Category: Nevin Manimala

JAMA Netw Open. 2025 Aug 1;8(8):e2527769. doi: 10.1001/jamanetworkopen.2025.27769.

ABSTRACT

IMPORTANCE: Immune checkpoint inhibitors (ICIs) show efficacy in treatment of several solid tumors, but microsatellite-stable rectal cancer is largely resistant. Radiotherapy may enhance tumor immunogenicity and thus may make the combination of radiotherapy and ICIs a promising strategy to treat rectal cancer. While anti-programmed cell death protein 1 antibodies in neoadjuvant regimens have been linked to higher complete response rates, the added benefit of including a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor remains unclear.

OBJECTIVE: To evaluate the safety and feasibility of combining ipilimumab and nivolumab with neoadjuvant chemoradiotherapy (CRT) for rectal cancer.

DESIGN, SETTING, AND PARTICIPANTS: The CHINOREC trial was a prospective, randomized, open-label, multicenter phase 2 clinical trial conducted from June 2, 2020, to March 15, 2024, across multiple academic and tertiary medical centers in Austria. Analysis was based on intention to treat.

INTERVENTION: Neoadjuvant CRT consisted of 50 Gy in 2-Gy fractions with concurrent capecitabine (1650 mg/m2/d). The experimental arm received additional intravenous ipilimumab (1 mg/kg on day 7) and nivolumab (3 mg/kg every 2 weeks starting on day 14) (CRT plus ipilimumab and nivolumab group). Surgical resection was performed 10 to 12 weeks after CRT.

MAIN OUTCOME AND MEASURES: The primary outcome was the safety and feasibility of combining CRT with sequential ipilimumab and nivolumab, assessed by surgical complications and reoperation rates. Secondary outcomes included clinical and pathological response rates.

RESULTS: Of the 145 patients assessed, 80 were randomized to receive either CRT alone (CRT group) (n = 30) or to the CRT plus ipilimumab and nivolumab group (n = 50) (49 male [61%]; median age, 60 [range, 36-83] years). Differences in surgical complication rates were not statistically significant between the CRT and CRT plus ipilimumab and nivolumab groups (any grade, 20 of 26 patients [77%] vs 33 of 43 [77%]; P > .99), as were reoperation rates (2 of 26 [8%] vs 3 of 43 [7%]; P > .99). Major pathological response (10 of 26 [38%] vs 16 of 43 [37%]; P > .99) and complete response (9 of 30 [30%] vs 11 of 50 [22%]; P = .44) rates were overall high in both groups.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of patients with rectal cancer, integrating ipilimumab and nivolumab into neoadjuvant CRT was safe and feasible, with no increase in surgical complications. Although complete response rates did not significantly improve, the dual ICI regimen demonstrated promising clinical activity. These findings support further translational research to optimize timing, dosing, and fractionation of radiotherapy and ICI therapy and to guide patient selection.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04124601.

PMID:40844778 | DOI:10.1001/jamanetworkopen.2025.27769

JAMA Health Forum. 2025 Aug 1;6(8):e252273. doi: 10.1001/jamahealthforum.2025.2273.

ABSTRACT

IMPORTANCE: Persons from marginalized racial and ethnic groups and of low socioeconomic status are at high risk of dementia but are underrepresented in clinical trials. Financial incentives may improve representation.

OBJECTIVE: To evaluate the effect of financial incentives on enrollment of county health system patients into a memory concerns registry.

DESIGN, SETTING, AND PARTICIPANTS: Between March 1, 2024, and April 24, 2024, patients 50 years and older without a dementia diagnosis within a single integrated county health system that includes a hospital and 9 outpatient health centers were invited to enroll in the Alzheimer Prevention Trials (APT) Webstudy, an online observational study aimed at accelerating enrollment into Alzheimer disease clinical trials.

INTERVENTIONS: Patients were randomized 1:1:1 to an invitation message (arm 1), a message with a small ($25) enrollment incentive (arm 2), or a message with an enrollment incentive of entry into a $2500 lottery with 1 in 100 odds of award (arm 3).

MAIN OUTCOMES AND MEASURES: The primary outcome was enrollment, defined as APT Webstudy registration and completion of at least 1 of 2 remote cognitive assessments. Outcomes were measured through April 30, 2024.

RESULTS: Of 44 844 patients invited to the APT Webstudy, the mean (SD) age was 64.7 (10.1) years, 25 447 (56.8%) were women, 25 044 (55.8%) had Medicaid insurance, 11 347 (25.3%) were Hispanic/Latino, 9526 (21.2%) were non-Hispanic Asian, 6044 (13.5%) were non-Hispanic Black, and 12 109 (27%) were non-Hispanic White. A total of 401 participants (0.9%) enrolled in the APT Webstudy. Relative to the message-only arm, participants randomized to the small incentive arm were more likely to enroll (adjusted odds ratio [OR], 1.39; 95% CI, 1.09-1.76; P = .008) in the APT Webstudy while those in the prize incentive arm were not more likely to enroll (adjusted OR, 1.08; 95% CI, 0.84-1.39; P > .99). Enrollment in the prize incentive arm was lower relative to the small incentive arm (adjusted OR, 0.78; 95% CI, 0.61-0.98; P = .04). Secondary heterogeneity analyses indicated that patients of White race (adjusted OR, 1.61; 95% CI, 1.15-2.25; P = .006) and male sex (adjusted OR, 2.40; 95% CI, 1.55-3.75; P < .001) were most responsive to the small $25 incentive relative to the message-only arm.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, relative to message invitations, invitations with guaranteed, small financial incentives but not lottery incentives increased enrollment of economically but not necessarily racially or ethnically diverse participants to a study that aimed to increase enrollment in clinical studies.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06033066.

PMID:40844772 | DOI:10.1001/jamahealthforum.2025.2273

JAMA Health Forum. 2025 Aug 1;6(8):e252631. doi: 10.1001/jamahealthforum.2025.2631.

ABSTRACT

IMPORTANCE: Brand-name drugs in the US are sold at high prices during market exclusivity periods defined by their patents, before prices are lowered by generic competition. Drug manufacturers use several strategies to extend these market exclusivity periods and delay generic competition, including obtaining overlapping thickets of patents.

OBJECTIVE: To estimate excess US spending associated with delays in generic competition due to extended market exclusivity for 4 top-selling drugs.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective serial cross-sectional study focused on 4 top-selling drugs that experienced new generic competition between 2014 and 2018 to allow enough time for determining postexclusivity price trajectories: imatinib (Gleevec, cancer), glatiramer (Copaxone, multiple sclerosis), celecoxib (Celebrex, arthritis), and bimatoprost (Lumigan, glaucoma). Drug monthly spending data from 2011 to 2021 were retrieved from a large commercial claims database (Merative MarketScan) and a random sample of Medicare beneficiaries with at least 1 month of Medicare Parts A, B, and D coverage and adjusted for estimated rebates obtained from SSR Health, LLC. The analysis was performed between March 2023 and January 2024.

EXPOSURES: Extended market exclusivity was calculated as the time between expiration of the key patent and first generic marketing.

MAIN OUTCOMES AND MEASURES: The primary outcome was net monthly national drug spending in commercial insurance and Medicare Part D. Spending was estimated under 2 scenarios: (1) the status quo, reflecting observed spending trends, and (2) a counterfactual scenario, modeling spending in the absence of extended market exclusivity. Segmented linear regression analyses were used to assess level and slope changes in monthly spending following generic entry. Weights were applied to extrapolate sample-based estimates to the full US commercially insured and Medicare Part D populations.

RESULTS: Market exclusivity extensions beyond expiration of the key patent ranged from 7 (celecoxib) to 13 (glatiramer) months. In the absence of extended market exclusivity, and over a 2-year period following generic competition, net spending would have decreased by $3.5 billion, including $1.9 (95% CI, $1.3-$2.5) billion in commercial plans and $1.6 (95% CI, $1.1-$2.1) billion in Medicare-including $67 (95% CI, $22-$115) million for bimatoprost, $726 (95% CI, $516-$938) million for celecoxib, $1.7 (95% CI, $1.0-$2.4) billion for glatiramer, and $1.0 (95% CI, $0.8-$1.2) billion for imatinib.

CONCLUSIONS AND RELEVANCE: This study found that promoting timely generic availability and avoiding extending market exclusivity for top-selling drugs may result in substantial savings for US patients and payers, including both public and private health insurance programs.

PMID:40844771 | DOI:10.1001/jamahealthforum.2025.2631

JAMA Health Forum. 2025 Aug 1;6(8):e253014. doi: 10.1001/jamahealthforum.2025.3014.

ABSTRACT

IMPORTANCE: Transgender and gender diverse (TGD) people have significantly higher rates of cardiovascular-related conditions than cisgender people, and Black and Hispanic people have higher rates of cardiovascular-related conditions than non-Hispanic White people. However, little is known about the prevalence of cardiovascular-related conditions among racial and ethnic subgroups of TGD people.

OBJECTIVE: To compare the prevalence of cardiovascular-related conditions across racial and ethnic groups for TGD and cisgender people using quantitative intersectional methods.

DESIGN, SETTING, AND PARTICIPANTS: Medicare enrollment and claims data were used from TGD and cisgender beneficiaries from 2011 to 2020. Using an established algorithm, likely TGD people were identified based on their diagnosis codes and care utilization. The 10 nearest-neighbor cisgender matches for each TGD beneficiary were identified based on propensity scores estimated from the original basis of eligibility, years of enrollment, age, and hospital service area.

EXPOSURE: Race, ethnicity, and gender modality (TGD and cisgender). These data were analyzed from November 7, 2023, to October 31, 2024.

MAIN OUTCOMES AND MEASURES: Rate of cardiovascular-related conditions (peripheral vascular disease, congestive heart failure, diabetes, hypertension, and chronic obstructive pulmonary disease) among Asian and Pacific Islander, Black, and Hispanic TGD beneficiaries compared with non-Hispanic White cisgender counterparts using generalized estimating equations, cardiovascular diseases and their risk factors. Attributable proportions for TGD Asian and Pacific Islander, Black, and Hispanic beneficiaries were calculated.

RESULTS: Of the 36 004 TGD beneficiaries, 714 Asian and Pacific Islander (2%), 4518 Black (13%), and Hispanic 2545 (7%) had higher rates of cardiovascular-related conditions than 28 227 non-Hispanic White (78%) beneficiaries and higher than the 323 613 cisgender beneficiaries (5981 Asian and Pacific Islander [2%]; 40 781 Black [13%]; 22 417 Hispanic [7%]; 254 434 White [79%]). Black TGD beneficiaries had a 74% higher prevalence of peripheral vascular disease, 76% higher prevalence of congestive heart failure, and 50% higher prevalence of diabetes than similar non-Hispanic White cisgender beneficiaries. Overall, 6.3% of the excess peripheral vascular disease among Black TGD beneficiaries and 19.9% of the excess peripheral vascular disease among Asian and Pacific Islander TGD beneficiaries were associated with being at the intersection of gender, race, and ethnicity.

CONCLUSIONS AND RELEVANCE: This cross-sectional study found that Asian and Pacific Islander, Black, and Hispanic TGD beneficiaries had a high prevalence of cardiovascular-related conditions and had an elevated prevalence of several conditions, attributable to the intersection of gender, race, and ethnicity. Medicare should use the tools at its disposal to support the health of TGD beneficiaries.

PMID:40844770 | DOI:10.1001/jamahealthforum.2025.3014

Spine (Phila Pa 1976). 2025 Aug 22. doi: 10.1097/BRS.0000000000005480. Online ahead of print.

ABSTRACT

STUDY DESIGN: A retrospective cohort analysis.

OBJECTIVE: This study investigates the association between initial postoperative gabapentinoid prescription and long-term opioid use following long-segment posterior lumbar instrumentation.

SUMMARY OF BACKGROUND DATA: Gabapentinoids have gained traction for their neuropathic pain-relieving properties and potential synergy with opioids. However, their long-term efficacy in minimizing postoperative opioid consumption remains uncertain, particularly in patients undergoing extensive spinal surgery.

METHODS: The TriNetX Research Network was queried to identify patients with preoperative diagnoses of lumbar spinal stenosis, spondylolisthesis or scoliosis who underwent posterior lumbar instrumentation spanning 3 to 12 vertebral segments. The study population was stratified by based on the extent of instrumentation, defined as either 3-6 or 7-12 spinal segments. These patients were further divided into two cohorts: those who were prescribed a gabapentinoid (gabapentin or pregabalin) within 30 days postoperatively and those who were not. To address potential confounders, 1:1 propensity score matching (PSM) was performed, adjusting for demographics, comorbidities, and preoperative prescriptions of opioids and gabapentinoids. Presence of select postoperative opioid prescriptions were assessed at 1 to 3 months, 3 to 6 months, 6 to 12 months, and 12 to 24 months.

RESULTS: A total of 28,827 patients met all initial inclusion criteria. Following 1:1 PSM, the 3-6 segment group included 1,816 patients per cohort and the 7-12 segment group consisted of 344 patients per cohort. Among 3-6 level instrumentations, patients who received gabapentinoids within 30 days of surgery demonstrated significantly lower odds of being prescribed non-codeine-based and strong opioids at all postoperative intervals. In contrast, these gabapentinoid-treated patients exhibited higher odds of weak opioid prescriptions at 3 to 6 months. No statistically significant difference in opioid prescribing was observed among 7-12 segment instrumentation patients at any period.

CONCLUSION: This study demonstrates that early postoperative gabapentinoid prescription is associated with a sustained reduction in chronic non-codeine-based and strong opioid use following 3-6 segment lumbar fusion. These findings underscore the utility of gabapentinoids as part of a multimodal analgesia strategy, potentially minimizing the need for more potent opioids and reducing the risk of long-term dependence in spine surgery patients.

PMID:40844769 | DOI:10.1097/BRS.0000000000005480

Proc Natl Acad Sci U S A. 2025 Aug 26;122(34):e2507516122. doi: 10.1073/pnas.2507516122. Epub 2025 Aug 22.

ABSTRACT

Humans can implicitly learn about multistep sequential relationships between events in the environment from their statistical co-occurrence. Theoretical work has suggested that neural replay is a candidate mechanism that aids such learning. Here, we used functional MRI (fMRI) to test whether replay is related to implicit learning of higher-order sequential relationships. Human participants viewed sequences of images that followed probabilistic transitions determined by ring-like graph structures. Behavioral modeling of response times revealed that participants acquired multistep transition knowledge in a manner consistent with gradual updating of an internal successor representation (SR) model. Yet, half of participants did not report being aware of any sequential task structure, and most participants failed to provide meaningful transition probability ratings in a posttask test. Analyses of temporal dynamics of multivariate fMRI patterns during brief 10 s pauses from the ongoing statistical learning task indicated backward sequential replay of multistep sequences in visual cortical areas. Variations in model parameters between participants that captured response time patterns related to strength of neural replay. No corresponding relations between replay and measures of explicit awareness were found. These findings indicate that implicit learning of higher-order relationships establishes an internal SR-based map of the task and is accompanied by cortical on-task replay.

PMID:40844766 | DOI:10.1073/pnas.2507516122

Eur Radiol. 2025 Aug 22. doi: 10.1007/s00330-025-11859-9. Online ahead of print.

NO ABSTRACT

PMID:40844754 | DOI:10.1007/s00330-025-11859-9

Eur Radiol. 2025 Aug 22. doi: 10.1007/s00330-025-11960-z. Online ahead of print.

NO ABSTRACT

PMID:40844753 | DOI:10.1007/s00330-025-11960-z

Eur Radiol. 2025 Aug 22. doi: 10.1007/s00330-025-11959-6. Online ahead of print.

NO ABSTRACT

PMID:40844752 | DOI:10.1007/s00330-025-11959-6

Eur Radiol. 2025 Aug 22. doi: 10.1007/s00330-025-11877-7. Online ahead of print.

NO ABSTRACT

PMID:40844751 | DOI:10.1007/s00330-025-11877-7