Citations

Background Peripheral nerve stimulation (PNS) is an emerging neuromodulation therapy for chronic pain, yet its use in clinical practice varies significantly. Although temporary PNS is widely incorporated, either as a screening trial or a treatment itself, the evidence supporting the use of temporary PNS prior to permanent implantation is limited. We aimed to compare pain relief, opioid consumption, and adverse events between an approach implementing temporary PNS before permanent implantation (temporary-to-permanent (TTP)) vs proceeding directly to permanent PNS implantation (direct-to-permanent (DTP)). Methods A multicenter retrospective study was undertaken at seven major academic institutions from January 1, 2014, to January 1, 2024. Adult patients who underwent permanent PNS implantation for the treatment of chronic pain conditions were included and were divided into TTP or DTP cohorts based on their clinical approach. The dual primary outcomes were pain relief and opioid consumption (in oral morphine equivalents) at 6 months compared with baseline before any PNS therapy. Multivariable Tobit regression analysis was performed to identify predictors of pain relief at 6 months using a stepwise approach. Results A total of 130 patients were analyzed (54 in TTP approach, 76 in DTP approach). Patient-reported percentage pain relief was 56.7%±27.9% at 6 months compared with baseline (before PNS implantation) in the TTP cohort, and 45.1%±33.6% in the DTP cohort. The estimated mean percentage pain relief at 6 months was similar in the TTP and DTP cohorts (between-group difference 15.24%; 95% CI −0.32 to 30.80, p=0.052), with consistent findings after sensitivity analysis with multiple imputation. Opioid consumption declined similarly in the TTP (−3.1±9.9 mg) and DTP (−2.1±8.1 mg) cohorts at 6 months with no statistical difference between cohorts (mean between-group difference: −1.00, 95% CI −4.57 to 2.57, p=0.580), and with consistent findings after sensitivity analysis. Device explantation rates and adverse event profiles were comparable between cohorts. Conclusion Although temporary PNS is widely performed prior to permanent PNS implantation, there was no evidence that the TTP approach is associated with superior analgesic outcomes compared with the DTP approach. Further, patients in both approaches achieved clinically meaningful pain relief at 6 months compared with baseline status prior to PNS therapy.

This study introduces Logarithmic Positional Partition Interval Encoding (LPPIE), a novel lossless compression methodology employing iterative logarithmic transformations to drastically reduce data size. While conventional dictionary-based algorithms rely on repeated sequences, LPPIE translates numeric data sequences into highly compact logarithmic representations. This achieves significant reduction in data size, especially on large integer datasets. Experimental comparisons with established compression methods—such as ZIP, Brotli, and Zstandard—demonstrate LPPIE’s exceptional effectiveness, attaining compression ratios nearly 13 times superior to established methods. However, these substantial storage savings come with elevated computational overhead due to LPPIE’s complex numerical operations. The method’s robustness across diverse datasets and minimal scalability limitations underscore its potential for specialized archival scenarios where data fidelity is paramount and processing latency is tolerable. Future enhancements, such as GPU-accelerated computations and hybrid entropy encoding integration, are proposed to further optimize performance and broaden LPPIE’s applicability. Overall, LPPIE offers a compelling alternative in lossless data compression, substantially redefining efficiency boundaries in high-volume numeric data storage.

Abstract Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features of amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), two degenerative diseases of the CNS and muscle. The loss of TDP-43 nuclear function results in the aberrant inclusion of cryptic exons in mRNA transcripts, leading to the expression of de novo proteins. Clonally expanded and highly differentiated CD8 + T cells have been observed in individuals with TDP-43 proteinopathies and therapeutics modulating the T cell response have recently been found to extend survival. However, the target antigens mediating T cell activation have remained elusive. Here, we investigate whether the de novo proteins induced by aberrant cryptic splicing due to TDP-43 nuclear loss can act as neo-antigens. We detect the HDGFL2 cryptic peptide and multiple other TDP-43 cryptic exons in IBM skeletal muscle, where their presence correlates with enrichment of T cells and class I antigen presentation pathways. Furthermore, we identify epitopes deriving from HDGFL2 and IGLON5 cryptic peptides which are recognized by clonally expanded and functionally differentiated populations of CD8 + T cells in ALS and IBM Patients. Finally, we demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to the cryptic peptide derived epitopes (cryptic epitopes) and are able to kill TDP-43 deficient astrocytes. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology.

Abstract Donor-derived tuberculosis is a rare complication following solid organ transplantation, and tuberculosis screening is not a current transplant prerequisite for most donors. Donor-derived tuberculosis usually presents sooner than reactivation tuberculosis, and the most common finding is fever. We present 3 cases of donor-derived tuberculosis in the recipients of 2 kidneys and 1 liver from the same donor, who presented with unexplained fevers occurring 4–5 weeks after transplantation. Initial antibacterial therapy failed in all 3 patients, leading to further testing, which identified Mycobacterium tuberculosis by culture and molecular studies. All recipients successfully received tuberculosis therapy but had significant morbidity and prolonged hospital stays. Donor-derived tuberculosis should be among the differential diagnoses of unexplained fever in solid organ transplant recipients in the first few months after transplantation. Screening protocols should be implemented for donors with an epidemiologic risk of tuberculosis, with special emphasis on deceased donors.

10019 Background: The reported incidence of second malignant neoplasms (SMN) in long-term survivors of Hodgkin lymphoma (HL) is derived from patients treated with outdated radiation therapy (RT) techniques. We modeled the risk of SMN in pediatric patients with high-risk classic HL treated with modern mediastinal RT. Methods: In patients who received mediastinal RT on the Children’s Oncology Group study AHOD1331, we modeled the lifetime attributable risk (LAR) at 70 years of age of thyroid, lung, and breast carcinoma. This value indicates the absolute increased risk of SMN at 70 years of age due to RT, above the baseline population risk (mean baseline rates at 70 years of age are 0.7%, 3.3%, and 8.9% for thyroid, lung, and breast carcinoma, respectively, https://seer.cancer.gov/data/ ). Results: In 296 patients who received protocol-directed mediastinal RT, median age at diagnosis was 15.1 years, 55% were female, and 98% had large mediastinal adenopathy. Following 5 cycles of chemotherapy, patients received RT targeting the mediastinum based on criteria of this study; in addition, some patients received RT to other supradiaphragmatic sites that contained slowly responding lesions, including the axilla (n = 3, 1%), lung (n = 7, 2.4%), upper neck (n = 4, 1.3%), and lower neck (n = 8, 2.7%). The RT modality was proton therapy in 25.3%, photon intensity modulated RT (IMRT) in 45.6%, and photon 3-dimensional conformal RT (3D-CRT) in 27.7%. The RT prescription dose was 21 Gy in 83% and 30 Gy in 16% who had a partial metabolic response at the completion of chemotherapy. The mean (range) doses to the thyroid, lungs, and breasts were 12.8 Gy (0-30.3), 8.0 Gy (0.1-15.2), and 4.2 Gy (0.2-14.5), respectively. For the complete cohort, the mean LAR at 70 years of age of thyroid carcinoma was 0.063% and of lung carcinoma was 5.34%. For females, the mean LAR at 70 years of age of breast carcinoma was 2.92%. The Table summarizes the LAR for each SMN, stratified by RT modality. Conclusions: In patients treated with mediastinal RT on a recent multi-institutional study of pediatric HL, the predicted long-term risk of SMN is substantially lower than in historical cohorts. Clinicians should consider the toxicity associated with a current RT approach when selecting therapies and counseling patients. Clinical trial information: NCT02166463 , this is a post hoc modeling study that includes patients enrolled on this study. Mean [range] lifetime attributable risk (%) at an attained age of 70 years for thyroid, lung, and breast carcinoma. Thyroid Lung Breast (females) 3D-CRT 0.046 [0.002-0.332]N=81 5.07 [0.12-10.82]N=82 1.82 [0.67-5.98]N=46 IMRT 0.064 [0.001-0.386]N=135 6.24 [2.22-11.79]N=135 4.36 [0.66-8.43]N=76 Proton 0.086 [0-1.160]N=74 4.15 [0.94-7.77]N=75 1.45 [0.17-7.23]N=40

e12562 Background: Previous research has suggested that breast cancer (BC) diagnosed during pregnancy or the postpartum period exhibits more aggressive clinical features, possibly due to pregnancy-related hormonal changes, immune modulation, and alterations in the mammary microenvironment compared to nulligravid or women many years out from pregnancy. Emerging data have demonstrated potential worse outcomes for patients (pts) diagnosed in post-partum. This study evaluated the influence of timing of diagnosis in relation to pregnancy history and recency of childbirth on long-term outcomes in a modern cohort of young pts with early-stage BC. Methods: Pts with stage I–III BC age < 40y in the prospective Young Women’s Breast Cancer Study (YWBCS) were categorized at diagnosis as Nulligravid (no prior pregnancy), Nulliparous (prior pregnancy without live birth), Currently Pregnant, or Parous (subdivided by time since last childbirth: within 5 years [≤ 5y PP], and 5–10 years postpartum [5–10y PP]). Baseline characteristics and outcomes were compared across BC subtypes (estrogen receptor+/HER2- [ER+/HER2-], HER2+, and triple-negative BC [TNBC]). Prognostic analyses for distant recurrence-free survival (DRFS) used Cox models. Results: 859 pts were included, 257 (30%) nulligravid, 50 (6%) nulliparous, 37 (4%) pregnant, and 515 (60%) parous (348 [68%] were ≤5y PP, and 167 [32%] were 5–10y PP). Median follow-up was 133 (6–209) months. Median age at diagnosis was lower in nulligravid pts (33 vs. 35–38 years); T1 tumors were most common in pts >5y PP (62%), and N0 status was highest in nulligravid pts (64%) (all p < 0.0001). Pregnant pts had higher rates of TNBC (27%), and T3 tumors (14%), N1 status, N1 (41%), and Grade 3 (81%) tumors compared to other groups (all p < 0.0001). Overall, only tumor size (T2-T4 vs T1, HR 2.03; 95% CI 1.37–3.03) and nodal status (N1 vs N0, HR 2.22; 1.48–3.34; N2/3 vs N0, HR 3.23; 1.96-5.33) were independently associated with worse DRFS; pregnancy history was not: nulligravid + nulliparous pts had no significant differences in DRFS compared to Pregnant (HR 1.46; 0.75–2.86), Parous <5y PP (HR 0.86; 0.58–1.26), and Parous 5–10y PP (HR 0.89; 0.54–1.48). Subgroup analyses by BC subtype (Table) and sensitivity analyses (excluding currently pregnant pts or separating nulligravid and nulliparous pts) demonstrated no significant associations between pregnancy history and DRFS. Conclusions: In this cohort study of very young patients with early breast cancer with contemporary treatment including management of breast cancer during pregnancy, pregnancy history and recency of pregnancy were not independent predictors of long-term disease outcomes. DRFS results by subgroup. Pregnancy Group N (%) HR (95% CI) ER+/HER2- Nulligravid + Nulliparous 173 (38.1) Ref Pregnant 16 (3.5) 0.93 (0.32–2.70) Parous ≤5y PP 177 (39.0) 0.77 (0.45–1.29) Parous 5–10y PP 88 (19.4) 0.78 (0.39–1.53) HER2+ Nulligravid + Nulliparous 77 (30.8) Ref Pregnant 11 (4.4) 3.27 (0.80–13.38) Parous ≤5y PP 113 (45.2) 1.50 (0.60–3.75) Parous 5–10y PP 49 (19.6) 1.45 (0.45–4.66) TNBC Nulligravid + Nulliparous 56 (36.8) Ref Pregnant 10 (6.6) 1.92 (0.61–6.09) Parous ≤5y PP 57 (37.5) 0.68 (0.28–1.63) Parous 5–10y PP 29 (19.1) 1.16 (0.43–3.14)

Abstract Introduction Comparing sleep and rest-activity rhythms (RARs) across the spectrum of cognitive aging can reveal novel risk factors and potential mechanisms underlying dementia disorders. However, our current understanding is restricted by differences in sleep measurement, limited longitudinal data, and heterogeneous cognitive aging processes. We aimed to determine (1) which sleep/RAR features exhibit meaningful changes within three distinct cognitive pathways; and (2) which sleep/RAR features differ between cognitive aging pathways prior to and after the onset of mild cognitive impairment (MCI) and/or dementia. Methods Longitudinal self-reported sleep and actigraphy data were obtained from 1,449 participants in the Rush Memory and Aging Project (mean age= 81.2±7.1 years, 75.2% female, 5.2% Black, 94.8% White). We applied flexible cubic spline models to quantify differences in the levels and trajectories of sleep amount (self-reported duration; actigraphy rest interval length and alpha), regularity (actigraphy interdaily stability, intradaily variability, and midpoint standard deviation), and timing (self-reported midpoint; actigraphy midpoint and acrophase) within and between three cognitive aging pathways over 12 years: Normal Cognitive Aging (‘Normal’), Progression to MCI (‘Stable MCI’), and Progression to Dementia (‘Dementia’). Models were adjusted for key sociodemographic and health variables. Results Sleep amount was lowest in the Dementia pathway prior to MCI or dementia, but increased with age, most rapidly following dementia. The greatest effect was observed in self-reported duration (standardized mean change, d[95%CI]=0.912 [0.47, 1.36]. Regularity declined across all pathways, most rapidly after cognitive diagnoses, with the largest increases in intradaily variability occurring among the Stable MCI (d=0.97 [0.70, 1.23]) and Dementia paths (d=1.11 [0.84, 1.38). Shifts toward earlier sleep timing were observed in actigraphy measures across all three pathways (-0.54≤d≤-0.31). Conclusion Shorter sleep amount in cognitively healthy older adults may be a risk factor or prodromal indicator of dementia, while longer sleep amounts and decreasing regularity following dementia may reflect neurodegeneration. Advances in sleep timing may be less useful as a clinical indicator of future cognitive impairment or decline. Differences between self-reported and actigraphy-measured sleep/RAR outcomes may reflect distinct underlying mechanisms, warranting further research. Support (if any) NIH: T32HL082610, RF1AG056331, R01AG052488, R01AG071638, RF1AG070436, R01AG17917

Abstract Single-cell sequencing technologies provide us with information at the level of individual cells. Combining single-cell RNA-seq and single-cell TCR-seq profiling enables the exploration of cell heterogeneity and T-cell receptor repertoires simultaneously. Integrating both types of data can play a crucial role in enhancing our understanding of T-cell-mediated immunity and, in turn, facilitate the advancement of immunotherapy. Here, we present immunopipe, a comprehensive and flexible pipeline to perform integrated analysis of scRNA-seq and scTCR-seq data. In addition to the command line tool, we provide a user-friendly web interface for pipeline configuration and execution monitoring, benefiting researchers without extensive programming experience. With its comprehensive functionality and ease of use, immunopipe empowers researchers to uncover valuable insights from scRNA-seq and scTCR-seq data, ultimately advancing the understanding of immune responses and immunotherapy development.

The growing global freshwater scarcity urgently requires innovative wastewater treatment technologies. This study hypothesized that biomimicry-inspired automated machine learning (AML) could effectively manage wastewater variability through adaptive processing techniques. Utilizing decentralized swarm intelligence, specifically the Respected Parametric Insecta Swarm (RPIS), the system demonstrated robust adaptability to fluctuating influent conditions, maintaining stable effluent quality without centralized control. Bio-inspired oscillatory control algorithms maintained stability under dynamic influent scenarios, while adaptive sensor feedback enhanced real-time responsiveness. Machine learning (ML) methods inspired by biological morphological evolution accurately classified influent characteristics (F1 score of 0.91), optimizing resource allocation dynamically. Significant reductions were observed, with chemical consumption decreasing by approximately 11% and additional energy usage declining by 14%. Furthermore, bio-inspired membranes with selective permeability substantially reduced fouling, maintaining minimal fouling for up to 30 days. Polynomial chaos expansions efficiently approximated complex nonlinear interactions, reducing computational overhead by approximately 35% through parallel processing. Decentralized swarm algorithms allowed the rapid recalibration of system parameters, achieving stable pathogen removal and maintaining effluent turbidity near 3.2 NTU (Nephelometric Turbidity Units), with total suspended solids consistently below 8 mg/L. Integrating biomimicry with AML thus significantly advances sustainable wastewater reclamation practices, offering quantifiable improvements critical for resource-efficient water management.

AbstractINTRODUCTIONComparing sleep and rest–activity rhythms across different cognitive aging pathways can identify novel risk factors and potential mechanisms. However, our current understanding is restricted by differences in sleep measurement, limited longitudinal data, and heterogeneous cognitive aging processes.METHODSWe applied cubic splines to longitudinal self‐reported sleep and actigraphy data from 1449 participants in the Rush Memory and Aging Project and quantified differences in the levels and trajectories of sleep amount, regularity, and timing within and between three cognitive aging pathways: normal, stable mild cognitive impairment, dementia.RESULTSSleep amount was lowest in the dementia pathway prior to cognitive impairment but increased with age, most rapidly after dementia. Regularity declined across all pathways, most rapidly after cognitive diagnoses. Timing advanced across all pathways.DISCUSSIONShorter sleep amount in cognitively healthy older adults may be a risk factor or prodromal indicator of dementia, while longer sleep amounts and decreasing regularity may reflect neurodegeneration.Highlights We quantified longitudinal changes in sleep across three cognitive‐aging pathways. We incorporated both subjective and objective measures of sleep health. Self‐report duration increased noticeably from before to after cognitive diagnosis. Sleep irregularity increased most prominently after cognitive diagnosis. Advances in sleep timing occurred in both normal and pathological aging.