Citations

BACKGROUND: While minimally invasive surgery is the current surgical standard of care for excision of deep endometriosis of the bowel, there is little literature evaluating patient-reported outcome measures following a multidisciplinary, robotic approach. OBJECTIVE: This study aimed to assess the functional outcomes of robotic surgery for patients undergoing resection of deep endometriosis involving the bowel. DESIGN: Retrospective cohort review. SETTINGS: A single academic tertiary institution. PATIENTS: Patients with endometriosis of the bowel undergoing multidisciplinary resection between January 1, 2018, and October 1, 2023. MAIN OUTCOME MEASURES: A survey assessing functional outcomes on a Numeric Rating Scale preoperatively and at multiple points postoperatively. RESULTS: Of 92 eligible patients, 41 completed a preoperative survey and at least one postoperative survey. Among these 41 patients, overall pain improved postoperatively from 5.3 ± 2.7 (Numeric Rating Scale) to a nadir of 1.6 ± 1.9 at 6 months and 2.3 ± 3.0 at 12 months ( p < 0.001). Preoperative pain at ovulation (mean 4.2 Numeric Rating Scale ± 3.7), pre-period pain (4.9 ± 3.5), period pain (5.7 ± 3.6) and post-period pain (3.3 ± 3.3) all decreased to a mean of 1 at 12 months postoperatively ( p < 0.001). The proportion of patients reporting pain impacting work decreased from 88% preoperatively to <40% postoperatively ( p < 0.001). The proportion of patients happy with their bowel function increased from 39% preoperatively to 63.2% at 1 month, 80.0% at 6 months, and 69.2% at 12 months postoperatively ( p = 0.014). LIMITATIONS: Only 31.7% of patients responded to their 12-month survey, tertiary care center, low diversity in patient demographics, retrospective design. CONCLUSION: In this cohort of patients undergoing multi-disciplinary robotic excision for advanced endometriosis involving the bowel, patients reported significantly improved pain and quality of life measures. See Video Abstract.

ABSTRACT Artificial intelligence (AI) has emerged as a transformative technology in the fields of medicine and ophthalmology. Recent advances in machine learning, deep learning and convolutional neural networks have significantly improved cataract detection and grading, intraocular lens power calculations, surgical decision‐making, risk prediction and patient education. Intraoperative AI‐assisted surgical phase recognition, workflow analysis, real‐time guidance, robotic technologies and femtosecond laser integration can improve surgical precision, efficiency and safety. AI has shown promise in predicting visual outcomes, detecting postoperative complications and facilitating telemedicine follow‐up. Though challenges with AI include transparency, data diversity, regulatory oversight and clinical validation, continued advances are expected to further personalise cataract surgery, support clinical decision‐making, optimise surgical performance and improve patient outcomes. This narrative summarises the current and emerging applications of AI in preoperative, intraoperative and postoperative management of cataracts.

Importance The incidence of human papillomavirus type 16 (HPV16–positive) recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is rising. Approved therapies offer a durable response to a minority of patients. Objective To determine the efficacy and safety of a therapeutic HPV16-targeted immunotherapy, PDS0101, in combination with pembrolizumab in participants with HPV16-positive R/M HNSCC, with separate evaluation of immune checkpoint inhibitor (ICI)–naive and ICI-resistant cohorts. Design, Setting, and Participants VERSATILE-002 was a phase 2, open-label, multicenter nonrandomized clinical trial conducted at 26 oncology centers from March 29, 2021, to May 15, 2025, across the US, UK, and Ireland using the Simon 2-stage optimal design. Efficacy analyses were performed on modified intent-to-treat (mITT) population; safety analyses included all participants who received 1 or more doses. Eighty-eight participants with histologically confirmed R/M HPV16-positive HNSCC were enrolled, of whom 87 (98.9%) received treatment and composed the safety population. Seventy five (85.2%) were in the mITT population used for efficacy analyses, of whom 53 (70.7%) were ICI-naive with a programmed cell death ligand 1 combined positive score of 1 or greater and 22 (29.3%) were ICI-resistant. Exposures Pembrolizumab (200 mg, intravenously, every 3 weeks for up to 35 cycles) plus subcutaneous PDS0101 (5 scheduled doses per protocol). Main Outcomes and Measures The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors , version 1.1, by a masked independent central reviewer. Secondary end points included progression-free survival (PFS), median overall survival (mOS), and safety, with exploratory end points of duration of response, disease control rate, and response rates by programmed cell death ligand 1 status. Results Of the 75 patients in the mITT population, the mean (SD) age was 64.0 (8.3) years; 4 individuals (5%) were female and 71 (95%) were male; and 2 individuals (3%) were Asian, 1 (1%) was Black, 5 (7%) were Hispanic, and 71 (95%) were White. Among 53 ICI-naive participants in the mITT cohort, ORR by the central reviewer was 34.0%, median PFS was 5.3 months (95% CI, 2.10-9.00), and mOS was 39.3 months (95% CI, 23.90 to not evaluable). Among 22 ICI-resistant patients in the mITT cohort, no objective responses were observed and the primary end point (ORR by central reviewer) was not met, but mOS was 14.8 months (95% CI, 8.50-26.00). The treatment was well tolerated, with 13.8% experiencing grade 3 or higher treatment-related adverse events. Conclusions and Relevance The results of this nonrandomized clinical trial suggest that PDS0101 plus pembrolizumab showed antitumor activity in ICI-naive HPV16-positive R/M HNSCC, with favorable safety, response rates, and survival outcomes. The findings support further evaluation in a first-line setting. Trial Registration ClinicalTrials.gov Identifier: NCT04260126

Introduction: Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is characterized by chronic kidney disease (CKD) with an average age of end-stage renal disease (ESRD) of approximately 45 years, bland urinary sediment, the absence of proteinuria and autosomal dominant inheritance. While several causative genes have been found, there remain families in whom no molecular diagnosis has been identified (ADTKD-NMD). Methods: We identified BICC1 truncating variants in several families with ADTKD-NMD in the Wake Forest Rare Inherited Kidney Disease Registry and then screened families in our database and other referred families for BICC1 truncating variants. We performed segregation analysis and characterized affected individuals for clinical and histopathologic phenotypes. We analyzed oligomer formation of BICC1 mutants with wild-type BICC1-, ANKS3- and ANKS6 proteins through co-immunoprecipitation and Western blotting, and we tested for posttranscriptional regulation of the BICC1 target mRNA, Dand5, in a Luciferase reporter assay. Results: We found 6 heterozygous truncating mutations in BICC1 segregating with the ADTKD phenotype in 8 independent pedigrees worldwide. Affected individuals developed kidney failure in the 6th to 7th decade of life that was characterized pathologically by tubular atrophy and interstitial fibrosis. The truncated gene products localized to cytoplasmic bodies and demonstrated various degrees of self-association or binding to the known interaction partners, ANKS3 and ANKS6. While the wild-type BICC1 gene product acts as a posttranscriptional repressor of target mRNAs, all truncation variants exhibited increased expression of substrate mRNA. Conclusions: Truncating variants in BICC1 are a novel cause of ADTKD, segregating with the disease phenotype and upregulating BICC1 target gene expression through a dominant-negative- or a gain-of-function mode of action.

Background/Objectives: Retained airway secretions are a common complication of mechanical ventilation and a major contributor to ventilator-associated pneumonia. Airway Pressure Release Ventilation following a Time-Controlled Adaptive Ventilation protocol (APRV-TCAV) has been anecdotally observed to improve secretion clearance, but the mechanism is not well established. Because TCAV sets the release time (TLow) from each patient’s own expiratory flow decay, we hypothesized that the resulting expiratory-dominant flow profile would generate a net antegrade force on secretions. This bench study compared secretion movement between APRV-TCAV and conventional Volume-Control Continuous Mandatory Ventilation (VC-CMV), with and without an in-line oscillatory device. Methods: A critical care ventilator was connected to a 3 L test lung via a 7 mm endotracheal tube (ETT). Simulated mucus (1% guar gum) was instilled into the ETT, and secretion movement was measured under VC-CMV (positive end-expiratory pressure (PEEP) 5, 10, 15 cmH2O) and APRV-TCAV (PHigh 20, 25, 30 cmH2O; PLow 0 cmH2O). Each condition was repeated with an in-line oscillatory device. Results: All VC-CMV settings produced retrograde secretion movement toward the test lung; all APRV-TCAV settings produced antegrade movement. The largest antegrade movement was observed at the widest PHigh-to-PLow differential. Adding the oscillatory device raised peak expiratory flow above peak inspiratory flow in every condition, yet abolished antegrade movement under APRV-TCAV. Conclusions: In this bench study, APRV-TCAV reversed the direction of secretion movement within the ETT, with larger antegrade movement at wider PHigh-to-PLow differentials. This suggests a potential mechanism by which the ventilator flow profile itself may influence secretion movement. The directional effect depended on the intact release-phase waveform and was abolished by in-line oscillatory therapy despite preserved peak flow asymmetry.

Abstract Introduction Cystoid macular edema (CME) is a recognized complication associated with penetrating keratoplasty (PK) and Endothelial Keratoplasty (EK). The purpose of this study was to determine the incidence of acute CME within the first 6 months after PK, Descemet stripping automated EK, or Descemet’s membrane EK. Methods A retrospective cohort analysis of the TriNetX United States collaborative database was conducted. Patients with a diagnosis of Fuchs dystrophy or keratoconus who underwent PK or EK between January 1, 2004 and August 30, 2024 were included. Those with a history of uveitis, retinal vascular occlusion, diabetic macular edema, or prior vitrectomy were excluded. Outcomes and diagnoses were defined using current procedural terminology and International Classification of Diseases, Tenth edition (ICD-10) codes. Cohorts were stratified based on a history of prior PK or EK with >6 months follow-up. Propensity score matching was performed on both cohorts to control for age at index, sex, race, ethnicity, and the diagnosis of Fuchs dystrophy and keratoconus. The incidence of acute CME during a 6-month postoperative follow-up period was assessed. Odds ratios were calculated between cohorts. Results A total of 2516 eyes were included in the study (PK: 1258; EK: 1258). At six months postoperatively, the incidence of acute CME in the EK cohort (46 of 1258) was significantly higher than in the PK cohort (20 of 1258) (P = 0.0012) (OR 0.426, 95% confidence interval 0.25–0.72). Conclusions Our findings suggest that the incidence of acute CME is higher in patients undergoing EK compared to PK.

ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating complication of cancer therapy. Although axonal degeneration defines CIPN, the initiating cellular events remain unknown. Here, we show that CIPN is initiated by senescent peripheral fibroblasts rather than by the neuron itself. Across the mechanistically distinct chemotherapeutic agents paclitaxel and cisplatin, chemotherapy-induced senescence is unexpectedly restricted to peripheral fibroblasts rather than neurons and acts upstream of neuronal SARM1 activation. Genetic or pharmacological ablation of senescent fibroblasts prevents neuropathy and reverses established disease, demonstrating that these cells are required for both disease initiation and maintenance. Mechanistically, senescent fibroblasts drive neuropathic injury through an MK2-dependent senescence-associated secretory phenotype (SASP), and genetic or pharmacological inhibition of MK2 suppresses the SASP, preserves peripheral innervation and restores sensory function. Together, these findings redefine the cellular origin of CIPN and identify MK2-dependent fibroblast senescence as a therapeutic target.

Pediatric sarcomas are a heterogeneous group of rare mesodermal malignancies. These cancers, which affect children from infancy through adolescence and young adulthood, are in general challenging to treat with currently available therapies. Biologically, many are characterized by quiet genomes, fusion oncoproteins, immune “cold” microenvironments, and vast epigenetic deregulation that contributes to diverse and complex mechanistic drivers. Multifaceted advancements in research strategies, including high-throughput screening, new model systems, surfaceome profiling, and study of oncogenic fusion condensates have led to new opportunities for understanding the biology of pediatric sarcomas. To continue to make progress for these difficult to treat cancers, it will be critical to continue to improve access to bioinformatic data, approach patient care using innovative clinical trial frameworks, and foster interdisciplinary partnerships among medicinal chemists, scientists, clinicians, advocates, and industry partners.

Background With improvements in in vitro culture techniques, there has been a steady shift in practice to transfer in vitro fertilisation (IVF) embryos at the blastocyst-stage to increase pregnancy rates per embryo transfer (ET) and reduce the risk of multiple pregnancy. In patients with fewer embryos (≤5 zygotes), fresh cleavage-stage ET is still commonly performed to reduce the risk of cycle cancellation if no embryo survives to the blastocyst-stage in vitro. However, evidence for improved outcomes with cleavage-stage embryo transfer in this subgroup of patients is lacking. We will compare blastocyst-stage to cleavage-stage ET with regard to cumulative live birth rates (CLBR) per oocyte retrieval and other patient-centred cycle outcomes in patients with ≤5 zygotes. Methods and analysis Multicentre, randomised pragmatic comparative effectiveness trial with superiority design comparing blastocyst-stage to cleavage-stage ET in patients with ≤5 zygotes. This trial will enrol and randomise 1126 women aged 18–44 undergoing IVF to either fresh cleavage-stage or blastocyst-stage ET at eleven IVF centres. Surplus embryos will be vitrified at the blastocyst-stage. The primary outcome is the CLBR per oocyte retrieval. Secondary outcomes include: multiple pregnancy, pregnancy loss <20 weeks and cycle cancellation. Exploratory outcomes include: live birth per fresh ET, ectopic pregnancy, time to pregnancy, stillbirth, preterm birth, financial burden, patient distress and facilitators and barriers for patient involvement and implementation. All primary analyses will be conducted according to the intent-to-treat principle. We also will report per-protocol analyses as a sensitivity analysis. A multidisciplinary stakeholder team, including a 5-patient stakeholder panel, will participate in study design, conduct and oversight. Ethics and dissemination The Institutional Review Board at Beth Israel Deaconess Medical Center (BIDMC) provides central regulatory oversight. Results will inform timing of embryo transfer in patients with ≤5 zygotes and will be disseminated through academic publications, meeting presentations and communications to advocacy groups and patient participants. Trial registration number NCT06746129 .