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Abstract The aging process is universal, and it is characterized by a progressive deterioration and decrease in physiological function leading to decline on the organismal level. Nevertheless, a number of genetic and nongenetic interventions have been described, which successfully extend healthspan and lifespan in different species. Furthermore, a number of clinical trials have been evaluating the feasibility of different interventions to promote human health. The goal of the annual Biological Sciences Section of the Gerontological Society of America meeting was to share current knowledge of different topics in aging research and provide a vision of the future of aging research. The meeting gathered international experts in diverse areas of aging research including basic biology, demography, and clinical and translational studies. Specific topics included metabolism, inflammaging, epigenetic clocks, frailty, senescence, neuroscience, stem cells, reproductive aging, inter-organelle crosstalk, comparative transcriptomics of longevity, circadian clock, metabolomics, and biodemography.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

Introduction: Systemic amyloid light chain (AL) amyloidosis is a rare disease with severe sequelae, including cardiac and renal dysfunction and failure. Various biomarker-based staging systems have been established to inform prognosis and treatment. However, a single International Classification of Diseases, Tenth Revision (ICD-10) diagnosis code collectively applies to all stages of the disease, and while several studies have reported disease costs using healthcare claims data, stage-specific costs are not well understood. The current study aimed to estimate the healthcare utilization and costs of prevalent patients with AL amyloidosis by Mayo 2012 stage (I, II, III, IV). Methods: A multi-center medical chart review of patients with AL amyloidosis was conducted across six hematology clinics in the United States. Enrolled patients were ≥18 years old with a diagnosis of AL amyloidosis, documentation of Mayo 2012 stage at diagnosis, ≥1 office visit during the 6 months prior to the site's IRB approval date, and ≥1 year of available medical records. We collected 1 year of healthcare utilization data for each patient, in addition to clinical characteristics at diagnosis, which was prior to the 1-year observation period for most patients. Observation periods ranged from 11/2020 to 6/2023. Demographics, AL amyloidosis clinical history (e.g., organ involvement, lines of therapy, treatment response), laboratory values, and AL amyloidosis-related healthcare utilization (e.g., office visits, laboratory tests, procedures, medications, emergency department visits, inpatient stays) were collected. Patients were stratified by Mayo 2012 stage at diagnosis. Patients' 1-year healthcare costs were calculated by combining abstracted utilization data with the Centers for Medicare and Medicaid Services 2023 Physician Fee Schedule for procedures, Medi-Span® Price Rx® Pro for pharmacy and drug administration costs, and published literature for costs unavailable in these sources. Costs were adjusted to 2023 USD using the Consumer Price Index inflation calculator from the US Bureau of Labor Statistics. Results: The study included 61 patients: 15 stage I, 16 stage II, 17 stage III, and 13 stage IV. Overall, patients had a mean age at diagnosis of 62.4 years (standard deviation ([SD] 10.1), 39.3% were female (n=24), and 67.2% (n=41) of patients were non-Hispanic White, 14.8 % (n=9) Non-Hispanic Black, 6.6% (n=4) Asian, 1.6% (n=1) Hispanic, and 9.8% (n=6) other race/ethnicity. Most patients had Medicare (45.9%, n=28) or private health insurance (34.4%, n=21). The average duration of disease (i.e., time from diagnosis to date of last office visit prior to their site's IRB approval date) was 4.5 years (SD 3.5). All patients had involvement of ≥1 organ system and 45.9% (n=28) had involvement of ≥2 organ systems at diagnosis. More than half of patients had renal (55.7%, n=34) or cardiac (52.5%, n=32) involvement. Nearly all patients completed first-line therapy at any point prior to their last office visit (93.4%, n=57); a minority of patients (9.8%, n=6) initiated first-line therapy, and 3 patients (4.9%) had a hematopoietic stem cell transplantation, one each in stages I, II, and III, during the study period. The median estimated AL amyloidosis-related healthcare costs (USD) during the 1-year study period were $95,253 (interquartile range [IQR] $2,869-497,504) for stage I, $190,796 ($5,249-499,470) for stage II, $414,677 ($28,365-533,081) for stage III, and $523,504 ($191,830-526,596) for stage IV. Discussion: This is the first study of AL amyloidosis that reports costs of care stratified by Mayo 2012 stage. In a prevalent population with AL amyloidosis, we found that overall, patients with AL amyloidosis have significant ongoing costs of care after completion of initial therapy at each Mayo 2012 stage, with stage IV patients having the highest AL amyloidosis-related costs. The percent of patients with cardiac or renal organ involvement is possibly higher than represented in this study; given the rapid progression and high early mortality rate seen with stage III and IV disease, some of these patients may not have fulfilled the 1-year observation period requirement and thus were excluded from the study. These data describe the significant and continued burden faced by patients with AL amyloidosis and the health care system for the years beyond initial diagnosis and completion of front-line treatment.

Background: Acute promyelocytic leukemia (APL) is one of the most treatable leukemias in the current era, with cure rates upwards of 90%. Early mortality due to coagulopathies often seen at diagnosis is a major driver of adverse outcomes. Prompt initiation of all-trans retinoic acid (ATRA) is crucial for suspected APL, as it is known to reverse these coagulopathies. Chemotherapy-free protocols consisting of arsenic trioxide (ATO) and ATRA have become the standard of care for low-risk APL with high cure rates and reduced hematologic toxicities. For high-risk disease, there are multiple treatment options that have not been compared. Since APL is rare, there is a lack of real-world data for this disease. This retrospective review aimed to assess the outcomes of APL patients (pts) across multiple institutions and to examine the most common induction regimens, characteristics linked to early (30-day) mortality, and supportive care strategies. Methods: This retrospective study involved 9 institutions in the US and was conducted through the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND). Data included pts admitted from 8/5/2006 through 2/3/2024 with a confirmed diagnosis of APL. Each institution received a data-collection form and contributed data on APL pts from presentation to last follow-up. Key data categories included patient demographics, presenting laboratory and molecular data, treatment regimen, supportive care, and patient outcomes. Results: Data for 412 pts were identified with a median age of 51 (range 17-90) and 49% were female. Cardiovascular comorbidities were present in 44% of pts and 16% had a known pulmonary comorbidity. At presentation 109 (27%) had high risk-disease, defined as a white blood cell count (WBC) greater than 10 x 109/L. A FLT3 mutation was seen in 50% of tested pts, WT1 (22%), KRAS (3.6%), and NRAS (6.5%). The median WBC at presentation was 2 x 109/L (range: 0-166 x 109/L) and the median platelet count was 27 x 109/L (range: 2.0-315 109/L). Twenty-six percent presented with grade 2+ thrombosis, bleeding, or both. A higher percentage of pts with high-risk vs. low-risk disease presented with grade 2+ thrombosis, bleeding, or both (43% vs. 20%), DIC (60% vs. 36%), and mutated FLT3 (81% vs. 37%). The majority of pts received a chemotherapy-free induction regimen consisting of ATRA plus ATO. It was determined that 36 (8.7%) pts received induction with intermittent ATO plus ATRA (Burnett AK, Lancet Oncol 2015), 276 (67%) received daily ATO plus ATRA (Ravandi F, J Clin Oncol 2009 and Lo Coco, NEJM 2013), and 70 (17%) received a regimen inclusive of an anthracycline plus ATRA. Eleven pts did not start an induction regimen other than single-agent ATRA due to early death, while 19 had their regimen classified as “other” because they did not follow a conventional induction path. In total, 295/358 (82%) received ATRA within 24 hours of admission. At least 1 dose of gemtuzumab ozogamicin was given to 58 (14%) pts, of which 35 (60%) were considered high risk. The incidence of differentiation syndrome (DS) was 37% (n=154). Among the 243 pts who received steroid prophylaxis, 30% developed DS, compared to 52% of those who did not receive prophylaxis. Among the 360 pts with at least 1 available PCR result after starting induction, 94% achieved PCR-negativity. The 30-day mortality rate was 6.6%. On univariate analysis, presenting variables associated with a higher 30-day mortality include older age, diabetes, cardiovascular comorbidities, thrombosis or bleeding, DIC, eGFR < 60, elevated total bilirubin and D-dimer levels, and high-risk disease. The median overall survival (OS) of the cohort was not reached, and the 5- and 10-year OS was 88% (95% CI: 84-91%) and 79% (95% CI: 72-87%) respectively. The cumulative incidence of relapse at 3 years was 2.7% (95% CI: 1.4 - 5.1%), with no additional relapses observed. The incidence of CNS relapse at 3 years was 0.9% (95% CI: 0.3% - 2.8%), with 2 of the 4 pts classified as high-risk. Conclusion: This is the largest real-world evidence data collection in the US evaluating the outcome of pts with APL in the current era, inclusive of ATO as front-line induction. Outcomes for this disease remain extremely positive, with low 30-day mortality rates noted in this study along with durable OS rates and low incidence of relapse. Additional information on outcomes, safety, and supportive care will be presented at the meeting.

Objective Drug-induced long QT syndrome (diLQTS) is an adverse reaction from over 150 FDA-approved medications, posing the risk of triggering torsades de pointes and sudden death. While common genetic variants may modestly impact QT interval individually, their collective effect can significantly amplify risk of diLQTS. Consequently, this study aimed to validate a polygenic risk score (PRS) for diLQTS previously proposed by Strauss et al. Methods A retrospective cohort study was conducted utilizing patients from the Michigan Genomics Initiative prescribed 27 high-risk QT-prolonging drugs and an ECG during the prescription. The primary outcome was marked prolongation of the QTc interval (either >60 ms change from baseline or >500 ms absolute value) during treatment with a high-risk QT-prolonging drug. Results The primary outcome occurred in 12.0% of n = 6070 self-reported White, 12.4% of 558 African American, and 8.2% of 110 Asian patients. The PRS significantly associated with diLQTS in White patients [adjusted odds ratio = 1.44 (95% CI: 1.09–1.89); P = 0.009]. However the study lacked sufficient statistical power to confirm the PRS as a risk factor in African Americans [adjusted odds ratio = 2.18 (95% CI: 0.98–5.49); P = 0.073] and Asians [adjusted odds ratio = 3.21 (95% CI: 0.69–16.87); P = 0.139] due to smaller sample sizes in these groups. Conclusion The previously published PRS for diLQTS was validated in a large, real-world cohort, demonstrating its potential as a tool for identifying high-risk patients. Incorporating this PRS into routine clinical practice could enable proactive measures to prevent life-threatening diLQTS.

Many patients with malignant spinal cord compression (MSCC) who are not candidates for neurosurgery receive radiotherapy alone. This study compared 15 × 2.633 Gy over three weeks to 20 × 2.0 Gy over four weeks in patients with favorable survival prognoses. The outcomes of 34 patients treated with 15 × 2.633 Gy (equivalent dose 41.6 Gy10) in the RAMSES-01 trial were compared to 239 patients from an existing database receiving 20 × 2.0 Gy using propensity-score-adjusted Cox and logistic regression models. All patients had favorable survival prognoses. Endpoints included local progression-free survival (LPFS), improvement of motor function, post-treatment ambulatory status, and overall survival (OS). After propensity score adjustment, the 12-month rates of LPFS and OS were 98.1% (RAMSES-01 cohort) vs. 91.6% (p = 0.265) and 79.1% vs. 82.2% (p = 0.704), respectively. Regarding improvement of motor function, 15 × 2.633 Gy appeared superior (p = 0.073). No significant difference was observed regarding ambulatory status (p = 0.822). The three-week regimen for MSCC has similar outcomes and reduces treatment time when compared to a four-week regimen.

Background: Bipolar disorder (BD) involves significant mood and energy shifts reflected in speech patterns. Detecting these patterns is crucial for diagnosis and monitoring, currently assessed subjectively. Advances in natural language processing offer opportunities to objectively analyze them. Aims: To (i) correlate speech features with manic-depressive symptom severity in BD, (ii) develop predictive models for diagnostic and treatment outcomes, and (iii) determine the most relevant speech features and tasks for these analyses. Methods: This naturalistic, observational study involved longitudinal audio recordings of BD patients at euthymia, during acute manic/depressive phases, and after-response. Patients participated in clinical evaluations, cognitive tasks, standard text readings, and storytelling. After automatic diarization and transcription, speech features, including acoustics, content, formal aspects, and emotionality, will be extracted. Statistical analyses will (i) correlate speech features with clinical scales, (ii) use lasso logistic regression to develop predictive models, and (iii) identify relevant speech features. Results: Audio recordings from 76 patients (24 manic, 21 depressed, 31 euthymic) were collected. The mean age was 46.0 ± 14.4 years, with 63.2% female. The mean YMRS score for manic patients was 22.9 ± 7.1, reducing to 5.3 ± 5.3 post-response. Depressed patients had a mean HDRS-17 score of 17.1 ± 4.4, decreasing to 3.3 ± 2.8 post-response. Euthymic patients had mean YMRS and HDRS-17 scores of 0.97 ± 1.4 and 3.9 ± 2.9, respectively. Following data pre-processing, including noise reduction and feature extraction, comprehensive statistical analyses will be conducted to explore correlations and develop predictive models. Conclusions: Automated speech analysis in BD could provide objective markers for psychopathological alterations, improving diagnosis, monitoring, and response prediction. This technology could identify subtle alterations, signaling early signs of relapse. Establishing standardized protocols is crucial for creating a global speech cohort, fostering collaboration, and advancing BD understanding.

The World Health Organization’s Operational Framework for Climate Resilient and Low Carbon Health Systems outlines 10 broad components for the development and maintenance of health systems that respond effectively to climate-related challenges. This work analyses the WHO framework from a participatory health informatics perspective and identifies specific initiatives involving non-professionals that align with the framework. Citizen and patient participation in the development of climate-resilient health systems is not only possible but also necessary to maximize climate resiliency at the community and global levels.