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Background The use of 3D imaging with navigation bronchoscopy has increased with the introduction of mobile cone-beam CT (mCBCT). Shape-sensing robotic-assisted bronchoscopy (ssRAB) integrated with mCBCT has been introduced to correct for CT to body divergence (CT-BD) during the biopsy of peripheral pulmonary nodules (PPNs). Methods Prospective observational multicentre study, enrolling patients with a PPN of ≤20 mm suspicious for malignancy, assessing tool-in-lesion (TIL), diagnostic yield, sensitivity for malignancy and incidence of pneumothorax or airway bleeding. Non-malignant index biopsies were followed for 12 months. Descriptive statistics are reported for all variables along with 95% CI for primary endpoints. Results 155 consecutive patients were enrolled at six centres. Median nodule size was 14.0 mm (IQR 11.0–17.0), with 54.8% of nodules (85/155) in the upper lobes, 25.8% (40/155) with CT bronchus sign present and median distance to the nearest pleural surface of 8.2 mm (IQR 1.8–20.0). TIL was achieved in 154/155 (99.4%, 95% CI 96.5 to 100.0) procedures. A median of two (IQR 1–3) mCBCT spins were performed, with median dose area product of 25.7 Gy · cm 2 (IQR 11.0–46.7). Diagnostic yield per the American Thoracic Society/American College of Chest Physicians (ATC/ACCP) definition was 89.0% (n=138/155; 95% CI 83.0 to 93.5) and sensitivity for malignancy was 91.5% (95% CI 86.4 to 96.5). No pneumothorax (0%, 95% CI 0.0 to 2.4) and two Nashville Grade three bleeding events were reported (1.3%, 95% CI 0.2 to 4.6). Interpretation The first prospective multicentre study of integrated ssRAB and mCBCT for small peripheral nodules resulted in diagnostic outcomes similar to those reported for transthoracic biopsy with a more favourable safety profile. Trial registration number ClinicalTrials.gov ID: NCT05562895 .

BACKGROUND: With pulmonary hypertension (PH), a pulmonary artery wedge pressure (PAWP)>15 mm Hg is used to diagnose left heart dysfunction, but some patients with adjudicated group 1 PH demonstrate PAWP>15 mm Hg. The primary objective of the study was to evaluate group 1 PH with high PAWP>15 mm Hg. METHODS: Patients with adjudicated group 1 PH from PVDOMICS between 2016 and 2019 were separated into high PAWP(>15 mm Hg) or normal PAWP and compared with adjudicated combined pre- and postcapillary (Cpc) PH related to heart failure with preserved ejection fraction (HFpEF). Participants underwent dynamic right heart catheterization and metabolomics. Findings were validated in 3 independent cohorts with adjudicated group 1 PH (validation cohorts 1 and 2 with exercise right heart catheterization and validation cohort 3 with resting right heart catheterization). RESULTS: Of 325 patients with group 1 PH (73% women, mean age 53.0±14.3 years), 15% (n=48) had high PAWP. Group 1 PH+high PAWP demonstrated greater obesity, left ventricular hypertrophy ( P <0.0002), left ventricular strain impairment ( P <0.0001), and decreased left ventricular compliance ( P <0.0001) compared with group 1 PH+normal PAWP, with changes comparable to Cpc-PH HFpEF (n=75). Compared with Cpc-PH HFpEF, left atrial function was better in group 1 PH+high PAWP with lower PAWP V wave, higher left atrial compliance, and left atrial ejection fraction ( P <0.0001 for all). Metabolomics demonstrated little difference between group 1 PH with high versus normal PAWP but large differences between group 1 PH+high PAWP versus Cpc-PH HFpEF (100 metabolites altered at false discovery rate P <0.05). Elevated PAWP was also observed in 18% of group 1 PH in the validation cohort 1 (n=402), with exercise PAWP response intermediately abnormal in group 1 PH+high PAWP relative to Cpc-PH HFpEF and group 1 PH+normal PAWP (interaction P <0.0001). Elevated PAWP was similarly observed in 22% and 19% of group 1 PH in validation cohorts 2 (n=55) and 3 (n=787), respectively. CONCLUSIONS: Approximately 1 in 5 adjudicated patients with group 1 PH has elevation in resting PAWP despite severe pulmonary vascular dysfunction and metabolomics consistent with traditionally defined group 1 PH. Despite resting PAWP elevation, these patients with group 1 PH were metabolomically and biologically distinct from Cpc PH HFpEF, with better left atrial function and diastolic reserve during exercise. These data emphasize the limitations of using resting PAWP alone to separate group 1 PH from HFpEF and call for development of more integrated clinical diagnostic criteria.

Abstract Introduction: Recruitment for rare disease studies is challenging due to small eligible populations. Traditional clinical research management systems often lack tools to track recruitment contacts prior to enrollment. The NET-PRO study, focused on neuroendocrine tumors (NETs), implemented a participation monitoring system to enhance recruitment efficiency and representativeness. Methods: NET-PRO is a multicenter cohort study of 2538 adults diagnosed with gastroenteropancreatic (GEP) or lung NETs between January 2018 and September 2024. Recruitment occurred from January 2022 to February 2025 across 14 U.S. medical centers. Sites used flexible recruitment methods (email, mail, phone, in-clinic) and tracked contacts using REDCap-based tools. Participant characteristics were analyzed by enrollment mode (online or mail) and recruitment difficulty (number of contacts required prior to enrollment) using standardized mean differences, chi-square tests, and ANOVA. Results: Of 9279 contacted patients, 2675 consented (28.8%) and 2538 enrolled (27.4%). Most enrolled online (83.2%), while 16.8% enrolled by mail. Mail respondents were older, had lower education and income, and more comorbidities. Among those enrolled, recruitment difficulty was associated with older age, lower education and income, but not comorbidity. Over half of the most difficult-to-recruit participants enrolled online. Contact methods varied by attempt, with email dominating early contacts and phone/mail used more in later attempts. Conclusions: A participation monitoring tool supported flexible, multimodal recruitment and improved sample representativeness in a rare cancer study. Tracking recruitment contacts enabled adaptive strategies and may reduce bias in observational research by enabling better outreach to harder-to-reach populations.

BACKGROUND: Obstructed defecation syndrome and posterior compartment (rectal) prolapse significantly impact patients’ quality of life. Pelvic floor physical therapy is a critical part of multidisciplinary management for these conditions, yet there is little guidance or standardization to guide providers’ referral practices, diagnostic approaches, or treatment. OBJECTIVE: To develop multidisciplinary consensus-based recommendations for incorporating pelvic floor physical therapy into the treatment of obstructed defecation syndrome and posterior compartment prolapse. DATA SOURCES: MEDLINE, PubMed, Embase, and the Cochrane Database of Systematic Reviews were searched for English-language studies on pelvic floor physical therapy, obstructed defecation, diagnostic criteria, imaging, and pelvic organ prolapse. STUDY SELECTION: Studies identified in the literature search were reviewed by multidisciplinary expert subgroups, who formulated draft statements based on the available evidence. INTERVENTION: Consensus meetings were conducted and included experts from colorectal surgery, urogynecology, physical therapy, gastroenterology, radiology, and urology. Statements were evaluated via structured discussions and voting processes. Those reaching more than 70% consensus were adopted for inclusion. Statements underwent final review and editing by the leadership of the American Society of Colon and Rectal Surgeons and the International Urogynecological Association. MAIN OUTCOME MEASURES: Consensus statements addressed referral criteria, diagnostic evaluations, therapy protocols, timing, coordination with surgery, and management of anatomical abnormalities. RESULTS: Fifteen statements reached consensus. Key recommendations included prompt referral to pelvic floor physical therapy for patients without contraindications, individualized therapy based on appropriate diagnostic evaluation and patient goals, timing of pelvic floor physical therapy relative to surgery, and trauma-informed patient care. LIMITATIONS: Recommendations primarily reflect expert consensus due to limited high-quality evidence. Variability in practitioner expertise and geographic access to trained therapists are barriers to consistent implementation. CONCLUSIONS: These recommendations provide structured guidance for integrating pelvic floor physical therapy into the management of obstructed defecation syndrome and rectal prolapse. Additional research and standardized training are essential to optimize patient outcomes.

Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

ABSTRACT Background Patients with gastric dysmotility exhibit abnormal transit and reduced contractility, for which quantification is limited with current methodologies. The Atmo Capsule is a wireless motility capsule that measures regional gastrointestinal transit. We tested its technical capabilities to evaluate gastric contractility by detecting changes in capsule acceleration during transit. Methods Data from 91 healthy controls and 182 patients with suspected dysmotility who ingested the Atmo Capsule following a standardized protocol were included. Gastric emptying times (GET) ≥ 5 h were considered delayed. Contraction frequencies (cycles per minute [cpm]) and amplitudes (as arbitrary units [au]) were identified following Fast Fourier Transformation of accelerometer data using 5‐min windows and were assessed in 30‐min windows post‐ingestion (early gastric phase) and before gastric emptying (late gastric phase). Data were compared via ANOVA, using Bonferroni corrections, between healthy controls, patients with normal gastric emptying, and patients with delayed gastric emptying. Key Results Gastric emptying was delayed in 53/182 (29%) patients. Three cpm contraction frequencies were identified across both gastric phases in controls and patients. Contraction amplitudes did not differ between groups in the early gastric phase. In the late phase, mean amplitudes were lower in patients with delayed gastric emptying (6.4 au) compared with subjects with normal gastric emptying (controls, 9.7 au, p < 0.0001; patients, 8.6 au, p < 0.0001). Conclusions & Inference The Atmo Capsule enables precise quantification of gastric contraction profiles, permitting differentiation of normal from pathological motor patterns. Findings of this technical assessment support its potential for evaluating gastric physiology and detecting pathophysiological patterns of gastric dysmotility.

Background Monensin, a Na + ionophore, can increase cytosolic Ca 2+ ([Ca 2+ ] i ) by reversing the Na + /Ca 2+ exchange mechanism. This study provided additional insights into the mechanism of this Na + ionophore-induced increase in [Ca 2+ ] i , and emphasized the critical role of phospholipase C (PLC) in amplifying Na + /Ca 2+ exchange-induced Ca 2+ influx and subsequent arachidonic acid (AA) release in FRTL-5 thyroid cells. The possible involvement of protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and GTP-binding (G) protein in mediating monensin-induced AA release was also explored. Methods FRTL-5 thyroid cells were maintained in Coon's modified Ham's F-12 medium supplemented with a 6-hormone (6H) mixture. Cytosolic Ca 2+ was measured by using indo-1 AM and a dual-wave-length spectrofluorometer. Release of 3 H-labeled inositol trisphosphates and arachidonic acid were determined by a scintillation counter. Results In Hank's balanced salt solution with Ca 2+ (HBSS+), monensin (100 µmol/L) induced a 2.3-fold sustained Ca 2+ increase associated with IP 3 generation and a 6-fold increase in AA release. Deletion of extracellular Ca 2+ , or replacement of Na + by choline chloride in the medium, reduced the [Ca 2+ ] i increase by 77% and completely prevented the monensin-induced rise in AA release. Similar inhibitory effects were observed in cells pretreated with a Na + channel blocker, or Na + /Ca 2+ exchange inhibitors. In HBSS without Ca 2+ (HBSS-), monensin induced a 1-fold transient [Ca 2+ ] i increase but did not increase the AA. This Ca 2+ increase was not suppressed by U-73122, a PLC inhibitor. In HBSS+, U-73122 did not affect the monensin-induced initial transient peak increase of [Ca 2+ ] i , but reduced the sustained second phase of [Ca 2+ ] i from 400 nmol/L to 250 nmol/L, and completely blocked AA release. A phospholipase A 2 (PLA 2 ) inhibitor blocked the monensin-induced AA release without affecting the [Ca 2+ ] i increase. Inhibition of PKC prevented 87% to 94% of the monensin-stimulated AA release. The monensin-induced AA release was also inhibited 94% by pertussis and 51% by a MAP kinase cascade inhibitor. Conclusions The results suggest that monensin initiates an increase in [Ca 2+ ] i via a Na + /Ca 2+ exchange mechanism that triggers more pronounced and sustained [Ca 2+ ] i increase via activation of PLC and Ca 2+ influx. The PLC activation, followed by sustained Ca 2+ influx and PKC activation, is a prerequisite for PLA 2 -mediated processes in monensin-challenged FRTL-5 thyroid cells. Key words: FRTL-5 thyroid cells • phospholipases • protein kinase C • MAP kinase • cell calcium

Abstract Sinonasal squamous cell carcinoma (SNSCC) is an aggressive head and neck cancer of the sinonasal cavity which has not benefitted from therapeutic advances over decades 1 . Though historically attributed to inhaled carcinogens such as hardwood dust and tobacco smoking 2 , SNSCC is incidentally associated with human papillomavirus (HPV) 3,4 . Importantly, HPV is the primary oncogenic driver of >80% of anatomically adjacent oropharyngeal cancers 5 . While viral status drives clinical staging and treatment guidelines in these malignancies 6,7 , the potentially oncogenic consequences and prognostic value of host–virus interactions in SNSCC remain incompletely defined. Here, through paired host and viral whole-genome sequencing (WGS), we map the genomic footprint of HPV in SNSCC. Strikingly, lesser studied strains such as HPV45, 51, and 39 constitute driver infections in this rare but clinically credentialed cancer, where extrachromosomal DNA (ecDNA)-associated viral integration and APOBEC mutagenesis are shown to underpin somatic tumor evolution. Statement of Significance Paired host viral and whole-genome sequencing of SNSCC nominates HPV as a primary oncogenic driver of SNSCC. HPV–human ecDNA amplicons harboring noncanonical strains such as HPV45, 51 mediate viral carcinogenesis. Routine clinical diagnostic HPV panels should be expanded to capture the activity of lesser studied strains.

ABSTRACT Background Sentinel lymph node (SLN) biopsy is a critical staging tool in skin and soft tissue cancers. Although technetium lymphoscintigraphy is the most common adjunct, indocyanine green (ICG) demonstrates a promising alternative in pediatric, adolescent, and young adult (AYA) skin and soft tissue cancers. Methods and Objectives Evaluate the safety and efficacy of ICG in SLN biopsy (SLNB) in diverse pediatric and AYA solid cancers in a multi‐institutional environment. This is a prospective, observational study conducted at 13 member institutions in the Pediatric Surgical Oncology Research Collaborative between 2019 and 2023. Eligible patients underwent SLNB for primary or recurrent solid skin and soft tissue tumors. Peritumoral ICG was administered intraoperatively. Outcomes included SLN detection rates, histopathology of excised specimens, and surgeon‐reported assessment of utility. Safety was assessed through adverse event reporting. Results Forty SLNB procedures yielded 84 specimens: 13 melanoma (32.5%), 12 squamous cell carcinoma (30%), 11 non‐rhabdomyosarcoma soft tissue sarcoma (27.5%), two rhabdomyosarcoma (5%), one Ewing sarcoma (2.5%), and one malignant peripheral nerve sheath tumor (2.5%). Histologic evaluation identified 81 lymph nodes, 75 benign (89.3%) and six malignant (7.1%); three specimens were adipose tissue (3.6%). Of 81 lymph nodes, 76% were ICG‐positive. ICG had a sensitivity of 79.5%, a specificity of 33%, and a positive predictive value of 96%. All malignant nodes were ICG‐avid. There were no adverse reactions to ICG at 30 days. Conclusions ICG is a safe and effective adjunct for SLNB in pediatric and AYA soft tissue and skin malignancies.

BACKGROUND: Stoma-free survival represents a key quality-of-life outcome after surgery for locally advanced rectal cancer. Despite advances in neoadjuvant and surgical management, up to 30% of patients ultimately require a permanent fecal diversion. OBJECTIVE: To evaluate stoma-free survival and identify factors associated with permanent stoma formation in patients with locally advanced rectal cancer undergoing coloanal anastomosis. DESIGN: Retrospective cohort study. SETTINGS: Single tertiary referral center (2017–2021). PATIENTS: A total of 126 patients with clinical stage II and III rectal adenocarcinoma who received neoadjuvant therapy and underwent curative-intent resection with coloanal anastomosis were included. INTERVENTION: Curative-intent resection with coloanal anastomosis. MAIN OUTCOME MEASURES: The primary outcome was stoma-free survival. Secondary analyses examined factors associated with permanent fecal diversion. RESULTS: The medical records of 126 patients were analyzed, comprising 62.5% men, with a mean age of 54 ± 10 years and a median BMI of 27.7 (interquartile range 24.5–31.4). At a median follow-up of 53.0 months, the 5-year stoma-free survival rate was 88.9%. Univariate Cox regression analysis showed that BMI ≥35 (HR 3.80; 95% CI, 1.04–13.91, p = 0.044) and handsewn coloanal anastomosis with mucosectomy compared to stapled coloanal anastomosis without mucosectomy (HR 5.58; 95% CI, 1.71–18.14, p = 0.004), as well as local recurrence (HR 6.51; 95% CI, 1.44–29.46), were associated with worse stoma-free survival. The 30-day major morbidity rate was 7.9% after the index surgery. Sixteen patients required permanent fecal diversion due to bowel dysfunction (n = 11), disease recurrence (n = 4), or bowel obstruction (n = 1). LIMITATIONS: Retrospective, single-institution design with limited generalizability. CONCLUSIONS: Coloanal anastomosis in the era of total neoadjuvant therapy resulted in favorable 5-year stoma-free survival. BMI ≥35, handsewn coloanal anastomosis with mucosectomy, and local recurrence were associated with worse stoma-free survival. See Video Abstract . SUPERVIVENCIA SIN ESTOMA TRAS UNA RESECCIÓN ANTERIOR BAJA CON ANASTOMOSIS COLOANAL PARA EL CÁNCER RECTAL EN ESTADIO II-III ANTECEDENTES: La supervivencia sin estoma representa un resultado clave para la calidad de vida tras la cirugía de cáncer rectal localmente avanzado. A pesar de los avances en el tratamiento neoadyuvante y quirúrgico, hasta un 30 % de los pacientes requieren finalmente una derivación fecal permanente. OBJETIVO: Evaluar la supervivencia sin estoma e identificar los factores asociados con la formación de un estoma permanente en pacientes con cáncer rectal localmente avanzado sometidos a anastomosis coloanal. DISEÑO: Estudio de cohorte retrospectivo. ENTORNO: Centro terciario de referencia único, 2017-2021. PACIENTES: Se incluyó a un total de 126 pacientes con adenocarcinoma rectal en estadio clínico II-III que recibieron terapia neoadyuvante y se sometieron a una resección con intención curativa con anastomosis coloanal. INTERVENCIÓN: Resección con intención curativa con anastomosis coloanal. PRINCIPALES MEDIDAS DE RESULTADO: El resultado principal fue la supervivencia sin estoma. Los análisis secundarios examinaron los factores asociados con la derivación fecal permanente. RESULTADOS: Se analizaron 126 pacientes, de los cuales el 62,5 % eran hombres, con una edad media de 54 ± 10 años y un índice de masa corporal medio de 27,7 kg/m 2 (rango intercuartílico: 24,5-31,4 kg/m 2 ). Con una mediana de seguimiento de 53,0 meses, la tasa de supervivencia sin estoma a 5 años fue del 88,9 %. El análisis de regresión de Cox univariante mostró que el índice de masa corporal ≥ 35 kg/m 2 (razón de riesgo = 3,80, intervalo de confianza del 95 %: 1,04-13,91, p = 0,044) y la anastomosis coloanal cosida a mano con mucosectomía, en comparación con la anastomosis coloanal grapada sin mucosectomía (razón de riesgo = 5,58, intervalo de confianza del 95 %: 1,71-18,14, p = 0,004), así como la recurrencia local (razón de riesgo = 6,51, intervalo de confianza del 95 %: 1,44-29,46) se asociaron con una peor supervivencia sin estoma. La tasa de morbilidad grave a los 30 días fue del 7,9 % tras la cirugía índice. Dieciséis pacientes requirieron una derivación fecal permanente debido a disfunción intestinal (n = 11), recurrencia de la enfermedad (n = 4) u obstrucción intestinal (n = 1). LIMITACIONES: Diseño retrospectivo, de una sola institución, con una generalización limitada. CONCLUSIONES: La anastomosis coloanal en la era de la terapia neoadyuvante total dio lugar a una supervivencia sin estoma favorable a los 5 años. El índice de masa corporal ≥ 35 kg/m2, la anastomosis coloanal cosida a mano con mucosectomía y la recurrencia local se asociaron con una peor supervivencia sin estoma. (AI-generated translation )