Nevin Manimala

Proc Natl Acad Sci U S A. 2025 Feb 4;122(5):e2401237121. doi: 10.1073/pnas.2401237121. Epub 2025 Jan 27.

ABSTRACT

Funding of curiosity-driven science is the lifeblood of scientific and technological innovation. Various models of funding allocation became institutionalized in the 20th century, shaping the present landscape of research funding. There are numerous reasons for scientists to be dissatisfied with current funding schemes, including the imbalance between funding for curiosity-driven and mission-directed research, regional and country disparities, path-dependency of who gets funded, gender and race disparities, low inter-reviewer reliability, and the trade-off between the effort and time spent on writing or reviewing proposals and doing research. We discuss possible alternative models for dealing with these issues. These alternatives include incremental changes such as placing more weight on the proposals or on the investigators and representative composition of panel members, along with deeper reforms such as distributed or concentrated funding and partial lotteries in response to low inter-reviewer reliability. We also consider radical alternatives to current funding schemes: the removal of political governance and the introduction of international competitive applications to a World Research Council alongside national funding sources. There is likely no single best way to fund curiosity-driven research; we examine arguments for and against the possibility of systematically evaluating alternative models empirically.

PMID:39869812 | DOI:10.1073/pnas.2401237121

Int J Surg. 2025 Jan 24. doi: 10.1097/JS9.0000000000002240. Online ahead of print.

ABSTRACT

BACKGROUND: Liver malignancies present substantial challenges to surgeons due to the extensive hepatic resections required, frequently resulting in posthepatectomy liver failure. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) was designed to increase the resectable liver volume, yet it is associated with significant mortality and morbidity rates. Recently, minimally invasive techniques have been incorporated into ALPPS, with the potential to improve the procedure’s safety profile whilst maintaining efficacy.

MATERIALS AND METHODS: This PRISMA-adherent systematic review involved a systematic search of PubMed, Embase and Cochrane for all interventional studies that evaluated the operative outcomes of minimally invasive ALPPS compared to open ALPPS. Two independent reviewers appraised and extracted the summary data from published studies. Random effects meta-analyses were used for primary analysis.

RESULTS: Nine studies with 637 patients undergoing ALPPS were included. Meta-analyses indicated a statistically significant decreased risk of 90-day mortality (RR = 0.48, 95%CI: 0.29;0.80) and decreased overall length of hospital stay (MD = -8, 95%CI: -11.25;-4.74) in patients undergoing minimally invasive ALPPS compared to patients undergoing open ALPPS. No significant differences in terms of the rate of future liver remnant growth (MD = 11.37, 95%CI: -4.02;26.77) and risk of posthepatectomy liver failure (RR = 0.52, 95%CI: 0.09;2.97) were identified. Subgroup analyses identified a trend in lowering the risk of posthepatectomy liver failure in patients undergoing laparoscopic ALPPS compared to robotic ALPPS. In terms of oncologic surgical outcomes, 92% of patients undergoing minimally invasive ALPPS achieved negative margin resections, while 86% of patients undergoing open ALPPS achieved negative margin resections.

CONCLUSION: This systematic review and meta-analysis provide evidence that minimally invasive ALPPS offers a safer alternative with reduced mortality and shorter hospital stays, while maintaining comparable efficacy in liver remnant growth and R0 resections. These findings highlight the potential of minimally invasive techniques to combat the criticism that ALPPS has been placed under.

PMID:39869398 | DOI:10.1097/JS9.0000000000002240

Int J Surg. 2025 Jan 24. doi: 10.1097/JS9.0000000000002232. Online ahead of print.

ABSTRACT

BACKGROUND: The impact of aortic arch (AA) morphology on the management of the procedural details and the clinical outcomes of the transfemoral artery (TF)-transcatheter aortic valve replacement (TAVR) has not been evaluated. The goal of this study was to evaluate the AA morphology of patients who had TF-TAVR using an artificial intelligence algorithm and then to evaluate its predictive value for clinical outcomes.

MATERIALS AND METHODS: A total of 1480 consecutive patients undergoing TF-TAVR using a new-generation transcatheter heart valve at 12 institutes were included in this retrospective study. The AA measurements were evaluated by deep learning, and then the approach index (IA) was determined. The machine learning algorithm was used to construct the predictive model and was validated externally.

RESULTS: The area under the curve of the IA model using random forest and logistic regression was 0.675 [95% confidence interval (CI): 0.586-0.764] and 0.757 (95% CI: 0.665-0.849), respectively. The IA model was validated externally, and consistent distinctions were obtained. After we used a generalized propensity score matching method for continuous exposure, the IA was the strongest correlation factor for major procedural events (odds ratio: 3.87; 95% CI: 2.13-7.59, P < 0.001). When leaflet morphology or transcatheter heart valve type was an interactive item with IA, neither of them was statistically significant in terms of clinical outcomes.

CONCLUSION: IA may be used to identify the impact of AA morphology on procedural and clinical outcomes in patients having TF-TAVR and to help to predict the procedural complications.

PMID:39869394 | DOI:10.1097/JS9.0000000000002232

Q J Nucl Med Mol Imaging. 2025 Jan 27. doi: 10.23736/S1824-4785.24.03567-2. Online ahead of print.

ABSTRACT

BACKGROUND: One can assess cortical defects on the early images of [99mTc]Tc-MAG3 renography. We aimed to assess interobserver and intraobserver reproducibility for detecting renal cortical defects using [99mTc]Tc-MAG3 for adults and children; identify causes for poor inter- and intraobserver reproducibility and to assess the effect of the kidney to background ratio (KTBR) on reproducibility.

METHODS: One hundred adult and 200 pediatric renograms were included. The observers reviewed the summed 1-minute posterior images for the first four minutes to detect cortical defects. Interobserver reproducibility between three observers and intra-observer reproducibility for two observers were determined. Agreement was tested using percentage agreement, Krippendorff’s reliability coefficient alpha and Cohen’s kappa statistic. The association between KTBR and agreement was evaluated.

RESULTS: Interobserver agreement on the 1-2 minutes images was 78 (95% CI: 74.8-82.7%) and 79.7 (95% CI: 75.9-83.5%) for left and right kidneys respectively. Intraobserver percentage was 89.7% (95% CI: 86.2-93.1%) for the senior and 80.7% (95% CI: 76.2-85.2%) for the junior observer. In 13.5% (27) of the adult and 4.5% (19) of the pediatric kidneys the difference in image interpretation between the observers would have had a clinical impact. If the KTBR is ≤2, the percentage agreement was between 61.5% and 64.8%. In cases with a KTBR >2, the percentage agreement was between 83.6% and 87.1%.

CONCLUSIONS: The percentage interobserver agreement was moderate. Disagreement between normal and abnormal cases were infrequent. The interobserver reproducibility was decreased when the KTBR was ≤2.

PMID:39869360 | DOI:10.23736/S1824-4785.24.03567-2

JAMA Netw Open. 2025 Jan 2;8(1):e2456392. doi: 10.1001/jamanetworkopen.2024.56392.

ABSTRACT

IMPORTANCE: Medication nonadherence imposes high morbidity, mortality, and costs but is challenging to address given its multiple causes. Subscription models are increasingly used in health care to encourage healthy behaviors; in January 2023, Amazon Pharmacy launched RxPass, a subscription program offering Amazon Prime members (hereafter, company members) in 45 states access to 60 common generic medications for a flat $5 monthly fee.

OBJECTIVE: To evaluate the associations of program enrollment with medication refills, days’ supply, and out-of-pocket costs.

DESIGN, SETTING, AND PARTICIPANTS: In this retrospective, population-based cohort study, a difference-in-differences approach with doubly robust estimation was used to assess outcomes 6 months before and after program enrollment, compared with a contemporaneous control group (study period included July 24, 2022, to January 24, 2024). Participants were younger than 65 years, company members, and not enrolled in Medicare or Medicaid. Exposure individuals were enrolled in the program in the first 6 months of program launch. Control individuals resided in the 5 states where the program was not available but who clicked on the enrollment webpage in the first 6 months of program launch.

EXPOSURE: Subscription program enrollment.

MAIN OUTCOMES AND MEASURES: The primary outcome was the number of days’ supply of medications on the subscription program list per person per month (PPPM). Secondary outcomes were the number of prescription refills and out-of-pocket costs of medications on the program list, including program subscription costs, PPPM.

RESULTS: After propensity score weighting, there were 5003 enrollees (mean [SD] age, 45.9 [11.1] years; 2076 female [41.5%]) and 5137 controls (mean [SD] age, 45.8 [11.1] years; 2116 female [41.2%]). The program was associated with an increase in days’ supply of 10.39 days PPPM (95% CI, 10.29-10.48 days PPPM), a 27% increase, an increase in prescription refills of 0.19 PPPM (95% CI, 0.19-0.19 refills PPPM), a 29% increase, and a decrease in out-of-pocket spending by $2.35 PPPM (95% CI, $2.37-$2.33 PPPM), a 30% decrease.

CONCLUSIONS AND RELEVANCE: In this cohort study, program enrollment was associated with increased medication refills and total days’ supply and reduced out-of-pocket costs. Future research should investigate the potential cognitive and/or behavioral mechanisms by which subscription programs encourage healthy behaviors and whether the results could be replicated among other pharmacies or cohorts.

PMID:39869337 | DOI:10.1001/jamanetworkopen.2024.56392

JAMA Netw Open. 2025 Jan 2;8(1):e2456429. doi: 10.1001/jamanetworkopen.2024.56429.

ABSTRACT

IMPORTANCE: Suicide rates among adolescents continue to rise, but there are a lack of clinical tools to predict when youths may be at risk for suicidal behaviors.

OBJECTIVE: To identify whether geolocation metrics, assessed through an app installed on adolescents’ personal smartphones, could detect the risk of next-week suicidal events and clinically meaningful suicidal ideation.

DESIGN, SETTING, AND PARTICIPANTS: This case series study included high-risk adolescents aged 13 to 18 years reporting a current affective and/or substance use disorder, oversampled for suicidal thoughts and behaviors (STB). Participants were recruited from the greater New York City and Pittsburgh communities through psychiatric outpatient programs, emergency departments, medical center research registries, and social media. Participants installed the Effortless Assessment Research System (EARS) software application onto their personal smartphones, which obtained passive sensor data, including geolocation metrics (via the global positioning system [GPS]), as well as weekly experience sampling data probing STB for the duration of the 6-month study. Adolescents also completed clinical assessments at baseline as well as during the 1-, 3-, and 6-month follow-up assessments. Statistical analysis was performed from March 2023 to November 2024.

MAIN OUTCOMES AND MEASURES: Repeated measures mixed-effects logistic models estimated whether weekly aggregates of geolocation features (ie, entropy, homestay, distance traveled) were associated with next-week suicidal events (ie, suicide attempts, psychiatric hospitalizations, emergency department visits for suicide concerns) and clinically meaningful ideation (via weekly experience sampling).

RESULTS: Overall, 186 participants were included in this study (148 [79.6%] female; 19 [10.2%] Asian, 23 [12.4%] Black, and 106 [57.0%] White), with a mean (SD) age of 16.4 (1.7) years. Greater homestay (amount of time spent at home) on a given week, relative to one’s own mean, was associated with 2-fold greater odds of suicidal events during the subsequent week (odds ratio, 1.99 [95% CI, 1.15-3.45]). Results were not significant for entropy and distance traveled metrics. However, using leave-future-out validation, the accuracy of the homestay model was modest (area under the receiver operating characteristic curve, 0.64 [95% CI, 0.50-0.78]).

CONCLUSIONS AND RELEVANCE: Advancements in smartphone technology afford unique opportunities to capture affective and behavioral dynamics that presage suicide risk. This case series study found that greater homestay obtained through smartphone GPS data over the course of a week, relative to one’s own mean, was associated with greater odds of a suicidal event in the subsequent week. Although accuracy was modest, these findings offer a novel starting point for suicide prevention research, particularly as smartphone sensor data may have the capacity to identify who is at risk while also providing an opportunity to deliver clinical tools when that risk is greatest.

PMID:39869336 | DOI:10.1001/jamanetworkopen.2024.56429

JAMA Netw Open. 2025 Jan 2;8(1):e2456787. doi: 10.1001/jamanetworkopen.2024.56787.

ABSTRACT

IMPORTANCE: An increasing number of older adults are undergoing surgery. Older adults face significant challenges throughout the spectrum of perioperative care. No frameworks exist to support primary care clinicians in helping older adults navigate perioperative care beyond preoperative medical clearance.

OBJECTIVE: We aimed to develop a framework to assist primary care clinicians in surgical care navigation for older patients.

DESIGN, SETTING, AND PARTICIPANTS: This qualitative study used semistructured interviews with a sample of geriatricians from across the US between January and June 2022. Interviews were conducted one on one via an online video conferencing platform without observers present. Demographics of participants were analyzed using descriptive statistics.

MAIN OUTCOME AND MEASURES: Directed content analysis of interview data was used to examine how primary care clinicians can optimally support older patients throughout the perioperative process.

RESULTS: This qualitative study included 24 geriatricians, 16 (67%) women, with median time in practice of 12.4 years (IQR, 5.0-24.5 years). Of those, 11 (46%) worked at an academic or tertiary referral center. Qualitative analysis identified 7 actions that geriatricians perform when caring for patients through the surgical continuum: conduct risk-benefit analysis of surgical referral, elicit and communicate patient goals, prepare patient and family for surgical consultation, set realistic expectations, assist with decision about surgery, advocate for patient and family, and coordinate postoperative care.

CONCLUSIONS AND RELEVANCE: In this qualitative study of geriatricians, 7 key domains of perioperative care for older adults were identified. The resulting framework can be used by primary care clinicians as they help their older patients navigate surgical care.

PMID:39869335 | DOI:10.1001/jamanetworkopen.2024.56787

JAMA Netw Open. 2025 Jan 2;8(1):e2456793. doi: 10.1001/jamanetworkopen.2024.56793.

ABSTRACT

IMPORTANCE: This study addresses the characteristics, kidney replacement therapy (KRT) modalities, and outcomes in children diagnosed with crush syndrome following an earthquake in Turkey.

OBJECTIVE: To analyze the associations of different KRT modalities with long-term dialysis dependency and length of stay (LOS) in the pediatric intensive care unit (PICU).

DESIGN, SETTING, AND PARTICIPANTS: This multicenter, prospective, and retrospective cohort study was conducted across 20 PICUs in Turkey. Participants included children diagnosed with crush syndrome after the 2023 Kahramanmaraş earthquake, and eligibility criteria included age, diagnosis, and need for KRT. Data were analyzed from August to October 2024.

EXPOSURE: Children diagnosed with crush syndrome who underwent KRT.

MAIN OUTCOMES AND MEASURES: The primary outcome was dialysis dependency at discharge. Secondary outcomes included LOS in the PICU.

RESULTS: The study included 183 pediatric patients (median [IQR] age, 158 (108-192) months; 49 [54.4%] males) with earthquake-related injury, of whom 90 required KRT. The median (IQR) time under the rubble was 25.7 (1-137) hours. At admission, 51 patients (56.6%) had stage 3 acute kidney injury, and the median (IQR) serum creatinine phosphokinase level was 15 555 (9386-59 274) IU/L. There was a significant association between the Kidney Disease-Improving Global Outcomes (KDIGO) stage at admission and serum creatinine phosphokinase level (area under the curve, 0.750; 95% CI, 0.621-0.879; P < .001). Among patients undergoing KRT, 33 (36.7%) received continuous venovenous hemodiafiltration, and 23 (25.6%) underwent intermittent hemodialysis (IHD). IHD treatment was the only independent factor associated with shorter PICU LOS (odds ratio [OR], 6.87; 95% CI, 1.54-30.67; P = .01). The dialysis dependency at discharge was higher in children who were transferred late to the PICU (β = 0.003; 95% CI, 0.001-0.005; P < .001) and those with a high Pediatric Trauma Score (β = 0.022; 95% CI, 0.003-0.041; P = 02). IHD was not statistically significantly associated with remaining dialysis-dependent at discharge (OR, 2.18; 95% CI, 0.53-8.98; P = .28). The overall mortality rate in the cohort was 6 patients (6.6%).

CONCLUSIONS AND RELEVANCE: This cohort study found that children who were transferred late to intensive care and those with a high trauma score after earthquake-related crush injury were more likely to remain dialysis-dependent at discharge. Furthermore, KDIGO stage at admission was associated with elevated serum creatinine phosphokinase levels. These findings highlight the critical importance of early intervention and appropriate treatment in children with AKI following prolonged entrapment.

PMID:39869334 | DOI:10.1001/jamanetworkopen.2024.56793

JAMA Netw Open. 2025 Jan 2;8(1):e2456825. doi: 10.1001/jamanetworkopen.2024.56825.

ABSTRACT

IMPORTANCE: Incidence of distant stage prostate cancer is increasing in the United States. Research is needed to understand trends by social and geographic factors.

OBJECTIVE: To examine trends in prostate cancer incidence and mortality rates in California by stage, age, race and ethnicity, and region.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used mortality data from the California Cancer Registry and California Department of Public Health’s Center for Health Statistics, and incidence data from the National Cancer Institute Surveillance, Epidemiology, and End Results program and the US Census. The dataset for these analyses was released in April 2024. Participants included males residing in California between 2004 and 2021. Analyses were conducted from April to October 2024.

EXPOSURES: Stage at diagnosis, age, race and ethnicity, and region of California.

MAIN OUTCOMES AND MEASURES: The delay-adjusted incidence rates and mortality rates were calculated and age-adjusted to the 2000 US standard population. Annual percentage changes (APC) were calculated using NCI’s Joinpoint Regression Program.

RESULTS: Between 2004 and 2021, there were 387 636 prostate cancer cases (27 938 distant stage) and 58 754 prostate cancer deaths in California. In this study, 203 038 cases (52.4%) occurred among males aged 55 to 69 years, and 153 884 (39.7%) occurred among males 70 years or older. The distribution of race and ethnicity among cases was: 1031 American Indian or Alaska Native (0.3%); 31 366 Asian American, Native Hawaiian, and Pacific Islander (8.1%); 66 695 Hispanic or Latino (17.2%); 36 808 non-Hispanic Black (9.5%); 238 229 non-Hispanic White (61.5%); and 13 507 unknown or other races (3.5%). On average, the incidence of distant prostate cancer increased 6.7% (95% CI, 6.2% to 7.3%) per year between 2011 and 2021. By race and ethnicity, the APC ranged from 6.5% (95% CI, 4.2% to 13.4%) among Asian American, Native Hawaiian, and Pacific Islander males between 2011 and 2021 to 8.0% (95% CI, 6.9% to 9.5%) among Hispanic males between 2014 and 2021. In 9 of the 10 California regions, the incidence of distant prostate cancer increased by approximately 6% or more per year. Prostate cancer mortality rates declined 2.6% per year between 2004 and 2012 but plateaued between 2012 to 2021 (APC, 0.1%; 95% CI, -0.6% to 1.6%). The plateau in mortality occurred across ages, races and ethnicities, and regions.

CONCLUSIONS AND RELEVANCE: In this cohort study among California residents, the incidence of distant stage prostate cancer increased throughout the state between 2011 and 2021. Mortality rates plateaued between 2012 and 2021, ending previous decades of decline. Implementation of more effective prostate cancer screening strategies are critically needed.

PMID:39869333 | DOI:10.1001/jamanetworkopen.2024.56825

JAMA Pediatr. 2025 Jan 27. doi: 10.1001/jamapediatrics.2024.5286. Online ahead of print.

ABSTRACT

IMPORTANCE: Cyclophosphamide and calcineurin inhibitors are the most used nonsteroid immunosuppressive medications globally for children with various chronic inflammatory conditions. Their comparative effectiveness remains uncertain, leading to worldwide practice variation. Nephrotic syndrome is the most common kidney disease managed by pediatricians globally and suboptimal treatment is associated with high morbidity.

OBJECTIVE: To evaluate the comparative effectiveness of cyclophosphamide vs calcineurin inhibitors (tacrolimus or cyclosporine) for childhood nephrotic syndrome relapse prevention.

DESIGN, SETTING, AND PARTICIPANTS: Using target trial emulation methods, the study team emulated a pragmatic, open-label clinical trial using available data from the Insight Into Nephrotic Syndrome: Investigating Genes, Health, and Therapeutics (INSIGHT) study. INSIGHT is a multicenter, prospective cohort study in the Greater Toronto Area, Canada. Participants included children (1 to 18 years) with steroid-sensitive nephrotic syndrome diagnosed between 1996 and 2019 from the Greater Toronto Area, who initiated cyclophosphamide or a calcineurin inhibitor treatment. Data analysis was performed in 2024.

EXPOSURES: Incident cyclophosphamide or calcineurin inhibitor treatment. Randomization was emulated by overlap weighting of propensity scores for treatment assignment.

MAIN OUTCOMES: The primary outcome was time to relapse, analyzed by weighted Kaplan-Meier and Cox proportional hazards models. Secondary outcomes included relapse rates, subsequent immunosuppression, kidney function, hypertension, adverse events, and quality of life.

RESULTS: Of 578 children (median age at diagnosis, 3.7 [IQR, 2.8-6.0] years; 371 male [64%] and 207 female [36%]), 252 initiated cyclophosphamide, 131 initiated calcineurin inhibitors, and 87 sequentially initiated both medications. Baseline characteristics were well balanced after propensity score weighting. During median 5.5-year (quarter 1 to quarter 3, 2.5-9.2) follow-up, there was no significant difference in time to relapse between calcineurin inhibitor vs cyclophosphamide treatment (hazard ratio [HR], 1.25; 95% CI, 0.84-1.87). Relapses were more common after calcineurin inhibitor treatment than cyclophosphamide (85% vs 73%) in the weighted cohorts, but not statistically significant. There were also no significant differences in subsequent relapse rates, nonsteroid immunosuppression use, or kidney function between medications. Calcineurin inhibitor treatment was associated with more hospitalizations (HR, 1.83; 95% CI, 1.14-2.92) and intravenous albumin use (HR, 2.81; 95% CI, 1.65-4.81).

CONCLUSIONS AND RELEVANCE: In this study, there was no evidence of difference in time to relapse after cyclophosphamide and calcineurin inhibitor treatment in children with nephrotic syndrome. Cyclophosphamide treatment is shorter in duration and more accessible globally than calcineurin inhibitors.

PMID:39869322 | DOI:10.1001/jamapediatrics.2024.5286