostic workflows often require sequential testing, which can delay the initiation of effective and individualized therapy. We evaluated the Sanity 2.0 assay, an integrated high-resolution melting test that simultaneously detects MTBC and resistance to rifampicin, isoniazid, and fluoroquinolone resistance directly from respiratory samples in about 2-3 hours. The assay demonstrated excellent performance, with MTBC detection sensitivity of 92.1% and drug resistance sensitivities exceeding 90% and specificities over 95% against a composite reference standard, as well as strong concordance with World Health Organization-endorsed molecular assays. Implementation of the Sanity 2.0 assay could streamline TB diagnostic workflows; enable rapid, single-step resistance profiling; and facilitate timely, individualized treatment-particularly in resource-limited settings where rapid and comprehensive resistance testing remains a critical unmet need.

OBJECTIVES:High-dose rifamycin (HDR) regimens have demonstrated significant potential in tuberculosis (TB) treatment. This study aims to evaluate the efficacy and safety profile of different HDR regimens. DESIGN:Using a systematic review and Bayesian network meta-analysis (NMA). DATA SOURCES:PubMed, Web of Science, Cochrane Library and Embase were searched up to 2 November 2024. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:Randomised controlled trials that compared the efficacy and safety of HDR regimens (rifampin 15-30 mg/kg/day and rifapentine 7.5-20 mg/kg/day) to standard-dose rifampin in patients with pulmonary drug-susceptible TB were included. DATA EXTRACTION AND SYNTHESIS:The risk of bias was assessed using Cochrane tools. We conducted NMA with GEMTC in R. The simulation was performed using the Markov Chain Monte Carlo technique set on four parallel chains, with 20 000 burn-in iterations, 50 000 inference iterations and a thinning factor of n=2.5. To check for model convergence, Gelman and Rubin diagnostic plots and density plots were applied. We assessed heterogeneity using the I² test, evaluated transitivity by comparing effect modifiers across studies and examined consistency via node-splitting analysis. The confidence in network meta-analysis online tool and Cochrane Risk of Bias 2.0 Tool were used to assess evidence certainty and risk of bias, respectively. Higher surface area under the cumulative rank curve scores indicated a higher probability of top-ranking treatments. RESULTS:Out of 15 766 citations screened, 15 randomised controlled trials were included, encompassing 6456 subjects. The risk of bias was low in 14 studies, with some concerns in one. Patients receiving rifapentine 20 mg/kg/day (risk ratio, 1.09; 95% credible interval, 1.03 to 1.17) had higher culture conversion rates at 8 weeks in solid culture compared with the control. There was no significant difference in primary efficacy within all HDR regimens. Rifapentine 20 mg/kg/day was ranked as the most effective intervention for primary efficacy. No statistical difference in the incidence of serious adverse events was found between all regimens. CONCLUSIONS:Rifapentine 20 mg/kg/day may be the most effective for achieving the strongest anti-TB activity. All HDR regimens demonstrated good safety. PROSPERO REGISTRATION NUMBER:CRD42024504575.

BACKGROUND:Gastrointestinal (GI) cancers are among the most prevalent and lethal malignancies worldwide. Early, non-invasive detection is essential for timely intervention and improved survival. To address this clinical need, we developed GutSeer, a blood-based assay combining DNA methylation and fragmentomics for multi-GI cancer detection. METHODS:Genome-wide methylome profiling identified 1,656 markers specific to five major GI cancers and their tissue origins. Based on these findings, we designed GutSeer, a targeted bisulfite sequencing panel, which was trained and validated using plasma samples from 1,057 cancer patients and 1,415 non-cancer controls. The locked model was blindly tested in an independent cohort of 846 participants, encompassing both inpatient and outpatient settings across five hospitals. RESULTS:In the validation cohort, GutSeer achieved an area under the curve (AUC) of 0.950 [95% Confidence Interval (CI): 0.937-0.962] for cancer detection, with 82.8% sensitivity (95% CI: 79.5-86.0) and 95.8% specificity (95% CI: 94.3-97.2). It detected 92.2% of colorectal, 75.5% of esophageal, 65.3% of gastric, 92.9% of liver, and 88.6% of pancreatic cancers. The independent test cohort included 198 early-stage cancers (stage I/II, 66.4%) and 63 advanced precancerous lesions. GutSeer maintained robust performance, with 81.5% sensitivity (95% CI: 77.1-85.9) for GI cancers and 94.4% specificity (95% CI: 92.4-96.5). It also demonstrated the ability to detect advanced precancerous lesions in the colorectum, esophagus, and stomach as a single, non-invasive blood test. CONCLUSIONS:By integrating DNA methylation and fragmentomics into a compact panel, GutSeer outperformed genome-wide sequencing in both accuracy and clinical applicability. Its high sensitivity for early-stage GI cancers and practicality as a non-invasive assay highlights its potential to revolutionize early cancer detection and improve patient outcomes. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT05431621.

Introduction: Potential hepatotoxicity, particularly significant hyperbilirubinemia, is a major challenge to promoting the rifapentine-based 4-month regimen (2HPMZ/2PMZ) for drug-sensitive tuberculosis. A more detailed description of hepatotoxicity profiles during the application of the 2HPMZ/2PMZ regimen is necessary to investigate a liver-friendly dosage range of rifapentine. Methods: The ORIENT study, a multicenter, open-label, phase II/III randomized controlled trial in China, was launched to evaluate the efficacy and safety of 2HPMZ/2PMZ regimen and search for the optimal dose of rifapentine. Participants were recruited and randomly assigned into the control arm using standardized six-month regimen (2HRZE/4HR) and three investigational arms of 2HPMZ/2PMZ with rifapentine at different dose levels (10 mg/kg, 15 mg/kg, and 20 mg/kg). Liver function tests were conducted at baseline and at weeks 1, 2, 3, 4, 6, 8, 12, 17, 21, and 26 after the initiation of treatment. We analyzed the liver function monitoring data among patients who received at least one dose of medication. All liver function parameters were converted to upper limit of normal (ULN) for analysis. Pearson's Chi-square (χ2) test, Fisher's exact test, or the Kruskal-Wallis test for comparisons was properly applied in statistics analysis, with Bonferroni correction used for pairwise comparison. Results: As of October 31, 2024, a total of 392 participants were included in the analysis. Elevations in ALT and ALP, as well as the median peak values of ALT and ALP, showed no statistic differences across the groups. The median peak total bilirubin (TBIL) levels increased sequentially in the rifapentine 10mg/kg, 15mg/kg and 20mg/kg groups, and were significantly higher than the control group (P<0.001). The frequency of TBIL elevation in the rifapentine 20mg/kg group was significantly higher than 10mg/kg arm (80.0% vs 53.6%, P<0.001) and control arm (80.0% vs 19.2%, P<0.001), while with no difference to 15mg/kg arm (80.0% vs 72.3%, P=1.000). Among patients with elevated TBIL, the median time to TBIL elevation was within two weeks in three rifapentine groups, significantly shorter than the control group (P=0.002). Hyperbilirubinemia was principally driven by direct bilirubin (DBIL) elevation, especially in three investigational arms. There was no statistical difference in drug-induced liver injury between groups, primarily manifesting as hepatocellular pattern (77.3%, 17/22). No patients experienced liver failure. Conclusions: The usage of daily, high-dose rifapentine in the 2HPMZ/2PMZ regimen led to significant, dose-dependent isolated hyperbilirubinemia, primarily characterized by DBIL elevation in the early stage of treatment.

ObjectiveTo evaluate the cost-utility of different dosing regimens of PCSK9 inhibitors, added to statin therapy, in patients with hypercholesterolemia or at high cardiovascular risk in China.MethodsA Markov cohort multistate-transition model was developed from the perspective of the Chinese healthcare system, with a 1-year cycle and lifetime horizon. Treatment effects were derived from a network meta-analysis. Costs, utilities, and mortality data were obtained from published literature and national databases. Both costs and outcomes were discounted at a rate of 5% annually. The primary outcome was the incremental cost-utility ratio (ICUR). The willingness-to-pay (WTP) threshold was set at 1–3 times China’s 2024 per capita gross domestic product. One-way, probabilistic, and scenario sensitivity analyses were performed to test model robustness.ResultsIn the base-case analysis, evolocumab 140 mg every 2 weeks (Q2W) was the most cost-effective option, dominating all other active regimens. Compared with statin therapy alone, it generated incremental costs of $11,109.27 and a quality-adjusted life year (QALY) gain of 0.42. The resulting ICUR was $26,217.47 per QALY, which is below the WTP threshold of $39,875.0 per QALY. Although less favorable than evolocumab, alirocumab 75 mg Q2W and tafolecimab 150 mg Q2W were also cost-effective versus statins alone, with ICURs of $34,279.73 and $34,002.10 per QALY, respectively. All other regimens were dominated, and inclisiran showed the least favorable cost-utility profile (ICUR $113,800.14 per QALY). Sensitivity analyses identified the discount rate as the key driver of uncertainty, with ICURs for evolocumab 140 mg Q2W versus statins alone ranging from $15,903.46 to $34,573.62 per QALY. Probabilistic sensitivity analysis showed a 98.9% probability of evolocumab 140 mg Q2W being cost-effective versus statins alone.ConclusionAt the current negotiated price, evolocumab 140 mg Q2W is the most cost-effective PCSK9 inhibitor regimen for Chinese patients with hypercholesterolemia or at high cardiovascular risk when added to statin therapy. Alirocumab 75 mg Q2W and tafolecimab 150 mg Q2W also represent cost-effective alternatives. These findings provide important evidence to support clinical decision-making and optimize resource allocation in China.

AIMS:Heart failure (HF) imposes a substantial economic burden, especially among populations with comorbidities in China. Sotagliflozin has shown clinical benefits in HF patients with type 2 diabetes mellitus (T2DM). This study evaluated the cost-utility of sotagliflozin in China and explored pricing strategies to support its potential market entry. METHODS:A multistate Markov model was developed to assess the cost-utility of adding sotagliflozin to standard therapy in HF-T2DM patients, using data from the SOLOIST-WHF trial. A hypothetical cohort of 1000 patients was simulated, with transition probabilities adjusted for the Chinese population. Costs and utilities were derived from Chinese sources where available, and both outcomes and costs were discounted at 5% annually. Deterministic, probabilistic and scenario-based sensitivity analyses were conducted to assess uncertainty and evaluate alternative pricing scenarios. RESULT:In the base-case analysis, the incremental cost-utility ratio of sotagliflozin was $50,072.77 per QALY, exceeding the Chinese willingness-to-pay threshold of $37,864. Deterministic analysis identified cardiovascular mortality in the control group as the most influential parameter. Probabilistic analysis showed a 38.84% probability of cost-utility. A 22.7% price reduction would be required for sotagliflozin to meet cost-effectiveness thresholds. Varying treatment duration did not change this outcome. CONCLUSION:This study found that sotagliflozin is not cost-effective for HF-T2DM patients in China at current prices. Its economic value is highly sensitive to drug cost, highlighting the need for localized pricing strategies. These findings can inform future reimbursement decisions and support value-based market entry planning.

The SARS-CoV-2 virus, particularly the Omicron BA.2 variant, led to a significant surge in Shanghai, 2022. However, the viral load dynamic in Omicron infections with varying clinical severities remain unclear. This prospective cohort included 48,830 hospitalized coronavirus disease 2019 (COVID-19) patients across three hospitals in Shanghai, China, between 23 March and 15 May, 2022. Systematic nucleic acid testing was performed using RT-PCR Cycle threshold (Ct) value as a proxy of viral load. We analyzed the kinetic characteristics of viral shedding by clinical severity and identified associated risk factors. The study comprised 31.06% asymptomatic cases, 67.66% mild-moderate cases, 1.00% severe cases, 0.29% critical and fatal cases. Upon admission, 57% of patients tested positive, with peak viral load observed at 4 days (median Ct value 27.5), followed by a decrease and an average viral shedding time (VST) of 6.1 days (Interquartile range, 4.0-8.8 days). Although viral load exhibited variation by age and clinical severity, peak Ct values occurred at similar times. Unvaccinated status, age exceeding 60, and comorbidities including hypertension, renal issues kidney dialysis and kidney transplantation, neurological disorders, rheumatism, and psychotic conditions were found to correlate with elevated peak viral load and extended VST. Asymptomatic cases demonstrated a 40% likelihood of contagiousness within 6 days of detection, while mild-moderate and severe cases exhibited post-symptom resolution infectious probabilities of 27% and over 50%, respectively. These findings revealed that the initial Ct values serve as a predictive indicator of severe outcomes. Unvaccinated elderly individuals with particular comorbidities are at high-risk for elevated viral load and prolonged VST.

Aims: The emergence of drug-resistant tuberculosis has necessitated novel treatments like the pretomanid, bedaquiline and linezolid (BPaL) regimen. This study investigated the association of drug-induced liver injury (DILI) with the BPaL regimen compared to first-line antituberculosis drugs (isoniazid, rifampin, pyrazinamide and ethambutol [HRZE]). Methods: A retrospective pharmacovigilance analysis was conducted using data from the US Food and Drug Administration Adverse Event Reporting System database from July 2019 to June 2023. Disproportionality analysis was employed to calculate the reporting odds ratio (ROR) of DILI for each component of the BPaL regimen. Onset time and mortality rates of DILI across different regimens were also compared. Results: We identified 1242 cases of BPaL-related DILI. Most cases occurred in individuals under 65 years of age (63.8%), with more male patients affected than females (51.4% vs 39.5%). The association between antituberculosis drugs and DILI was stronger for the HRZE regimen (ROR = 7.99, 95% confidence interval [CI] 7.74-8.25) than the BPaL regimen (ROR = 4.75, 95% CI 4.55-4.97). The median onset time for DILI was significantly shorter with the BPaL regimen (8 days, interquartile range [IQR] 3-28) compared to the HRZE regimen (20 days, IQR 6-48) (P < .001). Additionally, the BPaL regimen was associated with a higher risk of death due to DILI compared to the HRZE regimen (14.1% vs 10.4%, P = .003). Conclusions: Although the BPaL regimen had a lower overall risk of DILI compared to the HRZE regimen, it was significantly associated with DILI, indicating a need for careful monitoring during treatment.

OBJECTIVES:Efforts to shorten rifampicin-resistant tuberculosis (RR-TB) treatment have led to concerns about hepatotoxicity in shorter regimens. We evaluated hepatotoxicity in two novel regimens against the standard shorter regimen recommended by the World Health Organization (WHO). METHODS:Participants from the TB-TRUST and TB-TRUST plus trials were assigned to the WHO shorter regimen, a levofloxacin (Lfx)-based regimen, or a bedaquiline (Bdq)-based regimen. Liver function was tested bi-weekly in the first month, then monthly until treatment ended. Eligibility required receiving at least one drug dose and undergoing at least two liver function tests. RESULTS:Of 429 patients, hepatotoxicity was most prevalent in the WHO shorter group (26.7% of 169), compared to 4.7% in the Lfx group (172 patients), and 5.7% in the Bdq group (88 patients). The median peak alanine aminotransferase levels were 1.67 × upper limit of normal (ULN) for WHO, 0.82 × ULN for Lfx, and 0.88 × ULN for Bdq groups. The incidence of drug-induced liver injury was significantly higher in the WHO group (18.3%) than in the Lfx (3.5%) and Bdq (4.6%) groups. The time to significant alanine aminotransferase elevation was about 2.8 months, with no differences between groups. CONCLUSIONS:Two novel regimens demonstrated lower hepatotoxicity compared to the WHO's shorter regimen. Entire course management monitoring is recommended in RR-TB treatment.

The Hippo signaling pathway is first found in Drosophila and is highly conserved in evolution. Previous studies on this pathway in mammals have revealed its key role in cell proliferation and differentiation, organ size control, and carcinogenesis. Apart from these, recent findings indicate that mammalian Ste20-like kinases 1 and 2 (MST1/2) have significant effects on immune regulation. In this review, we summarize the updated understanding of how MST1/2 affect the regulation of the immune system and the specific mechanism. The effect of MST1/2 on immune cells and its role in the tumor immune microenvironment can alter the body's response to tumor cells. The relationship between MST1/2 and the immune system suggests new directions in the manipulation of immune responses for clinical immunotherapy, especially for tumor treatment.

Rhabdomyolysis is a life-threatening adverse drug reaction that is seldom reported in DPP-4 inhibitors. Here we present a case in which a 58-year-old female suffered from severe swelling and pain in bilateral lower limbs and oliguria for 1 week after a suicidal attempt that she took vildagliptin 1,400 mg and insulin aspart 60 IU. She was diagnosed with rhabdomyolysis, diabetic ketoacidosis (DKA), urinary tract infection (UTI) and drug-induced liver injury (DILI). After 20 days of hospitalization, significant improvement had occurred in almost all laboratory results, and the patient was discharged without sequelae. This is a rare case suggesting that severe adverse events (SAEs), such as rhabdomyolysis, may occur in relatively safe oral hypoglycemic drugs.

Background Individuals with diabetes have increased risk of depression, but there are limited nationally representative studies on this topic. We aimed to investigate the prevalence and predictors of depression, as well as its impact on all-cause and cardiovascular mortality in adults with type 2 diabetes (T2DM) using a prospective cohort study and a representative sample of the U.S. population. Methods We analyzed National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2018 and linked it with the most recent publicly available National Death Index (NDI) data. Individuals aged 20 years or old who had depression measurements were included. Depression was defined as a Patient Health Questionnaire (PHQ-9) score ≥ 10, and categorized into moderate (10–14 points) and moderately severe to severe (≥ 15 points). Cox proportional hazard models were used to estimate the association between depression and mortality. Results Among 5695 participants with T2DM, 11.6% had depression. Depression was associated with female gender, younger age, overweight, lower education, being unmarried, smoking, and a history of coronary heart disease and stroke. During a mean follow-up period of 78.2 months, 1161 all-cause deaths occurred. Total depression and moderately severe to severe depression significantly increased all-cause mortality (adjusted hazard ratio [aHR] 1.36, 95% CI [1.09–1.70]; 1.67 [1.19–2.34]) and non-cardiovascular mortality (aHR 1.36, 95% CI [1.04–1.78]; 1.78, 95% CI [1.20–2.64]), but not cardiovascular mortality. Subgroup analysis showed a significant association between total depression and all-cause mortality in males (aHR 1.46, 95% CI [1.08–1.98]) and those aged 60 years or older (aHR 1.35, 95% CI [1.02–1.78]). Any severity of depression was not significantly associated with cardiovascular mortality in age- or gender- stratified subgroups. Conclusions In a nationally representative sample of U.S. adults with T2DM, approximately 10% experienced depression. Depression did not significantly associate with cardiovascular mortality. However, comorbid depression in T2DM patients increased the risk of all-cause and non-cardiovascular mortality. The impact of depression on mortality varied across subgroups. Therefore, healthcare providers should consider incorporating depression screening and management into routine care, especially for subgroups with specific risk factors, due to the increased risk of all-cause mortality in T2DM patients with depression.

Introduction: Oral semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that improves glycated hemoglobin levels and body weight in patients with type 2 diabetes (T2DM). We aim to evaluate the cost-effectiveness of once-daily oral semaglutide in comparison to placebo and injectable GLP-1 RAs in Chinese patients with T2DM inadequately controlled on basal insulin. Methods: The United Kingdom Prospective Diabetes Study Outcomes Model (UKPDS OM2.1) was used to estimate the cost-effectiveness by calculating the incremental cost-effectiveness ratio (ICER). Baseline characteristics of the simulation cohort were obtained from the PIONEER 8 trial. Utility and safety inputs were derived from a network meta-analysis of 12 trials. Direct medical costs were retrieved from published literature and discounted at an annual rate of 5%. We used a willingness-to-pay (WTP) threshold of $36,528.3 per quality-adjusted life-year (QALY) gained. Scenario analysis, and one-way and probabilistic sensitivity analysis were performed. Results: The effectiveness of oral semaglutide was 10.39 QALYs with a total cost of $30,223.10, while placebo provided 10.13 QALYs at a lower total cost of $20,039.19. Oral semaglutide was not cost-effective at an ICER of $39,853.22 and $88,776.61 per QALY compared to placebo and exenatide at the WTP. However, at an annual price of $1,871.9, it was cost-effective compared with dulaglutide, liraglutide, and lixisenatide. The model was most sensitive to the discount rate and annual cost of oral semaglutide. The price of oral semaglutide needed to be reduced to $1,711.03 per year to be cost-effective compared to placebo and other injectable GLP-1 RAs except for exenatide and semaglutide injection. Conclusion: We found that once-daily oral semaglutide, at a comparable price of semaglutide injection, proves to be a cost-effective add-on therapy to insulin for Chinese patients with T2DM, especially when compared to subcutaneous GLP-1 RAs other than injectable semaglutide and exenatide. However, to achieve cost-effectiveness in comparison to placebo, further cost reduction of oral semaglutide is necessary. The estimated annual cost of $1,711.03 for oral semaglutide demonstrates a more cost-effective option than placebo, highlighting its potential value in the management of T2DM.

4169 Background: Five major gastrointestinal (GI) cancers - colorectal (CRC), gastric (GC), liver (LC), esophageal (EC), and pancreatic cancer (PC) - are responsible for hundreds of thousands of mortalities annually worldwide. Unfortunately, there is a lack of cost-effective, blood-based screening method for their early detection. To address this issue, we aimed to develop GutSeer, a noninvasive, targeted methylation sequencing-based test by leveraging methylation and fragmentomic signatures carried by cell-free DNA (cfDNA). Methods: The panel of GutSeer consists of 1656 target regions which were either differentially methylated between healthy and cancer samples, or distinctively methylated in a specific GI cancer. Cancer and healthy participants were recruited and randomly divided into a training and a validation cohort. Their plasma DNA samples were analyzed to generate DNA methylation and fragmentomic features. These multi-dimensional features were integrated to build ensemble stacked machine learning models to differentiate cancer against healthy, and to determine the tissue-of-origin (TOO) of the cancer. Results: A total of 1844 cases (787 healthy, 342 LC, 239 GC, 209 EC, 180 CRC, and 87 PC cases) were recruited for this study. A cancer- vs-healthy model achieved an AUC of 0.94 and 0.95 (sensitivity of 77.7% and 77.1% under the specificity around 96%) using either methylation or fragmentomic features only, respectively. Combining both methylation and fragmentomic features further improved performances, achieving an AUC of 0.96 (sensitivity = 86.2% at a specificity of 96.7%). For individual type of cancer, GutSeer has a sensitivity of 93.3% for CRC, 81.1% for EC, 70.3% for GC, 96.5% for LC, and 86.4% for PC. An independent test using 629 benign cases as controls achieved a specificity of 87.1%. A separate TOO model was built using all features and achieved an overall accuracy of 82% for all cancer cases (66.7% for CRC, 87.0% for GC and EC combined, 89.0% for LC, and 63.2% for PC). Same as the cancer detection model, using multi-dimensional features in TOO prediction yielded higher accuracy than when models using only methylation or fragmentomics features (accuracy = 75.6% or 75.4%, respectively). When compared with whole-genome sequencing (WGS) based approaches, GutSeer showed a comparable performance in cancer detection but a higher accuracy in TOO identification, further confirming its effectiveness for detection of GI cancers. Conclusions: GutSeer, a non-invasive test integrating multi-dimensional features, was demonstrated to detect and localize the 5 main types of GI cancer with high accuracy. Our results further showed that a reasonably sized panel can perform comparably or even better than WGS-based methods in cancer detection and TOO localization, indicating GutSeer may be a low-cost solution for blood-based early screening for GI cancers.