Citations

Introduction and Aim Periprosthetic joint infection (PJI) remains one of the most devastating complications following total joint arthroplasty, and a leading indication for revision surgery. As the incidence of PJI continues to rise, treatment outcomes remain constrained by sub-optimal standard-of-care treatment options. We conducted two prospective, randomized, multi-center, FDA-regulated clinical trials evaluating a novel PJI treatment* that uses cyclic, local, antibiotic irrigation to deliver high concentrations of vancomycin and tobramycin directly to the infected joint. Methods Patients with chronic hip or knee PJI were randomized to receive the CLEAR (cyclic, local, expedited, antibiotic-irrigation regimen) protocol with drug and device combination product* (CLEAR) or two-stage exchange arthroplasty (control) and followed for 24 months. CLEAR patients received 7 days of intra-articular cyclic irrigation with 80 mg tobramycin once daily, then hourly irrigation with 125 mg of vancomycin. The primary outcome was treatment success following explantation of the infected prosthesis, defined as infection control without suppressive antibiotics. Infection control included permanent prosthesis reimplantation, absence of reoperation, absence of PJI, and survival. Secondary outcomes included reimplantation rate, time to reimplantation, operative time, septic revision rate, and mortality. Results A total of 152 randomized patients underwent explantation [CLEAR: 76 patients; mean age: 67.0, 42.1% female, 89.5% White, mean BMI: 31.8, 56.6% knee; Control: 76 patients; mean age: 65.3, 32.9% female, 90.8% White, mean BMI: 34.0, 63.2% knee], of which 141 (93.0%) completed the 24-month assessment. At 24 months, 74.0% of patients (51/69) in the CLEAR group achieved treatment success compared to 51.4% in the control (37/72; significant nominal p=0.0058). Reimplantation rates were higher with the CLEAR protocol (100% vs. 87%), mean time to reimplantation was markedly shorter (7 vs. 127 days), and mean total operative time in the explant and reimplant surgeries was shorter (304 min vs 363 min). The control group experienced 83% more unplanned septic reoperations through 24 months (22 vs 12). The mortality rate at 24 months was higher in the control group (9.7% vs 7.2%). Conclusions The CLEAR protocol with the drug and device combination product* demonstrated superior outcomes at 24 months compared to two-stage exchange for chronic PJI. More patients treated using the CLEAR protocol with the drug and device combination product* received a permanent prosthesis, in a significantly shorter time, and more achieved treatment success, with shorter total operative time and fewer unplanned septic reoperations. These findings support the CLEAR protocol with the drug and device combination product* as a promising therapeutic strategy for the treatment of chronic PJI. * VT-X7 (Osteal Therapeutics)

ABSTRACT HLA‐DRB1*03:234 differs from HLA‐DRB1*03:01:01:01 by two adjacent nucleotide substitutions in exon 2.

The hospice setting is unique for patient care and requires different techniques to study than other populations.

Serrated polyposis syndrome (SPS) is the most common polyposis syndrome, yet SPS often goes unrecognized. SPS diagnosis is based on clinical criteria established by the World Health Organization and includes the size, cumulative lifetime number, and location of serrated polyps throughout the colon. Individuals with SPS have an increased risk of prevalent and incident colorectal cancer (CRC). Meticulous inspection, clearing of the colon and frequent surveillance colonoscopy is recommended to decrease incident CRC. Colorectal surgery is indicated for individuals diagnosed with cancer or whose polyp burden cannot be managed endoscopically by expert endoscopists. There is no common germline pathogenic variant associated with SPS. Germline genetic testing is indicated only in individuals who meet criteria for a known hereditary syndrome in the appropriate clinical setting. First-degree relatives of patients with SPS are at heightened risk of CRC and should undergo colonoscopic screening.

ABSTRACT Background Patients with cardiovascular implantable electronic devices (CIEDs) who develop bacteremia require risk stratification for device infection. Although prediction scores exist for Staphylococcus aureus bacteremia, no comparable CIED‐specific tool exists for non– S. aureus bacteremia. Our study aimed to estimate the probability of definite CIED infection in adults with non– S. aureus bacteremia without pocket infection. Methods We performed a prediction‐model analysis of adults with CIEDs and non– S. aureus bacteremia, comprising gram‐negative bacteremia (GNB) and gram‐positive cocci other than S. aureus (GPC) bacteremia, at Mayo Clinic Rochester during 2012–2019. Patients with pocket infection were excluded. Definite CIED infection was classified using 2019 European Heart Rhythm Association criteria. Penalized logistic regression was used to construct two prediction models for definite infection: a full model with nine prespecified predictors, and a reduced model from which a point‐based risk score could be obtained. Results A total of 282 patients with CIEDs developed non– S. aureus bacteremia. Median age was 75 years; 69% were men. GPC bacteremia occurred in 156 patients (55%) and GNB in 126 (45%). Sixty patients (21%) had definite CIED infection. Both the full and reduced models demonstrated excellent predictive discrimination (apparent area under receiver operating characteristic curve 0.946 and 0.940). The reduced model retained four predictors: GPC bacteremia, persistent bacteremia, longer time to positivity, and unknown bacteremia source. Conclusion A four‐variable risk score incorporating organism category, persistent bacteremia, time to positivity, and unknown bacteremia source may guide early device‐focused evaluation, but external validation is required before clinical adoption.

ABSTRACT Background Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are rare, chronic cholestatic liver diseases with heterogeneous progression and limited biomarkers of disease biology. Epigenetic age acceleration has been demonstrated in PSC and PBC, suggesting accelerated biological aging. DNA methylation–derived telomere length (DNAmTL) reflects replicative aging and cellular turnover, but its role in PSC and PBC remains unclear. We aimed to evaluate DNAmTL in PSC and PBC and its association with disease severity. Methods We analysed and compared DNAmTL and age‐adjusted DNAmTL among patients with PSC ( n = 474) versus PSC controls ( n = 484) and patients with PBC ( n = 291) versus PBC controls ( n = 291). Associations with clinical outcomes were assessed using nonparametric tests and multivariable logistic regression models. Correlations with primary sclerosing cholangitis Risk Estimate Tool (PREsTO) score and epigenetic age acceleration (AgeAccelGrim) were evaluated using linear regression. Results Patients with PSC demonstrated significantly shorter age‐adjusted DNAmTL compared with controls (median −0.036 vs. 0.016, p < 0.001). Patients with PBC also exhibited reduced DNAmTL relative to controls (median 6.814 vs. 6.885, p < 0.001). Within PSC, shorter DNAmTL was associated with cirrhosis (OR 0.21, 95% CI 0.06–0.69, p = 0.013) and advanced disease (OR 0.20, 95% CI 0.06–0.67, p = 0.009). Shorter DNAmTL was also observed in hepatic decompensation and hepatobiliary malignancy, including cholangiocarcinoma. DNAmTL inversely correlated with PReSTO score ( p < 0.001). DNAmTL was strongly inversely correlated with AgeAccelGrim in both PSC and PBC ( p < 0.001). Conclusion Cholestatic liver diseases are associated with shortened DNAmTL, which independently correlates with disease severity in PSC. Together with epigenetic age acceleration, these findings support a model of accelerated biological aging in PSC and PBC characterized by converging signatures of accelerated biological aging that may contribute to progressive biliary injury and fibrosis.

Abstract Varlilumab is a monoclonal antibody with agonistic activity on CD27. The efficacy of single-agent PD-1 inhibitors on aggressive B-cell non-Hodkin lymphoma is limited. Preclinical and phase 1 data suggest that Varlilumab is safe and may have synergistic activity with PD-1 inhibitors. In the DIAL study, we explored whether dual immunomodulatory therapy with Varlilumab and Nivolumab in patients with relapsed/refractory aggressive B-NHL was safe and effective. We conducted a randomized phase II clinical trial on adult patients with relapsed/refractory aggressive B-NHL. Patients were randomized to receive Nivolumab monotherapy in the control group and Varlilumab combined with Nivolumab in the experimental group. Crossover to the experimental group was allowed upon progression in the control group. The primary endpoint was the overall response rate based on the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC). 54 patients underwent randomization, and 51 received assigned intervention and were included in the intention-to-treat analysis. Objective response was observed in 6 out of 51 patients (ORR 12%). There were 4 responders (ORR 16%) in the Nivolumab group and 2 responders (ORR 7.6%) in the Nivolumab and Varlilumab combination group (p = 0.3). None of the 7 patients that crossed over to the experimental group responded to the addition of Varlilumab. The ORR of patients who were previously exposed to CAR-T cell therapy was 13% (5 out of 39) compared to 8.3% (1 out of 12) in the unexposed patients (p > 0.99). The rate of treatment emergent adverse events was similar between groups, and there was no fatal TEAE in the study. The addition of Varlilumab to Nivolumb did not improve outcomes in patients with aggressive B-NHL. Even though this trial was not designed to evaluate immunotherapy as a rescue therapy after CAR-T failure, most patients (76%) had previously received CAR-T therapy, and their outcomes were equally poor.

ABSTRACT Background Primary Biliary Cholangitis (PBC) is an autoimmune cholangiopathy with polygenic architecture and unknown aetiology. Evidence links Neanderthal‐derived genetic variants to autoimmune conditions; however, their contribution to PBC susceptibility remains unexplored. Objective We investigate whether archaic alleles influence PBC risk. Design Genotype data from four PBC cohorts were analysed: CANUK (4615 cases, 9233 controls), OLD IT (444 cases, 901 controls), NEW IT (255 cases, 579 controls) and MAYO (891 cases, 621 controls). Association testing with 235 592 Neanderthal Informative Markers (NIMs) was performed, adjusting for population stratification. Heritability was estimated using RHE‐mc and temporal haplotype dynamics were assessed using ancient DNA data from Europe and Asia. Results A Neanderthal‐derived variant in TNPO3 (rs12531711), previously reported by Cordell et al. showed strong association in CANUK ( p = 2.04 × 10 −26 ) and replicated across all validation cohorts. This variant functions as an eQTL, upregulating IRF5 and downregulating TNPO3 in blood. It is rare in African populations but common both in Europeans and Asians. Temporal analysis of the haplotype carrying rs12531711 revealed frequency increased substantially during the Bronze Age (5000–3000 BP), rising from 2.0% to 7.7% in Europe and 3.4% to 17.4% in Asia, before stabilizing. Despite this strong single‐variant association, the heritability explained by NIMs was not significantly different from that of non‐NIM variants. Conclusion A Neanderthal‐derived variant contributes to PBC risk and its frequency increased in the Bronze Age, possibly due to pathogen‐driven selection. Archaic introgression overall has limited influence on PBC heritability. Functional studies are needed to elucidate the role of rs12531711.

Introduction: Frontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform. Methods: Participants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing. Results: Passive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85). Discussion: Passive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.