Targeted Bmal1 restoration in muscle prolongs lifespan with systemic health effects in aging model.

Disruption of the circadian clock in skeletal muscle worsens local and systemic health, leading to decreased muscle strength, metabolic dysfunction, and aging-like phenotypes. Whole-body knockout mice that lack Bmal1, a key component of the molecular clock, display premature aging. Here, by using adeno-associated viruses, we rescued Bmal1 expression specifically in the skeletal muscle fibers of Bmal1-KO mice and found that this engaged the circadian clock and clock output gene expression contributing to extended lifespan. Time course phenotypic analyses found that muscle strength, mobility, and glucose tolerance were improved with no effects on muscle mass, fiber size or type. A multi-omics approach at two ages further determined that restored muscle Bmal1 improved glucose handling pathways while concomitantly reducing lipid and protein metabolic pathways. The improved glucose tolerance and metabolic flexibility resulted in the systemic reduction of inflammatory signatures across peripheral tissues including liver, lung, and white adipose fat. Together, these findings highlight the critical role of muscle Bmal1 and downstream target genes for skeletal muscle homeostasis with considerable implications for systemic health.

Tobacco Use and Trigeminal Neuralgia: Clinical Features and Outcome After Microvascular Decompression.

BACKGROUND AND OBJECTIVES: Tobacco use is known to affect incidence and postoperative outcome for several neurosurgical disorders, but its relationship to trigeminal neuralgia (TN) is not known. We sought to identify unique population characteristics that correlate with tobacco use in a cohort of patients with TN who underwent microvascular decompression (MVD), including effect on long-term postoperative outcome. METHODS: Data about 171 patients with classic TN treated with MVD were obtained from a prospectively maintained registry. Patients were classified as smokers or nonsmokers based on the use of tobacco within the 6 months before surgery. Analysis of clinical characteristics and postoperative outcome was performed. RESULTS: Compared with nonsmokers with TN, MVD patients using tobacco were significantly younger (53 vs 62 years, P < .01) and less likely to report pain in a single distribution of the trigeminal nerve (36% vs 65%, P < .01). There was no difference between smokers and nonsmokers in the presence of some degree of continuous pain, severity of neurovascular compression, sex, race, obesity, pain duration before presentation, immediate postoperative outcome, length of stay, or postoperative complication profile. Among 128 patients followed for at least 6 months, smokers were significantly less likely to be pain-free off medications at the last follow-up (36% vs 57%, P < .05). CONCLUSION: In patients undergoing MVD for TN, smoking is associated with younger age of TN onset, more widespread facial pain, and worse long-term postoperative outcome after MVD. These features suggest that TN in smokers may represent a more severe disease form compared with TN in nonsmokers with different responses to treatment.

Current Trial Report: A Multicenter Phase I/Ib study of Capmatinib Plus Trametinib in Patients With Metastatic Nonsmall Cell Lung Center Harboring MET Exon 14 Skipping Mutations and Other MET-Alterations.

INTRODUCTION: MET tyrosine kinase inhibitor (TKI) therapy is associated with improved outcomes in patients with nonsmall cell lung cancer (NSCLC) harboring a MET alteration, including MET exon 14 (METex14) skipping mutation, MET amplification, or MET fusion. However, primary or acquired resistance to TKI therapy ultimately develops. In preclinical models, hyperactivation of MAPK signaling was shown to promote resistance to MET TKI; resistance was overcome by co-treatment with a MET inhibitor and a MEK inhibitor. This phase I/Ib study offers a potential combination strategy simultaneously targeting MET (with capmatinib) and MEK signaling (with trametinib) to overcome resistance to MET inhibitor monotherapy in METex14 NSCLC. METHODS: In the dose escalation phase, a minimum of 6 and maximum of 18 patients will be enrolled using a conventional 3+3 design with the primary endpoint of identifying a recommended phase 2 dose (RP2D) of capmatinib in combination with trametinib. Once the RP2D is identified, patients will continue to enroll in a dose expansion phase to a total of 15 patients. The primary endpoint of the dose expansion phase is to further characterize the safety profile of the combination. CONCLUSION: This phase I/Ib clinical trial will assess the safety and efficacy of combination capmatinib and trametinib in NSCLC patients whose tumors harbor METex14 skipping mutations, MET amplification, or MET fusion and had developed progressive disease on single agent MET inhibitor therapy.

Dynamic macromolecular material design: the versatility of cucurbituril over cyclodextrin in host-guest chemistry.

The keto-enol tautomerism of avobenzone (AVO) is pivotal to its photostability, influenced by microenvironmental factors, such as, the type of solvent and complexation with macrocyclic compounds. This study explores the effect of host-guest complexation on AVO photostabilization, employing cucurbit[7]uril (CB[7]) and ß-cyclodextrin (ß-CD) to form inclusion complexes. CB[7] exhibits a higher affinity to the keto form of AVO, a UVC radiation absorber. The complexed keto form facilitates the regeneration of the enol form, reducing skin permeation. Spectroscopic and thermal analyses confirm 1 : 1 AVO-CB[7] and AVO-ß-CD complex formation. Computational and MD simulations show that host-guest complex is favored over isolated AVO and ß-CD or CB[7] molecules by 95-125 kJ mol-1, depending on the presence of implicit solvent. Both macrocycles enhance AVO photostabilization in aqueous environments, with CB[7] displaying greater selectivity for the keto form, while ß-CD shows ethanol concentration-dependent binding.

Alterations of the skeletal muscle nuclear proteome after acute exercise reveals a post-transcriptional influence.

Exercise is firmly established as a key contributor to overall well-being and is frequently employed as a therapeutic approach to mitigate various health conditions. One pivotal aspect of the impact of exercise lies in the systemic transcriptional response, which underpins its beneficial adaptations. While extensive research has been devoted to understanding the transcriptional response to exercise, our knowledge of the protein constituents of nuclear processes that accompany gene expression in skeletal muscle remains largely elusive. We hypothesize that alterations in the nuclear proteome following exercise hold vital clues for comprehending the transcriptional regulation and other related nuclear functions. We isolated skeletal muscle nuclei from C57BL/6 mice both sedentary control and one-hour post 30-minute treadmill running, to gain insights into the nuclear proteome after exercise. A substantial number of the 2,323 proteins identified, were related to nuclear functions. For instance, we found 59 proteins linked to nucleocytoplasmic transport were higher in sedentary mice compared to exercise, hinting at an exercise-induced modulation to nuclear trafficking. Furthermore, 135 proteins exhibited increased abundance after exercise (FDR < 0.1) while 89 proteins decreased, with the most prominent changes in proteins linked to mRNA processing and splicing. Super resolution microscopy further highlights potential localization change in mRNA processing proteins post-exercise, further suggesting changes in nuclear transport dynamics. Nonetheless, our data provide important considerations for the study of the nuclear proteome and supports a paradigm through which exercise downregulated mRNA processing and splicing, offering valuable insights into the broader landscape of the impact from acute exercise. New & Noteworthy: Exercise plays a crucial role in promoting muscle health, but our understanding of nuclear proteins orchestrating exercise responses is limited. Isolation of skeletal muscle nuclei coupled with mass spectrometry enhanced the identification of nuclear proteins. This approach was used to investigate the effects of acute exercise, revealing changes in the muscle nuclear proteome 1-hour post-exercise, including proteins linked to post-transcriptional processing and splicing. Our findings offer insights into the exercise-induced changes within muscle nuclear proteins.

Relationships Between Applied Mindfulness Practice, Chronic Pain, and Pain-Related Functioning in Veterans.

Mindfulness-based interventions (MBIs) have been shown to improve chronic pain and associated conditions like depression, anxiety, and sleep disorders. However, there is limited research on how veterans with chronic pain apply mindfulness skills to manage pain in daily life. This cross-sectional study examined the association between applied mindfulness practice, pain, and several pain-related conditions among 1,737 veterans with chronic pain prior to enrollment in a trial of 2 MBIs. Applied mindfulness practice was assessed using the Applied Mindfulness Process Scale (AMPS). The outcomes included pain interference, pain intensity, pain catastrophizing, fatigue, sleep disturbance, anxiety, depression, post-traumatic stress disorder, physical function, and social participation. Higher overall AMPS scores, as well as the positive and negative emotional regulation subscales of the AMPS, were associated with less pain interference and catastrophizing, as well as better outcomes for all pain-related conditions. The positive emotional regulation subscale had the strongest associations with outcomes. There was no significant association between the AMPS and pain intensity. The results suggest applied mindfulness practice, especially positive emotional regulation, may improve pain and functioning. In addition, the AMPS shows promise as a process measure of mindfulness skills applied in daily life. Additional research is needed to examine different aspects of mindfulness in the context of MBIs. PERSPECTIVE: This article describes the relationship between applied mindfulness practice and pain-related outcomes, prior to a MBI, using a novel measure of mindfulness practice. These findings underscore the importance of measuring applied mindfulness practice prior to and during clinical interventions to treat chronic pain.

Neoadjuvant Osimertinib for the Treatment of Stage I-IIIA Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: A Phase II Multicenter Study.

PURPOSE: To assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR-mutated non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling. RESULTS: A total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%). CONCLUSION: Treatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.

Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.

The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

Generalized cue reactivity in dopamine neurons after opioids.

Cue reactivity is the maladaptive neurobiological and behavioral response upon exposure to drug cues and is a major driver of relapse. The leading hypothesis is that dopamine release by addictive drugs represents a persistently positive reward prediction error that causes runaway enhancement of dopamine responses to drug cues, leading to their pathological overvaluation compared to non-drug reward alternatives. However, this hypothesis has not been directly tested. Here we developed Pavlovian and operant procedures to measure firing responses, within the same dopamine neurons, to drug versus natural reward cues, which we found to be similarly enhanced compared to cues predicting natural rewards in drug-naïve controls. This enhancement was associated with increased behavioral reactivity to the drug cue, suggesting that dopamine release is still critical to cue reactivity, albeit not as previously hypothesized. These results challenge the prevailing hypothesis of cue reactivity, warranting new models of dopaminergic function in drug addiction, and provide critical insights into the neurobiology of cue reactivity with potential implications for relapse prevention.

Detecting QT prolongation from a single-lead ECG with deep learning.

For a number of antiarrhythmics, drug loading requires a 3-day hospitalization with continuous monitoring for QT-prolongation. Automated QT monitoring with wearable ECG monitors would enable out-of-hospital care. We therefore develop a deep learning model that infers QT intervals from ECG Lead-I-the lead that is often available in ambulatory ECG monitors-and use this model to detect clinically meaningful QT-prolongation episodes during Dofetilide drug loading. QTNet-a deep neural network that infers QT intervals from Lead-I ECG-was trained using over 3 million ECGs from 653 thousand patients at the Massachusetts General Hospital and tested on an internal-test set consisting of 633 thousand ECGs from 135 thousand patients. QTNet is further evaluated on an external-validation set containing 3.1 million ECGs from 667 thousand patients at another healthcare institution. On both evaluations, the model achieves mean absolute errors of 12.63ms (internal-test) and 12.30ms (external-validation) for estimating absolute QT intervals. The associated Pearson correlation coefficients are 0.91 (internal-test) and 0.92 (external-validation). Finally, QTNet was used to detect Dofetilide-induced QT prolongation in a publicly available database (ECGRDVQ-dataset) containing ECGs from subjects enrolled in a clinical trial evaluating the effects of antiarrhythmic drugs. QTNet detects Dofetilide-induced QTc prolongation with 87% sensitivity and 77% specificity. The negative predictive value of the model is greater than 95% when the pre-test probability of drug-induced QTc prolongation is below 25%. These results show that drug-induced QT prolongation risk can be tracked from ECG Lead-I using deep learning.

The 5-Item Modified Frailty Index as a Predictor of Postoperative Outcomes in Thoracic Metastatic Epidural Spinal Cord Compression.

BACKGROUND: Patients with thoracic metastatic epidural spinal cord compression (MESCC) often undergo extensive surgical decompression to avoid functional decline. Though limited in scope, scales including the revised cardiac risk index (RCRI) are used to stratify surgical risk to predict perioperative morbidity. This study uses the 5-item modified frailty index (mFI-5) to predict outcomes following transpedicular decompression/fusion for high-grade MESCC. METHODS: A retrospective chart review was conducted on patients who underwent transpedicular decompression and fusion for MESCC (baseline demographics, spinal instability neoplastic score, preoperative and postoperative Bilsky scores, primary cancer type, and RCRI). Primary outcomes included length of stay (LOS), intraoperative estimated blood loss, readmission/reoperation within 90 days of index surgery, 90-day mortality, and posthospitalization disposition. RESULTS: One hundred twenty-seven patients were included in our study. Ninety percent of patients' lesions were Bilsky 2 or greater. Increasing frailty, measured by mFI-5, was a significant predictor of increased LOS (P < 0.01) and 90-day mortality (P < 0.05). Multivariate analysis adjusting for sex, body mass index , and age still showed statistical significance (P < 0.05). MFI-5 was not a significant predictor of readmission/reoperation within 90 days or estimated blood loss. Age - not mFI-5 or RCRI - was a significant predictor for posthospitalization nonhome disposition (P = 0.001). CONCLUSIONS: The mFI-5 can serve as a useful predictor of outcomes after transpedicular decompression and fusion for thoracic MESCC as it can account for the patient's frailty. Our study demonstrated the mFI-5 as a predictor of LOS and 90-day mortality. These results provide a background to both understanding and integrating frailty into decision-making in MESCC.

Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer.

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.

Association between potentially inappropriate medications prescription and health-related quality of life among US older adults.

BACKGROUND: Potentially inappropriate medications (PIMs) are associated with worse health outcomes among older adults. Our objective was to examine the association between PIM prescription and health-related quality of life (HRQoL) among older adults in the United States using nationally representative data. METHODS: This was a retrospective study utilizing 2011-2015 Medical Expenditure Panel Survey (MEPS) data. Community dwelling US adults aged 65 years or older were included. A qualified definition operationalized from the 2019 American Geriatrics Society Beers Criteria® was used to define exposure to PIMs during the study period. The Physical Component Summary (PCS) and Mental Component Summary (MCS) of the Medical Outcomes Study 12-Item Short Form Health Survey (SF-12) were used to measure HRQoL. Survey-weighted linear regression models were constructed to investigate the association between PIM exposure and participants' PCS and MCS scores. Analyses were stratified across three age cohorts (65-74, 75-85, and ≥85 years). RESULTS: Unadjusted analysis showed poorer scores in the PIM exposed group for both PCS and MCS (all p < 0.001). PIM exposure was associated with poorer PCS scores across all age groups with those aged 65-74 years (adjusted regression coefficient = -1.60 [95% CI = -2.27, -0.93; p < 0.001]), those 75-84 years (adjusted regression coefficient: -1.49 [95% CI = -2.45, -0.53; p = 0.003]), and those 85 years and older (adjusted regression coefficient = -1.65 [95% CI = -3.03, -0.27; p = 0.02]). PIM exposure was also associated with poorer MCS scores in participants aged 65-74 years (adjusted regression coefficient = -0.69 [95% CI = -1.16, -0.22; p = 0.004]) and 85 years and older (adjusted regression coefficient = -2.01 [95% CI = -3.25, -0.78; p = 0.002]). CONCLUSIONS: Our results suggest that patients' exposure to PIMs is associated with poorer HRQoL. Further work is needed to assess whether interventions to deprescribe PIMs may help to improve patients' HRQoL.

PERCEPTION predicts patient response and resistance to treatment using single-cell transcriptomics of their tumors.

Tailoring optimal treatment for individual cancer patients remains a significant challenge. To address this issue, we developed PERCEPTION (PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology), a precision oncology computational pipeline. Our approach uses publicly available matched bulk and single-cell (sc) expression profiles from large-scale cell-line drug screens. These profiles help build treatment response models based on patients' sc-tumor transcriptomics. PERCEPTION demonstrates success in predicting responses to targeted therapies in cultured and patient-tumor-derived primary cells, as well as in two clinical trials for multiple myeloma and breast cancer. It also captures the resistance development in patients with lung cancer treated with tyrosine kinase inhibitors. PERCEPTION outperforms published state-of-the-art sc-based and bulk-based predictors in all clinical cohorts. PERCEPTION is accessible at https://github.com/ruppinlab/PERCEPTION . Our work, showcasing patient stratification using sc-expression profiles of their tumors, will encourage the adoption of sc-omics profiling in clinical settings, enhancing precision oncology tools based on sc-omics.

Life-Threatening MOG Antibody-Associated Hemorrhagic ADEM With Elevated CSF IL-6.

Acute disseminated encephalomyelitis (ADEM) is one characteristic manifestation of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). A previously healthy man presented with retro-orbital headache and urinary retention 14 days after Tdap vaccination. Brain and spine MRI suggested a CNS demyelinating process. Despite treatment with IV steroids, he deteriorated, manifesting hemiparesis and later impaired consciousness, requiring intubation. A repeat brain MRI demonstrated new bilateral supratentorial lesions associated with venous sinus thrombosis, hemorrhage, and midline shift. Anti-MOG antibody was present at a high titer. CSF IL-6 protein was >2,000 times above the upper limits of normal. He improved after plasma exchange, then began monthly treatment alone with anti-IL-6 receptor antibody, tocilizumab, and has remained stable. This case highlights how adult-onset MOGAD, like childhood ADEM, can rapidly become life-threatening. The markedly elevated CSF IL-6 observed here supports consideration for evaluating CSF cytokines more broadly in patients with acute MOGAD.

Right Ventricular Function on Cardiovascular Magnetic Resonance Imaging and Long-Term Outcomes in Stable Heart Transplant Recipients.

BACKGROUND: In heart transplant recipients, right ventricular (RV) dysfunction may occur for a variety of reasons. Whether RV dysfunction in the stable phase after heart transplantation is associated with long-term adverse outcomes is unknown. We aimed to determine the long-term prognostic significance of RV dysfunction identified on cardiovascular magnetic resonance imaging (CMR) at least 1 year after heart transplantation. METHODS: In consecutive heart transplant recipients who underwent CMR for surveillance, we assessed 2 CMR measures of RV function: RV ejection fraction and RV global longitudinal strain (RVGLS). We investigated associations between RV dysfunction and a composite end point of death or major adverse cardiac events, including retransplantation, nonfatal myocardial infarction, coronary revascularization, and heart failure hospitalization. RESULTS: A total of 257 heart transplant recipients (median age, 59 years; 75% men) who had CMR at a median of 4.3 years after heart transplantation were included. Over a median follow-up of 4.4 years after the CMR, 108 recipients experienced death or major adverse cardiac events. In a multivariable Cox regression analysis adjusted for age, time since transplantation, indication for transplantation, cardiac allograft vasculopathy, history of rejection, and CMR covariates, RV ejection fraction was not associated with the composite end point, but RVGLS was independently associated with the composite end point with a hazard ratio of 1.08 per 1% worsening in RVGLS ([95% CI, 1.00-1.17]; P=0.046). RVGLS provided incremental prognostic value over other variables in multivariable analyses. The association was replicated in subgroups of recipients with normal RV ejection fraction and recipients with late gadolinium enhancement imaging. A similar association was seen with a composite end point of cardiovascular death or major adverse cardiac events. CONCLUSIONS: CMR feature tracking-derived RVGLS assessed at least 1 year after heart transplantation was independently associated with the long-term risk of death or major adverse cardiac events. Future studies should investigate its role in guiding clinical decision-making in heart transplant recipients.

An optimized approach to study nanoscale sarcomere structure utilizing super-resolution microscopy with nanobodies.

The sarcomere is the fundamental contractile unit in skeletal muscle, and the regularity of its structure is critical for function. Emerging data demonstrates that nanoscale changes to the regularity of sarcomere structure can affect the overall function of the protein dense ~2µm sarcomere. Further, sarcomere structure is implicated in many clinical conditions of muscle weakness. However, our understanding of how sarcomere structure changes in disease, especially at the nanoscale, has been limited in part due to the inability to robustly detect and measure at sub-sarcomere resolution. We optimized several methodological steps and developed a robust pipeline to analyze sarcomere structure using structured illumination super-resolution microscopy in conjunction with commercially-available and fluorescently-conjugated Variable Heavy-Chain only fragment secondary antibodies (nanobodies), and achieved a significant increase in resolution of z-disc width (353nm vs. 62nm) compared to confocal microscopy. The combination of these methods provides a unique approach to probe sarcomere protein localization at the nanoscale and may prove advantageous for analysis of other cellular structures.

Impact of the Duration of the Second Stage of Labor on Postpartum Pelvic Floor Symptoms.

IMPORTANCE: The associated effect of duration of the second stage of labor (SSL) on pelvic floor symptoms development is not well studied. OBJECTIVE: This study aimed to examine the association between duration of SSL and pelvic floor symptoms at 6 months postpartum among primiparous women. STUDY DESIGN: A planned secondary analysis of a multicenter randomized trial evaluating the impact of immediate versus delayed pushing on vaginal delivery rates, maternal morbidity, and neonatal outcomes was conducted between 2014 and 2018. For pelvic floor arm participants, demographic, pelvic examination, and validated questionnaire data were collected postpartum. Primary outcome was change in Pelvic Floor Distress Inventory 20 (PFDI-20) score from immediate to 6 months postpartum. Secondary outcomes included changes in the Pelvic Floor Impact Questionnaire, Fecal Incontinence Severity Index, Modified Manchester Health Questionnaire scores, and Pelvic Organ Prolapse Quantification measurements at 6 months postpartum. Participants were analyzed by SSL duration ≤60 minutes or >60 minutes. RESULTS: Of the 2,414 trial participants, 767 (32%) completed pelvic floor assessments at 6 months. Pelvic Floor Distress Inventory 20 scores significantly improved at 6 months in the ≤60 minutes SSL group compared with >60 minutes SSL (-14.3 ± 48.0 and -3.2 ± 45.3, respectively; P = 0.04). Changes from immediate postpartum in total and subscale scores for other questionnaires at 6 months did not differ between groups. Prolapse stage did not differ between groups. Perineal body was significantly shorter in the >60 minutes SSL group (3.7 ± 0.7, 3.5 ± 0.8; P = 0.03). CONCLUSIONS: Women with SSL >60 minutes experience less improvement in PFDI-20 scores at 6 months. Greater tissue and innervation trauma in those with SSL >60 minutes may explain persistently less improvement in PFDI-20 scores.