Citations

The translation of AI-generated brain metastases (BM) segmentation into clinical practice relies heavily on diverse, high-quality annotated medical imaging datasets. The BraTS-METS 2023 challenge has gained momentum for testing and benchmarking algorithms using rigorously annotated internationally compiled real-world datasets. This study presents the results of the segmentation challenge and characterizes the challenging cases that impacted the performance of the winning algorithms. Untreated brain metastases on standard anatomic MRI sequences (T1, T2, FLAIR, T1PG) from eight contributed international datasets were annotated in stepwise method: published UNET algorithms, student, neuroradiologist, final approver neuroradiologist. Segmentations were ranked based on lesion-wise Dice and Hausdorff distance (HD95) scores. False positives (FP) and false negatives (FN) were rigorously penalized, receiving a score of 0 for Dice and a fixed penalty of 374 for HD95. The mean scores for the teams were calculated. Eight datasets comprising 1303 studies were annotated, with 402 studies (3076 lesions) released on Synapse as publicly available datasets to challenge competitors. Additionally, 31 studies (139 lesions) were held out for validation, and 59 studies (218 lesions) were used for testing. Segmentation accuracy was measured as rank across subjects, with the winning team achieving a LesionWise mean score of 7.9. The Dice score for the winning team was 0.65 ± 0.25. Common errors among the leading teams included false negatives for small lesions and misregistration of masks in space. The Dice scores and lesion detection rates of all algorithms diminished with decreasing tumor size, particularly for tumors smaller than 100 mm3. In conclusion, algorithms for BM segmentation require further refinement to balance high sensitivity in lesion detection with the minimization of false positives and negatives. The BraTS-METS 2023 challenge successfully curated well- annotated, diverse datasets and identified common errors, facilitating the translation of BM segmentation across varied environments and providing the tools for future development of personalized volumetric reports to patients undergoing BM treatment.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Abstract Severe aplastic anemia (SAA) is a rare and life-threatening bone marrow failure disorder. Immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine has long been a frontline treatment option in SAA; however, its limited durability and risk of long-term complications such as secondary malignancies remain a drawback in this treatment modality. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative option with significantly improved outcomes over the long term, particularly with HLA-matched related donors. However, the use of alternative donors, such as haploidentical, mismatched, or matched unrelated donors, has previously been limited due to increased transplant-related morbidity, particularly graft-versus-host disease (GVHD). HCTs have therefore been limited to young recipients and those with HLA-matched related donors, creating significant disparity for older adults and those who lack matched donor options. Nevertheless, more recent advances in HCT, such as posttransplant cyclophosphamide for GVHD prophylaxis, have led to improved outcomes of HCT with alternative donors; however, alternative donor HCT remains underused as up-front therapy, in part because of limited multicenter trial data. This review discusses current SAA treatment approaches, including both IST and HCT, and highlights remaining gaps. It also discusses how ongoing clinical trials such as CureAA and TransIT could help address these gaps. Furthermore, we discuss the importance of stakeholder engagement and implementation science in the integration of research-based evidence into clinical practice. Bridging these gaps is necessary for achieving equitable access for patients historically excluded from frontline HCT, including older adults and racially or ethnically diverse populations.

Background and Aims: Reducing avoidable readmissions in cirrhosis is challenging. Enhanced engagement using health information technology (HIT) interventions and caregivers lowered readmissions in an open-label study of the Patient Buddy App (PBA). Aim : Multicenter trial of PBA versus standard of care (SOC) to reduce avoidable readmissions. Approach and Results: An open-label, randomized clinical trial was performed at 3 sites to study the effect of PBA (HIT) versus SOC in cirrhosis inpatients with adult caregivers (dyads). Initial randomization was 1:1:1 between SOC, HIT only, and HIT+ visits. However, due to COVID-19, an unplanned study redesign required a combined HIT versus SOC. Primary outcome : Avoidable readmissions (decided by a blinded monitoring board). Secondary outcomes were all-cause readmission and stakeholder input. PBA focused on medication adherence, cognitive testing, and symptoms, and was remotely monitored by study staff. In all, 464 subjects (232 dyads) were enrolled [Virginia Commonwealth University (VCU): 120, Mayo: 40, Department of Veterans Affairs (VA): 72; 116 dyads/group]. Avoidable readmissions were significantly higher in SOC versus HIT (19.8% vs. 10.3%, p =0.04) with OR of 2.14 (95% CI 1.01–4.54) and remained significant even after removing pre-COVID HIT+ visits patients (19.8% vs. 9.3%, p =0.040) with OR of 2.41 (95% CI 1.02–5.69). All-cause readmissions were higher in SOC versus HIT (48% vs. 30%, p =0.005). App evaluation/engagemen t : 1660 alerts were sent; mostly related to HE. Most dyads were satisfied with the app. Conclusions: In a multicenter randomized clinical trial of 464 cirrhosis inpatients and their CGs across several practice settings, the PBA was associated with lower avoidable readmissions at 30 days post-discharge compared to SOC.

Background The optimal timing and type of venous thromboembolism chemoprophylaxis (VTEp) for adults with acute traumatic brain injury (TBI) remains unknown. This systematic review synthesized evidence on the timing and type of VTEp in adults with TBI and highlights evidence gaps. Methods We searched Ovid MEDLINE, Embase, and the Cochrane Library through November 4, 2024 for English language, randomized or non-randomized studies with a comparator that reported VTEp timing or agent in adults with acute TBI, and reported intracranial hemorrhage progression (ICHP), VTE, pulmonary embolism (PE), deep vein thrombosis (DVT), neurosurgical intervention (NSI), adverse events (AEs), length of stay (LOS), function, or mortality. Risk of bias (ROB) was assessed with ROBINS-I as low, moderate, serious, or critical risk in studies that used advanced analytic methods (AAMs) to control selection bias; all other studies were deemed critical risk. We qualitatively synthesized evidence and focused text reporting on studies with AAM. Results From 738 citations, 21 non-randomized studies met criteria (1 moderate, 20 critical ROB): 16 on VTEp timing, 7 on agents. Seven studies used AAM. For VTEp timing (five AAM studies), one study of adults with mostly mild TBI found no significant difference between Early and Late VTEp on ICHP (moderate ROB); no timing studies with AAM reported ICHP for adults with moderate or severe TBI. Findings were mixed for VTE timing on NSI and PE. Early VTEp was associated with fewer DVTs. There was no difference in mortality or serious AEs by VTEp timing. For VTEp agents, three studies with AAM found no significant difference between low molecular weight heparin (LMWH) and unfractionated heparin (UH) on ICHP, PE, DVT, and serious or overall AEs. Results were mixed for LMWH versus UH effects on NSI after VTEp, VTE, LOS and mortality. TBI severity labeling varied across studies and within measures, reducing comparability. Conclusions Clinical evidence on the timing and type of VTEp for adults with acute TBI is of insufficient quality for clinical decision-making. Prospective research designs, standardization of TBI severity labeling, and improved reporting of interventions and outcomes would advance the field. PROSPERO registration number CRD42023421534 Level of evidence Systematic Review, Level IV

ABSTRACTObjectiveClinical outcome measures for autoimmune encephalitis (AE) are not yet well defined. Cognitive outcome measures (CogOs) and patient‐reported outcomes (PROs) may capture the symptoms of AE, beyond clinician‐reported outcomes (ClinROs) (the Modified Rankin Scale [mRS] and Clinical Assessment Scale in Autoimmune Encephalitis [CASE]).MethodsThis retrospective cohort study examined LGI‐1‐IgG AE patients at Cleveland Clinic. CogOs included the Rey Auditory Verbal Learning Test (RAVLT) and Brief Visuospatial Memory Test (BVMT). PROs included Neuro‐QoL, PROMIS Global Physical (GPH) and Mental Health (GMH). Abnormal RAVLT, BVMT (≤ −1.5 SD), Neuro‐QoL, and PROMIS (≥ 10 T‐scores) proportions were analyzed. CogOs and PROs were correlated with ClinROs using Spearman's rank correlation.ResultsForty‐four patients (64% male, mean age 68 [SD = 11], median follow‐up 19 months) were included. ClinROs improved, with median mRS decreasing from 2.5 (IQR = 2–3) to 2 (IQR = 1–2), and CASE from 5 (IQR = 3–6) to 3 (IQR = 2–3) (all p < 0.05). RAVLT (n = 15), BVMT (n = 16), Neuro‐QoL (n = 21), and PROMIS (n = 34) were available. At > 12 months from diagnosis, cognition was impaired on BVMT (56%) and RAVLT (20%). PROs showed impairments in Neuro‐QoL lower (38%) and upper (27%) extremity function, cognition (31%), and PROMIS‐GPH (25%). RAVLT correlated with Neuro‐QoL cognition, depression, and stigma, while BVMT correlated with PROMIS‐GMH (all unadjusted p < 0.05). Neither RAVLT nor BVMT correlated with ClinROs. ClinROs correlated with Neuro‐QoL lower extremity function, cognition, and social roles (all p < 0.05).InterpretationLGI‐1‐IgG AE patients have long‐term impairments in cognition, physical health, and social roles, which can be objectively measured using CogOs and PROs and are not captured by ClinROs.

Importance Bilateral vocal cord paralysis is a challenging problem to manage in adults, and a known complication of thyroid surgery which is more common in resource-limited settings. Posterior graft laryngotracheal reconstruction is a management option that has not been studied in this population or setting. Objective To report the surgical outcomes of posterior graft laryngotracheal reconstruction for bilateral vocal cord paralysis in a resource-limited setting, and to evaluate the efficacy of a hybrid system for teaching this technique in Kenya. Design Retrospective cohort study. Setting Tertiary public referral hospital, Eldoret, Kenya Participants Adults >18 years with tracheostomy dependence secondary to bilateral vocal cord paralysis after thyroid surgery or other iatrogenesis. The hybrid training program included Kenyan surgeons and surgical trainees. Intervention or Exposures Posterior graft laryngotracheal reconstruction and hybrid training system included didactic lectures, simulation-based training, case discussion and planning, and live cases. Main Outcomes Measures One-year airway outcomes measured by achievement of tracheostomy decannulation, and self-reported surgeon knowledge and skill acquisition. Results Ten patients met criteria and were included in the analysis, with mean age 42 years (range 30-62 years) and had been tracheostomy dependent for an average of 6 years (range 1-12 years). Seven (70%) had open reconstruction, and 3 (30%) had endoscopic reconstruction. All were decannulated and remained tracheostomy-free at 1 year. Three surgeons and 7 trainees participated in the hybrid teaching methods. All reported increased comfort in laryngotracheal reconstruction, with all 3 surgeons reporting comfort performing the surgeries independently. Conclusion Posterior graft laryngotracheal reconstruction shows promise as a potential method of treating bilateral vocal cord paralysis and achieving decannulation in a resource-limited setting. Relevance The methods reported in this study lend themselves to replication and expansion to other similar settings. The authors plan to replicate this work in other centers in East Africa.

PURPOSE Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+HER2–) patients from five IO arms. METHODS A total of 204 HR+HER2– (MammaPrint high-risk) patients from five IO arms (anti–PD-1, anti–PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti–PD-1/toll-like receptor 9 dual-IO combination, and anti–PD-1 ± lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint+ (likely sensitive) versus ImPrint– (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%). RESULTS Overall, the pCR rate across the five IO arms was 33%. 26% of HR+HER2– patients were ImPrint+, and pCR rates with IO were 75% in ImPrint+ versus 17% in ImPrint–, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint–. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR = 14.5). CONCLUSION Using an accurate selection strategy, HR+HER2– patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR+HER2– patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.