Explore the vast range of titles available.

Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis. ERG -negative tumor cells, compared to ERG -positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis. The changes that prostate cancer (PCa) induces in its microenvironment are not fully understood. Here the authors use single-cell RNA-seq and organoids to characterise how the microenvironment responds to PCa, and also identify tumour-associated epithelial cell states and club cells.

To cope with the increasing healthcare costs brought about by the universal health insurance programme, national volume-based procurement (NVBP) was implemented in China to reduce drug prices. However, the impact of NVBP remains unknown. We reported the effects of the NVBP pilot programme on medication affordability and discussed the challenges and recommendations for further reforms. A total of 25 molecules won the bidding in the NVBP pilot programme, and price cuts ranged from 25% to 96%. Medication affordability was measured as the number of days’ wages needed to pay for a course of treatment, and the medication was identified as affordable if the cost of a treatment course was less than the average daily wage. After the NVBP, the proportion of affordable drugs increased from 33% to 67%, and the mean affordability improved from 8.2 days’ wages to 2.8 days’ wages. Specifically, for rural residents, the proportion of affordable drugs increased from 13% to 58%, and the mean affordability improved from 15.7 days’ wages to 5.3 days’ wages. For urban residents, the proportion of affordable drugs increased from 54% to 71%, and the mean affordability improved from 5.9 days’ wages to 2.0 days’ wages. Implementing the NVBP substantially improved medication affordability. In future reforms, a multifaceted approach addressing all issues in the health system is needed to enhance medicine access.

Cancer is mainly caused by somatic genome alterations (SGAs). Precision oncology involves identifying and targeting tumor-specific aberrations resulting from causative SGAs. We developed a novel tumor-specific computational framework that finds the likely causative SGAs in an individual tumor and estimates their impact on oncogenic processes, which suggests the disease mechanisms that are acting in that tumor. This information can be used to guide precision oncology. We report a tumor-specific causal inference (TCI) framework, which estimates causative SGAs by modeling causal relationships between SGAs and molecular phenotypes (e.g., transcriptomic, proteomic, or metabolomic changes) within an individual tumor. We applied the TCI algorithm to tumors from The Cancer Genome Atlas (TCGA) and estimated for each tumor the SGAs that causally regulate the differentially expressed genes (DEGs) in that tumor. Overall, TCI identified 634 SGAs that are predicted to cause cancer-related DEGs in a significant number of tumors, including most of the previously known drivers and many novel candidate cancer drivers. The inferred causal relationships are statistically robust and biologically sensible, and multiple lines of experimental evidence support the predicted functional impact of both the well-known and the novel candidate drivers that are predicted by TCI. TCI provides a unified framework that integrates multiple types of SGAs and molecular phenotypes to estimate which genome perturbations are causally influencing one or more molecular/cellular phenotypes in an individual tumor. By identifying major candidate drivers and revealing their functional impact in an individual tumor, TCI sheds light on the disease mechanisms of that tumor, which can serve to advance our basic knowledge of cancer biology and to support precision oncology that provides tailored treatment of individual tumors.

ObjectivesTo assess the cost-effectiveness of aducanumab at its updated price for treating patients with mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD).DesignCost-effectiveness analysis.SettingsA five-state Markov model was constructed using 10 000 virtual patients to assess the cost-effectiveness of aducanumab from the perspective of the US healthcare system. The model employed a one-year cycle time and a lifetime time horizon. Transition probabilities and mortality rates were derived from a literature review. To address uncertainty and generalise the base case results, both one-way and probabilistic sensitivity analyses were conducted.Participants10 000 virtual patients with MCI and mild AD.InterventionsThe study group consisted of patients using aducanumab, while the control group consisted of those using a placebo.Primary and secondary outcome measuresPrimary outcomes included costs and quality-adjusted life years (QALYs). In line with the healthcare system perspective, only direct medical costs were included. Drug costs were obtained from official records, while other medical costs were derived from literature reviews. Utilities used to calculate QALYs were also obtained from the literature. Incremental analysis was conducted to assess cost-effectiveness in the base case analysis by comparing the incremental cost-effectiveness ratio (ICER) against the willingness-to-pay (WTP) threshold. A discount rate of 3% was applied to both costs and effectiveness.ResultsFrom the perspective of the US healthcare system, compared with the control group, the study group had an incremental cost of US$143 821.1 and an incremental QALY of 0.10. The ICER of patients using aducanumab compared with those using placebo was US$1 012 219.0 per QALY gained, which was much greater than the WTP threshold of US$50 000 to US$150 000, indicating that using aducanumab was not cost-effective. One-way sensitivity analysis showed the five most sensitive parameters were relative risk of progressing from MCI to mild AD, the utility of MCI, initial age, discount rate and the price of aducanumab. In the probabilistic sensitivity analysis, when the WTP was the WTP threshold of US$150 000, the probability of aducanumab being cost-effective was 0%. In addition, when the probability of aducanumab being cost-effective was 50%, the WTP was US$1 180 000, and when the probability of aducanumab being cost-effective was 95%, the WTP was US$1 906 000.ConclusionsEven with the updated price being half of the original, aducanumab is still not cost-effective, underscoring the need for affordable, evidence-based AD treatments.

Background Proxy responses are very common when surveys are conducted among the elderly or disabled population. Outcomes reported by proxy may be systematically different from those obtained from patients directly. The objective of the study is to examine the presence, direction, and magnitude of possible differences between proxy-reported and patient-reported outcomes in health and functional status measures among Medicare beneficiaries. Methods This study is a pooled cross-sectional study of a nationally representative sample of community-dwelling Medicare beneficiaries from 2006 to 2011. Survey respondents can respond to the Medicare Current Beneficiary Survey either by themselves or via proxies. Health and functional status was assessed across five domains: physical, affective, cognitive, social, and sensory status. Propensity score matching was used to get matched pairs of patient-reports and proxy-reports. Results After applying the propensity score matching, the study identified 7,780 person-years of patient-reports paired with 7,780 person-years of proxy-reports. Except for the sensory limitation, differences between proxy-reported and patient-reported outcomes were present in physical, affective, cognitive, and social limitations. Compared to patient-reports, a question regarding survey respondents’ difficulties in managing money was associated with the largest proxy response bias (relative risk, RR = 3.83). With few exceptions, the presence, direction, and magnitude of differences between proxy-reported and patient-reported outcomes did not vary much in the subgroup analysis. Conclusions When there is a difference between proxy-reported and patient-reported outcomes, proxies tended to report more health and functional limitations among the elderly and disabled population. The extent of proxy response bias depended on the domain being tested and the nature of the question being asked. Researchers should accept proxy reports for sensory status and objective, observable, or easy questions. For physical, affective, cognitive, or social status and private, unobservable, or complex questions, proxy-reported outcomes should be used with caution when patient-reported outcomes are not available.

Two broadly known characteristics of germ cells in many organisms are their development as a ‘cyst’ of interconnected cells and their high sensitivity to DNA damage. Here we provide evidence that in the Drosophila testis, connectivity serves as a mechanism that confers to spermatogonia a high sensitivity to DNA damage. We show that all spermatogonia within a cyst die synchronously even when only a subset of them exhibit detectable DNA damage. Mutants of the fusome, an organelle that is known to facilitate intracyst communication, compromise synchronous spermatogonial death and reduces overall germ cell death. Our data indicate that a death-promoting signal is shared within the cyst, leading to death of the entire cyst. Taken together, we propose that intercellular connectivity supported by the fusome uniquely increases the sensitivity of the germline to DNA damage, thereby protecting the integrity of gamete genomes that are passed on to the next generation.

Background: Two coronavirus disease 2019 (COVID-19) vaccines have received emergency use authorizations in the U.S. However, the safety of these vaccines in the real-world remains unknown. Methods: We reviewed adverse events (AEs) following COVID-19 vaccination among adults in the Vaccine Adverse Event Reporting System (VAERS) from December 14, 2020, through January 22, 2021. We compared the top 10 AEs, serious AEs, along with office and emergency room (ER) visits by age (18–64 years, ≥65 years) and gender (female, male). Results: There were age and gender disparities among adults with AEs following COVID-19 vaccination. Compared to younger adults aged between 18 and 64 years, older adults were more likely to report serious AEs, death, permanent disability, and hospitalization. Males were more likely to report serious AEs, death, and hospitalization compared to females. Conclusions: COVID-19 vaccines are generally safe but possible age and gender disparities in reported AEs may exist.

Background: Inappropriate medication use is common around the world, particularly among older patients, and, despite potentially being preventable, often leads to adverse clinical and economic outcomes. However, there is a dearth of information regarding this prominent issue in China. Objectives: To evaluate the extent to which the physician can correctly identify potentially inappropriate medication (PIM) in older patients and to understand physicians’ attitudes towards improving PIM knowledge. Methods: An online, cross-sectional survey was conducted anonymously among practicing physicians in China from November through December 2020. Knowledge of PIM was accessed using seven clinical vignettes covering a wide variety of therapeutic areas. Source of information and perceived barriers regarding PIM were also evaluated. We performed the ordinary least square regression analysis to understand the potential factors related to physicians’ knowledge of PIM. Results: A total of 597 study participants were included in the analysis. More than half of them had never heard of any screening tool for PIMs ( n = 328, 54.9%) and the most frequently acknowledged tool was the China PIM Criteria ( n = 259, 43.4%). For the seven clinical vignettes testing physicians’ knowledge on the medications that should be generally avoided in older patients, the mean score was 2.91 points out of 7 (SD: 1.32), with the median score of three points (IQR: 2–4). Only one-third of the respondents were feeling confident when prescribing for older patients ( n = 255, 35.08%). Package inserts have been used as the major source of PIM information (always, n = 177, 29.65%; frequently, n = 286, 47.91%). Perceived barriers to appropriate prescribing include polypharmacy ( n = 460, 77.05%), lack of formal education on prescribing for the older patients ( n = 428, 71.69%). Conclusion: In this online survey evaluating physicians’ ability to detect PIM for older patients, approximately 40% of PIM were recognized, suggesting an insufficient level of knowledge about appropriate prescribing.

Background The Inflation Reduction Act (IRA) did not introduce a cap on out-of-pocket (OOP) for newly approved Alzheimer’s Disease (AD) drugs, such as lecanemab which is covered under Medicare Part B. Therefore, expanding the use of conventional anti-dementia drugs is critical to addressing the growing economic burden of dementia. In this study, we aimed to evaluate the causal relationship between specific conventional anti-dementia drug use and various healthcare costs with the Double/Debiased Machine Learning (DML) approach. Methods Leveraging data from the Medicare Current Beneficiary Survey (MCBS) spanning 2015 to 2019, we utilized a nationally representative survey linked to Medicare data in this study. The presence of Alzheimer’s Disease and Related Dementias (ADRD) and anti-dementia drug use was determined through Medicare claims data. The health care costs were measured as total medical costs and categorized into Medicare costs, OOP costs, inpatient costs, and outpatient costs. Conventional anti-dementia drugs include Cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartate receptor (NMDAR) antagonists. The DML techniques were employed to investigate causal relationships. Results A total of 12,764,487 weighted older adults with ADRD were included, with 34.60% of them using anti-dementia drugs. Using anti-dementia drugs could significantly reduce Medicare costs and inpatient costs by $4,804.26 and $2,842.48 on average ( P  < 0.001), while did not significantly influence total costs, OOP costs, and outpatient costs. ChEIs use could help decrease Medicare costs and inpatient costs significantly ( P  < 0.05), whereas the NMDAR antagonist (memantine) showed no statistically significant effect across all cost types. Both donepezil and rivastigmine could help significantly decrease Medicare costs and inpatient costs ( P  < 0.001). Additionally, anti-dementia drug use could significantly reduce Medicare costs and inpatient costs among non-Hispanic Whites, and significantly lower inpatient costs among non-Hispanic Blacks ( P  < 0.05). Conclusion This study revealed the causal relationship between anti-dementia drug use and Medicare costs by employing DML. ChEIs were found to be contributors to the decreased Medicare costs and inpatient costs, which could mainly be attributed to donepezil. The use of donepezil should be expanded, considering the significant benefits. Furthermore, a lower OOP cap for ADRD beneficiaries should be established under the IRA.

Background Diabetes self-management education (DSME) has significant clinical benefits on diabetic glycemic control and reduction in the onset of complications. However, the economic benefits of DSME in older Medicare beneficiaries are not well known. The objective of this study is to examine the effect of DSME on different types of costs in older Medicare beneficiaries with diabetes. Methods This was a pooled cross-sectional study using the Medicare Current Beneficiary Survey (MCBS). The use of DSME was reported by survey respondents. Economic outcomes included total medical costs, total diabetes-related medical costs, total prescription costs, and total anti-diabetic prescription costs were measured based on Medicare claims and prescription drug events data from the perspective of the Medicare system. All costs were adjusted to 2012 U.S. dollars using the Consumer Price Index (CPI). Generalized linear models, with a log link and gamma distribution, were used to examine the effect of DSME on different costs. Results A total of 3,003 older Medicare beneficiaries with diabetes were included, among whom 35.50% ( n  = 1,066) had DSME. Individuals who did not have DSME had significantly higher total prescription costs than those who had DSME ($4,398.19 vs. $3,966.82, P  =.0134). After adjusting for covariates, compared to those who did not have DSME, those who had DSME had 16.36% (95% CI: 9.69% to 22.54%) lower total medical costs and 12.83% (95% CI: 6.41% to 18.80%) lower total prescription costs. Conclusion This study found that DSME is associated with significantly lower spending in total medical and prescription costs for older Medicare beneficiaries. Given the economic benefits associated with DSME, different healthcare providers should further promote and increase the awareness of DSME to ensure sustained activities, enrollment, and patient retention in older Medicare beneficiaries with diabetes.