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Many hormones and substances acting through G-protein coupled receptors and protein kinase A (PKA) activation inhibit the salt-inducible kinases (SIKs) by phosphorylation. SIKs tonically phosphorylate CREB-regulated transcriptional coactivators (CRTC1, 2 and 3), sequestering them in the cytoplasm and, thus, preventing their translocation into the nucleus. Once in the nucleus, CRTCs bind CREB family member transcription factors and enhance their activity. We and others have shown that parathyroid hormone (PTH) activation of PKA and resultant SIK2/3 inhibition allows CRTC2/3 nuclear translocation. One of the major actions of CRTC2/3 in the osteoblast lineage is the regulation of transcription of Rankl, as well as other PTH-controlled genes. However, little is known about the role of these co-activators in the osteoblast lineage in vivo. Here, we have investigated whether there are basal effects in vivo on bone examined at 2 different ages of conditional deletion of these two co-activators in the osteoblast lineage using Col2.3-Cre. We found significant increases in body weight, length, bone mineral density, bone volume/total volume, trabecular thickness and number with decreased trabecular separation in young (2 months old) male mice, all of which dissipated by 6 months of age. Female mice showed minimal changes in the bone phenotype at either age. Nevertheless, there were gene expression changes in bones of both sexes at both ages, and in particular decreases in Rankl, Runx2 and Sost, and accompanying changes in Wnt pathway genes. These effects may explain the changes in the bone phenotype in the young male mice, but it is notable that there is a sexual dimorphism in the action of CRTC2 and CRTC3. Overall, the work supports the data from research in vitro and forms a basis for investigation of the role of these co-activators in PTH action in vivo.

ABSTRACT The HLA‐C*06:358 allele is characterised by a single nucleotide substitution in codon 95 in exon 3.

Introduction Pluripotent stem cell-derived alpha cells (SC-α cells) represent a promising component of next-generation cell therapies designed to more fully recapitulate human islet function; however, heterogeneity and the presence of undesired side populations limit their functional maturity and therapeutic potential. Here, we identify the cell surface protein CD98hc (SLC3A2), that when highly expressed in precursor cells, is associated with differentiation toward a more transcriptionally and functionally mature population of human SC-α cells. Methods Directed differentiation was used to generate SC-α cells from pluripotent stem cells, which were assessed via single cell RNA sequencing, flow cytometry, and immunofluorescence imaging. Following magnetic activated cell sorting (MACS) of CD98hc enriched precursors, SC-α cell function was assessed using glucose stimulated glucagon secretion (GSGS). Results We show that CD98hc is upregulated in SC-α cells expressing high levels of genes known to play important roles in α cell identity and function, and that CD98hc expression is elevated at the pre-α precursor stage relative to non–α cell populations. We demonstrate that magnetic enrichment of CD98hc⁺ pre-α cells derived from multiple pluripotent stem cell lines selectively increases the proportion of the highest CD98hc expressing glucagon-copositive precursors while depleting multiple undesired side populations, including somatostatin-positive and SOX9-positive cells. Although total α cell yield equalizes following complete differentiation, SC-α cells derived from high-CD98hc enriched precursors exhibit significantly enhanced glucose-responsive glucagon secretion compared to sham-sorted controls, indicating improved functional maturation of this precursor population. Discussion Together, these findings establish that high expression levels of CD98hc marks a functionally superior α cell precursor, that enrichment at the precursor stage can bias differentiation toward higher functional α cell output, that stem cell-derived α cell populations harbor intrinsic functional heterogeneity, and that selective targeting of precursor populations represents a generalizable strategy to improve the quality and performance of stem cell-derived endocrine cell products.

BACKGROUND Anterior placental location has been cited as an independent risk factor for adverse obstetric outcomes, including need for induction of labor, postpartum hemorrhage (PPH), retained placenta, intrapartum Cesarean delivery, and pre-eclampsia diagnosis. (1-4) However, robust evidence to support this association is limited. OBJECTIVE To evaluate the relationship between placental location and subsequent maternal and neonatal outcomes. STUDY DESIGN We conducted a retrospective cohort study of patients who delivered at the Mayo Clinic (Rochester, MN) between May 2018 and May 2023. Patients with singleton pregnancies and ultrasound-confirmed placental location between 16-22 weeks were included. Patients with low-lying placenta, placenta previa, abnormal placentation, uterine anomalies or scheduled Cesarean delivery were excluded. Placental location was categorized as anterior, posterior, lateral, or fundal. Maternal outcomes included postpartum hemorrhage (PPH), prelabor rupture of membranes (PROM), mode of delivery, induction of labor, third-stage duration, and diagnosis of a hypertensive disorder of pregnancy or gestational diabetes. Neonatal outcomes included Apgar scores, birth weight, small for gestational age (SGA), large for gestational age (LGA), and NICU admission. Continuous variables were compared by one-way ANOVA; categorical variables by χ² or Fisher’s exact test. Bonferroni correction was applied for multiple comparisons. RESULTS A total of 4,145 patients were included (placental location: anterior n=2,039; posterior n=1,866; lateral = 158; fundal = 82). Demographic characteristics did not differ significantly across groups. The only maternal outcome achieving statistical significance after Bonferroni correction was PROM [including term or preterm rupture of membranes] (p=0.0003): rates were highest in fundal (18.3%) and lateral (11.4%) groups compared to anterior (7.3%) and posterior (6.8%) placentas. Rates of PPH, induction of labor, delivery modality, third-stage duration, and hypertensive disorders of pregnancy did not differ according to placental location. No neonatal outcomes met the Bonferroni-corrected significance threshold, though a trend toward higher rates of SGA neonates was noted in the lateral group (11.4% vs 5.9% posterior, overall unadjusted p=0.024). CONCLUSIONS Contrary to prevailing clinical assumptions, anterior placentation was not associated with increased rates of PPH, labor induction, or operative delivery in this cohort. Fundal placental location was associated with higher rates of PROM. These findings suggest clinical counselling about placenta-related obstetric risk may need to be reassessed, with particular attention to fundal placental location and PROM risk.

Nontuberculous mycobacterial (NTM) infections are a scourge that affect growing patient populations due to the rise of risk factors associated with these opportunistic pathogens. Cure rates are unacceptably low despite intensive multidrug and multi-year therapy. The issue of poor drug exposure relative to inferior potency of repurposed antibiotics against NTM pathogens is broadly recognized as a major factor underlying dismal success rates. Yet, a quantitative and systematic evaluation of probabilities of pharmacokinetic-pharmacodynamic (PK-PD) target attainment (PTA) is lacking. Here, we leveraged published population PK models and minimum inhibitory concentration distributions across large patient populations to generate PTAs for standard of care antibiotics used in the treatment of NTM infections. PTAs of tuberculosis drugs were included in our analysis as a baseline since tuberculosis cure rates are excellent compared to NTM diseases. We found that PK-PD target attainment for NTM was low overall and that PTAs were generally consistent with reported clinical outcomes. Specifically, drugs for which genetic resistance is associated with worse outcome showed favorable PTAs, consistent with their contribution to cure. These include macrolides for M. abscessus and the M. avium complex (MAC), and rifampicin for M. kansasii. Bedaquiline emerged as a promising option against M. abscessus and MAC, and clofazimine against the latter, consistent with recent clinical reports. Omadacycline PTAs predict improved efficacy compared to tigecycline for patients with M. abscessus and suggest clinical utility for MAC. As is common practice for antibacterials, PTA considerations could inform NTM treatment guidelines and help select drug combinations in future trials.

ABSTRACT Background and Objectives There is increasing use of neoadjuvant treatment (NAT) for patients with pancreatic adenocarcinoma (PDAC). The role of additional adjuvant chemotherapy (AT) is not well‐defined. This study aims to determine the impact of lymphovascular invasion (LVI) and lymph node (LN) involvement on overall survival (OS) in patients with resected PDAC and determine the impact of AT after NAT. Methods This is an observational cohort study of patients with PDAC who underwent NAT and surgical resection. A multivariable model was used to assess for differences in OS. An interaction term between LVI or LN involvement and AT use was utilized to test the benefit of additional AT. Results Seven thousand four hundred and fourteen patients were included; group A (LVI‐, LN‐) had 2787 patients, B (LVI + , LN‐) 652, C (LVI‐, LN + ) 1,712, and D (LVI + , LN + ) 2263. Median OS differed significantly between groups, A had the most favorable survival (34.1 months), followed by B (27.8 months), C (26.3 months), and D (21.2 months, p < 0.001). In patients with persistent LVI or LN involvement after NAT, additional AT was not associated with OS (group A, HR: 0.94, p = 0.4; B and C, HR: 1.0, p = 0.99; D, HR: 0.94, p = 0.32). Conclusions LVI and LN involvement were independently associated with worse OS. After NAT, the use of AT in patients with persistent LVI and LN involvement was not associated with improved OS.

ABSTRACT Background Prior studies in the pre‐MRI era suggest that patients with NCCN Intermediate and High Risk Grade Group 1 prostate cancer (GG1 PCa) on biopsy have increased risk for adverse oncologic outcomes. However, prostate MRI has altered patient selection for biopsy and improved prostate sampling. Herein, we examined factors associated with adverse pathologic features (APF) at radical prostatectomy (RP) and biochemical recurrence (BCR) among patients with GG1 in the MRI era. Methods A prospectively maintained institutional prostate cancer registry identified patients with GG1 PCa on biopsy who underwent RP from 2000 to 2023, stratified by MRI use. Multivariable logistic regression and Cox regression identified factors associated with APF at RP (GG3‐5, ≥ pT3a, or pN1) and BCR free survival (two consecutive PSA ≥ 0.2 ng/mL), respectively. Results Among patients without MRI ( n = 6732), NCCN risk group was associated with APF, BCR, and distant metastasis. Among 302 patients with GG1 and pre‐operative MRI, NCCN risk group was associated with neither APF nor BCR. Age (OR 1.07, 95% CI 1.01–1.14, p = 0.01), PIRADS ( p = 0.01), and % core positivity (OR 1.02, 95% CI 1.00–1.03, p = 0.04) were associated with APF. Age (HR 1.07, 95% CI 1.01–1.13, p = 0.03), APF (HR 4.36, 95% CI 2.14–8.86, p < 0.001), and positive margins (HR 4.88, 95% CI 2.39–9.98, p < 0.001) were associated with BCR. Conclusions Prior to prostate MRI, NCCN risk groups offered meaningful prognostication among patients with GG1 PCa. However, the utility of NCCN risk groups for GG1 in the MRI era appears limited. Contemporary risk stratification for GG1 should focus on biopsy and MRI characteristics rather than NCCN criteria.

Gut wall physiology in multiple sclerosis (MS) and autoimmune neurologic diseases remains underexplored. This review examines gut wall dysfunctions’ contribution to MS and autoimmune neurological disorder pathogenesis and progression. We discuss 3 inter‐related aspects of gut physiology: intestinal barrier, enteric nervous system (ENS), and mucosal immunity. We highlight the ENS as a putative target of immune injury in selected antibody‐mediated and T cell‐associated neurologic diseases. Finally, we propose a unifying framework in which the gut functions as a site of immune priming and target of autoimmune injury, bridging microbiome‐driven mechanisms in MS with ENS‐directed autoimmunity across neurologic diseases. ANN NEUROL 2026

Abstract Neuroanatomy remains a core competency in neurosurgical training, particularly in skull base education, where learners must integrate three‐dimensional spatial understanding, radiologic correlation, and stepwise procedural knowledge. Cadaveric dissection remains foundational, but adjunctive digital tools may strengthen repeated visualization and anatomical review. We describe the educational rationale and implementation of integrating stereoscopic teaching, a stepwise digital application, photogrammetry, and virtual reality within an established neurosurgical skull base curriculum. Within the Mayo Clinic cranial base course embedded in a broader longitudinal curriculum, four postgraduate year 4 neurosurgery residents participated in transcranial and endoscopic cadaveric dissections supported by stereoscopic lectures, workstation‐based tablet guidance, and immersive review using photogrammetry, virtual reality, and computed tomography/magnetic resonance imaging correlation. The integrated design aligned these modalities with course objectives in anatomical landmark recognition, operative corridor planning, radiologic‐anatomic translation, and stepwise procedural rehearsal. The educational contribution of this model lies in the intentional integration of digital adjuncts around cadaveric dissection rather than in a single technology alone. This multimodal sequence may support spatial understanding, procedural preparation, and competency‐oriented skull base training while extending review beyond the laboratory. Current evaluation is best interpreted as preliminary program evaluation rather than definitive learner‐outcome evidence. This model may offer a transferable approach for programs seeking to complement cadaveric education with emerging digital tools and provides a basis for future prospective evaluations using multiple low‐stakes assessment data points across the broader curriculum.