Search

Background: The 2022 clinical guidelines for management of heart failure with reduced ejection fraction call for quadruple therapy. Quadruple therapy consists of an angiotensin receptor-neprilysin inhibitor (ARNi), sodium-glucose cotransporter-2 inhibitor (SGLT2i), mineralocorticoid receptor antagonist, and beta blocker. The ARNi and sodium-glucose cotransporter-2 inhibitor are newer additions to standard of care with the ARNi replacing ACE (angiotensin-converting enzyme) inhibitors and angiotensin II receptor blockers., Methods: We investigate the cost-effectiveness of sequentially adding the SGLT2i and ARNi to form quadruple therapy as compared with the previous standard of care with ACE inhibitor/mineralocorticoid receptor antagonist/beta blocker. Using a 2-stage Markov model, we projected the expected lifetime discounted costs and quality-adjusted life years (QALYs) of a simulated cohort of US patients who underwent each treatment option and calculated incremental cost-effectiveness ratios. We assessed incremental cost-effectiveness ratios using criteria for health care value (<$50 000/quality-adjusted life year [QALY] indicating high-value, $50 000-150 000/QALY indicating intermediate value, and >$150 000/QALY indicating low-value) and a standard $100 000/QALY cost-effectiveness threshold., Results: Compared with the previous standard of care, the SGLT2i addition had an incremental cost-effectiveness ratio of $73 000/QALY and weakly dominated the ARNi addition. The addition of both the ARNi and SGLT2i for quadruple therapy offered 0.68 additional discounted QALYs over the SGLT2i addition alone at a lifetime discounted cost of $66 700, resulting in an incremental cost-effectiveness ratio of $98 500/QALY. In sensitivity analysis varying drug prices, the incremental cost-effectiveness ratio for quadruple therapy ranged from $73 500/QALY using prices available to the US Department of Veterans Affairs to $110 000/QALY using drug list prices., Conclusions: While quadruple therapy offers intermediate value, it is borderline cost effective compared with adding the SGLT2i alone to previous standard of care. Thus, its cost-effectiveness is sensitive to a payer's ability to negotiate discounts off the increasing list prices for ARNI and SGLT2is. The demonstrated benefits of ARNi and SGLT2is should be weighed against their high prices in payer and policy considerations., Competing Interests: Disclosures None.

The discovery of new tumor subtypes has been aided by transcriptomics profiling. However, some new subtypes can be irreproducible due to data artifacts that arise from disparate experimental handling. To deal with these artifacts, methods for data normalization and batch-effect correction have been utilized before performing sample clustering for disease subtyping, despite that these methods were primarily developed for group comparison. It remains to be elucidated whether they are effective for sample clustering. We examined this issue with a re-sampling-based simulation study that leverages a pair of microRNA microarray data sets. Our study showed that (i) normalization generally benefited the discovery of sample clusters and quantile normalization tended to be the best performer, (ii) batch-effect correction was harmful when data artifacts confounded with biological signals, and (iii) their performance can be influenced by the choice of clustering method with the Prediction Around Medoid method based on Pearson correlation being consistently a best performer. Our study provides important insights on the use of data normalization and batch-effect correction in connection with the design of array-to-sample assignment and the choice of clustering method for facilitating accurate and reproducible discovery of tumor subtypes with microRNAs., (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

The COVID pandemic disrupted health care spending and utilization, and the Medicare Shared Savings Program (MSSP), Medicare's largest value-based payment model with 11.2 million assigned beneficiaries, was no exception. Despite COVID, the 513 accountable care organizations (ACO) in MSSP returned a program record $1.9 billion in net savings to Medicare in 2020. To understand the extent of COVID's impact on MSSP cost and quality, we describe how ACO spending changed in 2020 and further analyze changes in measured quality and utilization. We found that non-COVID per capita spending in MSSP fell by 8.3 percent from $11,496 to $10,537 (95% confidence interval(CI),-1,223.8 to-695.4, p<0.001), driven by 14.6% and 7.5% reductions in per capita acute inpatient and outpatient spending, respectively. Utilization fell across inpatient, emergency, and outpatient settings. On quality metrics, preventive screening rates remained stable or improved, while control of diabetes and blood pressure worsened. Large reductions in non-COVID utilization helped ACOs succeed financially in 2020, but worsening chronic disease measures are concerning. The appropriateness of the benchmark methodology and exclusion of COVID-related spending, especially as the virus approaches endemicity, should be revisited to ensure bonus payments reflect advances in care delivery and health outcomes rather than COVID-related shifts in spending and utilization patterns., Competing Interests: The authors have declared that no competing interests exist.

Background: The 2016 presidential election and the controversial policy agenda of its victor have raised concerns about how the election may have impacted mental health., Objective: Assess how mental health changed from before to after the November 2016 election and how trends differed in states that voted for Donald Trump versus Hillary Clinton., Design: Pre- versus post-election study using monthly cross-sectional survey data., Participants: A total of 499,201 adults surveyed in the Behavioral Risk Factor Surveillance System from May 2016 to May 2017., Exposure: Residence in a state that voted for Trump versus state that voted for Clinton and the candidate's margin of victory in the state., Main Measures: Self-reported days of poor mental health in the last 30 days and depression rate., Key Results: Compared to October 2016, the mean days of poor mental health in the last 30 days per adult rose from 3.35 to 3.85 in December 2016 in Clinton states (0.50 days difference, p = 0.005) but remained statistically unchanged in Trump states, moving from 3.94 to 3.78 days (- 0.17 difference, p = 0.308). The rises in poor mental health days in Clinton states were driven by older adults, women, and white individuals. The depression rate in Clinton states began rising in January 2017. A 10-percentage point higher margin of victory for Clinton in a state predicted 0.41 more days of poor mental health per adult in December 2016 on average (p = 0.001)., Conclusions: In states that voted for Clinton, there were 54.6 million more days of poor mental health among adults in December 2016, the month following the election, compared to October 2016. Clinicians should consider that elections could cause at least transitory increases in poor mental health and tailor patient care accordingly, especially with the 2020 election upon us.

Background: Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of cancers. We aimed to evaluate the incidence and prognostic impact of hepatic adverse events (AEs) in a territory-wide cohort of patients who received ICIs., Methods: Patients were identified from a territory-wide database who received ICIs in 2014-2018. Hepatic AEs were defined as any elevation of liver biochemistries including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels. Hepatic AEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0., Results: Total of 1480 patients were identified (mean age 60 years, male 65.5%) and the commonest malignancies being lung cancer (39.6%), liver cancer (16.5%), and gastrointestinal cancer (10.0%). Grade 1-2 and grade 3-4 hepatic AEs occurred in 41.3% and 14.9% of patients during ICI treatment, respectively. Patients with liver cancer had the highest rate of hepatic AEs (grade 1-2:54.1%; grade 3-4:32.8%). Among 711 patients with hepatic AEs, 383 (53.9%) had raised ALT/AST only, and 328 (46.1%) had concomitant raised ALT/AST and bilirubin levels. In the whole cohort, median overall survival of patients without any hepatic AEs, grade 1-2 and grade 3-4 hepatic AEs during ICI treatment was 9.0 months, 7.2 months, and 3.3 months (P < .001), respectively. Similar results on overall survival were obtained among different types of cancers., Conclusions: Hepatic AEs occur in more than half of patients receiving ICIs for cancer treatment, with approximately 15% being grade 3-4 AEs. Occurrence of hepatic AEs is associated with worse prognosis., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background & Aims: Antiviral treatment is known to improve survival in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). Yet, the treatment uptake in CHB patients remains low. We aimed to report the secular trend in antiviral treatment uptake from 2007-2017, and to compare the effect of different nucleos(t)ide analogue (NA) initiation times (before vs. after HCC diagnosis) on survival., Methods: A 3-month landmark analysis was used to compare overall survival in patients not receiving NA treatment ( i.e. no NA), patients receiving NAs after their first HCC treatment ( i.e. post-HCC NA), and patients receiving NAs ≤3 months before their first HCC treatment ( i.e. pre-HCC NA). A propensity score-weighted Cox proportional hazards model was used to balance clinical characteristics between the 3 groups and to estimate hazard ratios (HRs)., Results: The uptake of antiviral treatment in HCC patients increased from 47.3% in 2007 to 98.3% in 2017. The pre-HCC NA group contributed mostly to the uptake rate, which increased from 72.7% to 96.0% in the past decade. In addition, 3,843 CHB patients (407 no NA; 2,932 pre-HCC NA; 504 post-HCC NA) with HCC, receiving at least 1 type of HCC treatment, were included in the analysis. Lack of NA treatment at the time of HCC diagnosis increased the risk of death (weighted HR 3.05; 95% CI 2.70-3.44; p <0.001). The impact of the timing of NA treatment was insignificant (weighted HR 0.90; 95% CI 0.78-1.04; p  = 0.161)., Conclusions: The uptake of antiviral treatment in HCC patients increased over the past decade. NA treatment, regardless of whether it was initiated before or after HCC diagnosis, improved survival. It is never too late to initiate NA treatment, even after HCC diagnosis., Lay Summary: More and more patients who have hepatitis B-related liver cancer received antiviral treatment over the past decade. The timing of starting antiviral treatment, regardless of whether it was before or after liver cancer happens, does not really matter in terms of survival benefits., Competing Interests: VWS Wong has served as an advisory committee member for 3vbio, AbbVie, Allergan, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Janssen, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, and Terns, and a speaker for Bristol Myers Squibb, Echosens, Gilead Sciences, and Merck. He has also received an unrestricted grant from Gilead Sciences. TCFY has served as an advisory committee member and a speaker for Gilead Sciences. HLYC has served as an advisory committee member for AbbVie, APTORUM, Aligos, Arbutus, Hepion, Intellia, Janssen, Gilead, MedImmune, Merck, Roche, Vir Biotechnology, GRAIL, Vaccitech, and VenatoRx, and as a speaker for Mylan, Gilead, and Roche. GLHW has served as an advisory committee member for Gilead Sciences and Janssen, and as a speaker for Abbott, AbbVie, Bristol Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen, and Roche. She received a research grant from Gilead. The other authors declare that they have no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)

Background: Because of high-risk behaviours, sedentary lifestyle and side effects of medications, psychiatric patients are at risk of viral hepatitis, alcohol-related liver disease and non-alcoholic fatty liver disease. We aimed to study the incidence of hepatocellular carcinoma (HCC) and cirrhotic complications in psychiatric patients., Methods: We identified consecutive adult patients in all public hospitals and clinics in Hong Kong with psychiatric diagnoses between year 2003 and 2007 using the Clinical Data Analysis and Reporting System, which represents in-patient and out-patient data of approximately 80% of the 7.4-million local population. The patients were followed for liver-related events (HCC and cirrhotic complications) and deaths until December 2017. Age- and sex-standardized incidence ratio (SIR) of HCC in psychiatric patients to the general population was estimated by Poisson model., Results: We included 105,763 psychiatric patients without prior liver-related events in the final analysis. During a median (interquartile range) follow-up of 12.4 (11.0-13.7) years, 1461 (1.4%) patients developed liver-related events; 472 (0.4%) patients developed HCC. Compared with the general population, psychiatric patients had increased incidence of HCC (SIR 1.42, 95% confidence interval [CI] 1.28-1.57, P < 0.001). The SIR was highest in patients with drug-induced (SIR 3.18, 95% CI 2.41-4.11, P < 0.001) and alcohol-induced mental disorders (SIR 2.98, 95% CI 2.30-3.81, P < 0.001), but was also increased in patients with psychotic disorders (SIR 1.39, 95% CI 1.16-1.65, P < 0.001) and mood disorders (SIR 1.16, 95% CI 1.00-1.34, P = 0.047). Liver disease was the fifth most common cause of death in this population, accounting for 595 of 10,614 (5.6%) deaths. Importantly, 569 (38.9%) patients were not known to have liver diseases at the time of liver-related events. The median age at HCC diagnosis (61 [range 26-83] years) was older and the median overall survival (8.0 [95% CI 5.0-10.9] months) after HCC diagnosis was shorter in this cohort of psychiatric patients than other reports from Hong Kong., Conclusions: HCC, cirrhotic complications, and liver-related deaths are common in psychiatric patients, but liver diseases are often undiagnosed. More efforts are needed to identify liver diseases in the psychiatric population so that treatments and screening for HCC and varices can be provided to patients in need.

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a unique geographical distribution. The genomic abnormalities leading to NPC pathogenesis remain unclear. In total, 135 NPC tumors were examined to characterize the mutational landscape using whole-exome sequencing and targeted resequencing. An APOBEC cytidine deaminase mutagenesis signature was revealed in the somatic mutations. Noticeably, multiple loss-of-function mutations were identified in several NF-κB signaling negative regulators NFKBIA, CYLD, and TNFAIP3 Functional studies confirmed that inhibition of NFKBIA had a significant impact on NF-κB activity and NPC cell growth. The identified loss-of-function mutations in NFKBIA leading to protein truncation contributed to the altered NF-κB activity, which is critical for NPC tumorigenesis. In addition, somatic mutations were found in several cancer-relevant pathways, including cell cycle-phase transition, cell death, EBV infection, and viral carcinogenesis. These data provide an enhanced road map for understanding the molecular basis underlying NPC., Competing Interests: The authors declare no conflict of interest.

Multiple factors, including host genetics, environmental factors, and Epstein-Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germline variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 × 10(-12)). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways.

Wnt/β-catenin signaling is responsible for the generation of cancer stem cells (CSCs) in many human tumors, including nasopharyngeal carcinoma (NPC). Recent studies demonstrate that Wnt or PORCN inhibitor, Wnt-C59, inhibits tumor growth in MMTV-WNT1 transgenic mice. The effect of Wnt-C59 in human tumors is not clear. In this study, the NPC cell lines investigated manifest heterogeneous responses to Wnt-C59 treatment. Wnt-C59 decreased tumor growth of SUNE1 cells in mice immediately following the administration of Wnt-C59. Mice injected with HNE1 cells did not develop visible tumors after the treatment of Wnt-C59, while control mice developed 100% tumors. Wnt-C59 inhibited stemness properties of NPC cells in a dosage-dependent manner by arresting sphere formation in both HNE1 and SUNE1 cells. Thus, Wnt-C59 has the potential to eradicate CSCs in human tumors. Active β-catenin and Axin2 proteins were strongly expressed in stromal cells surrounding growing tumors, confirming the importance of Wnt signaling activities in the microenvironment being driving forces for cell growth. These novel findings confirm the ability of Wnt-C59 to suppress Wnt-driven undifferentiated cell growth in NPC. Both anti-Wnt signaling and anti-CSC approaches are feasible strategies in cancer therapy.

Open release remains the gold standard in the treatment of carpal tunnel syndrome in cases where conservative treatment fails. However, the efficacy of carpal tunnel release in the elderly has been debated in the literature throughout the years. This review aims to review the current evidence pertaining to the efficacy of carpal tunnel release in the elderly. Based on the current evidence, the outcome of carpal tunnel release is unpredictable in the elderly. Elderly patients are also less satisfied with the operation compared to younger patients. The authors recommend that these messages be conveyed to elderly patients before surgery. Moreover, open carpal tunnel release should be offered in the early stages of treatment whenever operative management is indicated.