Citations

Pancreas transplant is the standard treatment for restoring endocrine function and limiting complications from diabetes, and radiologists should understand the surgical techniques, normal imaging spectrum, and various complications associated with this surgical procedure.

ABSTRACT Herpes simplex virus type 1 replicates in the nucleus of the host cell and utilizes many cellular proteins to facilitate DNA replication. HSV-1 DNA replication is closely linked with homologous recombination, and HSV-1 encodes a two-subunit recombinase consisting of an exonuclease (UL12) and a single-strand DNA-binding protein (ICP8). We identified the cellular deubiquitinating enzyme USP15 as a new UL12-binding partner. USP15 is one of the most enriched proteins on viral DNA and has recently been implicated in regulating cellular homologous recombination. Utilizing isolation of proteins on nascent DNA (iPOND) to compare the proteins on wild-type and UL12-deficient viruses, we observed that USP15 is not recruited to newly replicated DNA in the absence of UL12. We also observed that UL12 and USP15 interact directly in vitro using purified proteins. Together, these data suggest that UL12 directly recruits USP15 to viral DNA. UL12 stimulates a type of homology-directed repair called single-strand annealing (SSA). We generated a USP15 knockout cell line with an integrated GFP-based SSA reporter and observed that UL12 and USP15 both contribute to the maximal induction of SSA. In addition to the reporter cell line, there is a 10-fold reduction in the frequency of marker rescue, and individual replication forks move slower in the absence of USP15. These data support a role for USP15 in facilitating recombination during the virus life cycle and the maintenance of replication fork stability. IMPORTANCE HSV-1 is a ubiquitous pathogen in the global population that causes lifelong latent infection with sporadic reactivation in the host. It has long been appreciated that HSV-1 DNA replication exhibits high rates of recombination and is linked to the host DNA damage response. In this study, we show a novel interaction between UL12, a member of the HSV recombinase, and the deubiquitinating host enzyme USP15. We show that USP15 physically interacts with UL12 and is required for UL12 to maximally stimulate recombination. In the absence of USP15, we also observe an overall reduction in virus growth. This work demonstrated that host proteins facilitate viral-induced recombination. The interaction of USP15 with UL12 represents a potential target for intervention against HSV-1 infection and associated disease.

Abstract Changes in the clinical symptoms of acute graft-versus-host disease (GVHD) are currently used to assess treatment responses. The Mount Sinai Acute GVHD International Consortium (MAGIC) consortium has recently revealed that the integration of serum biomarkers with clinical symptoms at the onset of treatment in a MAGIC composite score (MCS) more accurately predicts treatment response and 6-month nonrelapse mortality (NRM) than clinical symptoms alone. In this study, we evaluated whether the integration of serum biomarkers and clinical symptoms on day 28 (D28) would also better predict NRM than clinical response only (CRO). We analyzed data from 1135 patients receiving systemic treatment for acute GVHD and created a fourth MCS category for patients with complete resolution of symptoms and low-risk clinical biomarkers on D28. Using a classification and regression tree model with 6-month NRM as the end point, we identified status of MCS 0 or MCS 1 at D28 as responses, which we termed the MAGIC composite response (MCR). In the validation cohort (n = 309), MCR more accurately predicted 6-month NRM than CRO (area under the curve: 0.77 vs 0.69; P = .014) and demonstrated higher negative and positive predictive values. MCR correctly reclassified both clinical nonresponders and responders: 28 of 213 clinical responders (13%) became nonresponders with fivefold higher NRM (34.3% vs 6.8%, P < .001) and a larger group (29/96, 30%) of clinical nonresponders became responders with sixfold lower NRM (7.6% vs 50.7%, P < .001). These findings support the use of MCR as a superior surrogate end point for long-term GVHD control and survival in future clinical trials.

Abstract The link between regional tau load and clinical manifestation of Alzheimer’s disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD (‘visual AD’) and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD (‘language AD’). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

Abstract Background: With over 1 billion individuals affected globally, obesity and obesity related diseases is now a leading cause of death. Metabolic and bariatric surgery (MBS) has emerged as a cornerstone intervention for severe obesity and its associated comorbidities. Despite its efficacy, postoperative care and follow-up after MBS remains highly variable worldwide. Objective: The PARTNER study aimed to evaluate global clinical practices in the postoperative management following MBS by surveying multidisciplinary healthcare professionals . Methods: This study was an international online survey conducted between October 2024 and January 2025. A multidisciplinary team developed the questionnaire based on existing literature and international guidelines. The survey assessed five domains: follow-up care, postoperative treatment, dietary management, patient support, and measurement of surgical outcomes. Responses were analysed descriptively. Results: A total of 262 responses were received from 62 countries. Most respondents were bariatric surgeons (72.1%) working in public healthcare systems (73.3%). While 78.7% reported conducting three-month postoperative reviews, only 23.7% offered indefinite follow-up. Hybrid models of care (virtual and in-person) were common (56.9%). VTE prophylaxis and postoperative PPI use were recommended by 64.1% and 84.3% respectively. Nearly all respondents (98.1%) provided dietary advice, with protein and micronutrient supplementation widely endorsed. Only 56.1% routinely referred patients for psychological follow-up. Definitions of surgical success and failure varied widely, with inconsistent objective outcome measures. Conclusion: The PARTNER study reveals significant international variation in postoperative management practices following MBS. These findings underscore the need for more standardized, evidence-based guidelines to improve long-term outcomes and equity of care worldwide.

ABSTRACT Rationale Longer duration of epilepsy before surgery is a predictor of poor outcome. While referral delays of surgical candidates are well documented, factors causing delay during the presurgical evaluation remain unclear and may vary depending on institutional characteristics. By benchmarking the duration of presurgical evaluation across multiple centers and identifying patient and evaluation characteristics contributing to duration, we can ascertain best practices and address modifiable contributors to reduce delays. Methods We queried the Pediatric Epilepsy Research Consortium Surgery Database, a prospective, observational multicenter study enrolling children 0–18 years at 27 US pediatric epilepsy centers, for all patients undergoing initial presurgical evaluation for drug‐resistant epilepsy (DRE). We included patients with completed evaluations and data on duration from initiation of presurgical evaluation to final surgical decision. We compared patient characteristics and evaluation components between those with long duration evaluations (> 75% quartile) and those with short evaluations (< 25% quartile). Akaike information criteria selection identified variables associated with longer duration. From these, we developed a logistic prediction model for evaluation duration, using a random 80/20 training/testing split of the entire cohort. The model was tested among institutions with ≥ 10 patients in the cohort to assess its accuracy in predicting long durations. Linear models for each site assessed each variable's impact on duration. Variables with < 10% of the patient population at each site were excluded. Beta values were compared to identify intra‐ and inter‐institution variability and to delineate institutions with the shortest added duration for each variable. Results Of 2318 patients undergoing surgical evaluation, 1655 (71%) from 23 sites had complete data. Median evaluation duration was 8 weeks (interquartile range 3–22); 453 (27%) were short‐duration evaluations and 414 (25%) were long‐duration evaluations. Multiple patient and evaluation characteristics were associated with duration (Table 1). Table 6 provides the average duration each variable contributes to evaluation by site, highlighting the shortest durations compared with other groups. Conclusions Duration of presurgical evaluation for DRE can be accurately modeled using multiple patient characteristics and testing strategies commonly employed in epilepsy surgery evaluations. This predictive model can not only estimate evaluation duration but also identify opportunities to improve systemic efficiency. Institution‐level modeling identifies specific program strengths, providing an opportunity to learn from successful processes. Subsequent research will focus on institutional process mapping to better understand systemic practices that lead to improved efficiencies, then sharing these processes across the consortium to shorten evaluation durations.

Abstract Background Despite advances in diagnosis and management, the interstitial lung disease (ILD) lexicon is plagued by ambiguous and inconsistent terminology that complicates communication and impedes knowledge generation. The objective of this Fleischner Society Consensus Statement was to produce standardized terminology for ILD multidisciplinary diagnoses and major phenotypes. Methods Interviews with 10 experts were used to identify ILD clinical diagnoses and major phenotypes. The preferred terms for each entity and potential alternatives were identified, alongside the rationale for the preferred term. Entities with more than one potential term were the subject of an online modified Delphi survey posed to the 29 committee members, aiming to achieve consensus. Committee members rated their agreement with the initially preferred term—5 (strongly agree), 4 (agree), 3 (neutral/unsure), 2 (disagree), and 1 (strongly disagree)—with the option to provide additional comments. Median score ≥4 and interquartile range ≤1 were considered consensus agreement. Terms not reaching agreement were discussed by video conference, followed by an additional survey that incorporated feedback. Results From the 60 initial terms, there were two root terms that required upfront consensus before survey initiation (ILD and interstitial pneumonia) and another eight terms that had no alternative suggested by the committee or in the literature. Agreement was met by 47/50 terms (94%) in Round 1 of the survey. The three terms (6%) that did not reach agreement met agreement in Round 2. Conclusions This document provides standardized recommended terms for ILD multidisciplinary diagnoses and major phenotypes that will facilitate communication among clinicians, researchers, patients, and other stakeholders.