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 Among 9457 aquaporin‐4 (AQP4) immunoglobulin G‐positive patients, 2071 underwent autoimmune encephalitis antibody testing and 85 (4%) had coexisting antibodies, most commonly cerebrospinal fluid glial fibrillary acidic protein‐IgG and N‐methyl‐D‐aspartate receptor‐IgG, or serum high‐titer GAD65‐IgG. Compared with AQP4‐IgG positive neuromyelitis optica spectrum disorder controls, dual‐positive patients were younger and more frequently exhibited encephalopathy, psychiatric symptoms, seizures, ovarian teratomas, and deep gray matter, temporal lobe, or diencephalic MRI abnormalities. GAD65‐IgG‐positive patients developed stiff‐person syndrome. These findings define a distinct mixed glial‐neuronal autoimmune phenotype and support additional neural antibody testing in atypical AQP4‐IgG‐positive presentations.

ABSTRACT Retrospective cohort study to investigate which factors most reliably distinguish incidental GAD65‐antibodies (iGAD65) from true GAD65‐antibody neurological disease (tGAD65). 167 adults with positive serum and CSF GAD65‐antibodies (> 0.02 nmol/L by radioimmunoassay) were classified as tGAD65 or iGAD65, with diagnostic performance of paraclinical parameters compared in discovery and validation cohorts. CSF GAD65‐antibody titers ≥ 1 nmol/L performed best in discovery (AUC 0.956) and validation (AUC 0.949; p = 0.814), with 89.7% sensitivity and 94% specificity for identifying tGAD65. Serum titers > 20 nmol/L and indices of intrathecal synthesis showed lower discriminative ability. Our finding aims to reduce misdiagnosis and identify potential immunotherapy‐responsive diseases.

Background General surgery malpractice premiums vary across states. We examined whether legal, regulatory, and payment measures were associated with premium levels and annual changes. Methods We analyzed 50 states during 2013-2023, expressing monetary measures in 2023 dollars. Between-state regressions evaluated mean premiums; annual models included state- and year-fixed effects. Generalized caps included restrictions on noneconomic recovery in at least one ordinary medical-liability claim category. Policy-change analyses were exploratory. Results Among 550 state-years, each additional mean annual payment report per million residents was associated with 2.32% higher mean premiums across states (95% CI, 1.20%-3.44%; P < .001). The adjusted cap association was −18.53% (95% CI, −37.11% to 5.53%; P = .118); judicial climate and premium regulation were also nonsignificant. Within-state payment-frequency and payment-size associations were nonsignificant. Three states changed generalized cap status; event-time estimates showed pre-change differences (joint P = .016), limiting causal interpretation. Discussion Higher payment frequency was associated with higher average premiums across states, but year-to-year changes in payment frequency within a given state were not detectably associated with that state’s own premium changes. Cap estimates varied depending on how caps were defined and remained statistically uncertain. These ecological findings do not establish causal effects or support specific policy prescriptions.

Background Sudden cardiac death (SCD) is the leading cause of duty‐related death among firefighters. Understanding postmortem cardiovascular abnormalities associated with SCD is critical to guiding fire service cardiovascular disease screening and prevention programs. Methods This study included US firefighters who had a duty‐related death over a 16‐year period (1999–2014) with available postmortem reports (autopsy/medical examiner reports). Cases were systematically reviewed to identify cases of SCD. For each SCD case, the primary etiology of SCD was adjudicated by experts in sports cardiology and cardiovascular pathology. Results Postmortem evaluations were available for 794 of 2100 (37.8%) on‐duty firefighter deaths over the study period (average age, 44±13 years; age range, 17–82 years; 4.0% women). A total of 312 of 794 (39.3%) firefighter deaths were adjudicated as SCD. A total of 255 of 312 (81.8%) SCD events were attributable to coronary artery disease/ischemic heart disease or hypertensive heart disease, which both are associated with traditional cardiovascular risk factors. The leading etiology of SCD among young firefighters (aged <40 years) was also coronary artery disease/ischemic heart disease (24/50 [48.0%]). Of firefighters who had an exertional SCD event thought to be secondary to coronary artery disease (n=97), a total of 62 of 91 (68.1%) had severe fixed coronary stenosis, while 29 of 91 (31.9%) demonstrated acute plaque rupture/thrombosis. Conclusions More than 80% of on‐duty SCD events among US firefighters are due to coronary artery disease and hypertensive heart disease that may be prevented by early disease identification and risk factor modification. Future studies should assess the efficacy of more rigorous firefighter cardiovascular disease screening and management practices.

Background: Hyperkinetic biliary dyskinesia, defined as a gallbladder ejection fraction (EF) ≥80% on cholecystokinin (CCK)-stimulated hepatobiliary iminodiacetic acid scans in the setting of biliary-type pain, has been increasingly recognized as a potential functional gallbladder disorder. The clinical significance of this entity and the role of cholecystectomy remain uncertain. Patients and Methods: We conducted a systematic review and meta-analysis of studies reporting outcomes in patients with CCK-hepatobiliary iminodiacetic acid EF ≥80% who underwent cholecystectomy due to non-acute biliary-type pain. Primary outcomes included mean EF, rates of symptom resolution and improvement following cholecystectomy, and prevalence of chronic cholecystitis on pathology. Secondary outcomes included normal histology rates and symptom reproduction with CCK stimulation. All statistical analyses were conducted in R (version 4.5.0) using a random-effects model to obtain pooled estimates. Results: A total of 14 retrospective studies, including 686 patients, were analyzed. The pooled mean gallbladder EF was 90.27% (95% CI: 88.73–91.80, I 2 = 86.6%). Symptom resolution occurred in 83.1% (95% CI: 76.7–89.4, I 2 = 76.8%), and symptom improvement in 91.6% (95% CI: 89.0–94.2, I 2 = 29.7%) of patients following cholecystectomy. Histopathologic analysis revealed chronic cholecystitis in 85.1% (95% CI: 76.9–93.4, I 2 = 90.6%) of surgical specimens, while normal gallbladder histology was rare, observed in only 9.9% (95% CI: 4.6–15.2, I 2 = 83.7%). The pooled risk ratio indicated a 6.70-fold higher likelihood of chronic cholecystitis compared with normal histology (95% CI: 3.69–12.17, I 2 = 65.2%, P = 0.0022). Functional reproduction of symptoms during CCK stimulation was frequent, with a pooled rate of 78.3% (95% CI: 70.4–86.3, I 2 = 35.6%). Egger regression test suggested potential publication bias for the normal histology outcome ( P = 0.0223), but not for symptom resolution ( P = 0.1589). Conclusions: This meta-analysis suggests that a high gallbladder EF in the setting of biliary-type pain could represent clinically relevant hyperkinetic biliary dyskinesia rather than normal physiology. Cholecystectomy appears to provide meaningful symptom relief in appropriately selected patients, and pathologic findings frequently indicate underlying chronic inflammation. Further studies are needed to establish clear diagnostic cutoffs and guide management.

BACKGROUND: The impact of life-course blood pressure (BP) trajectories on later-life focal left ventricular (LV) fibrosis by late gadolinium enhancement (LGE) remains elusive. METHODS: MyoFit46 prospectively recruited ≈500 participants from a 1946 birth cohort for a cardiovascular magnetic resonance scan at 77 years, assessing LV LGE calculated using the 3-SD method or 5-SD method. Systolic BP (SBP) and diastolic BP were recorded at 36, 43, 53, 63, 69, and 77 years. For each participant, annual rates of BP change (steepness) and area under the BP trajectory (cumulative burden) for each age interval were calculated using mixed-effects models. Associations between life-course BPs and LGE were tested using generalized linear models, adjusted for antihypertensives, demographics, lifestyle, and comorbidities. Time-to-event associations between LGE and incident major adverse cardiovascular event (hospitalizations for coronary artery disease, stroke, heart failure, and atrial/ventricular arrhythmias; n=29) were also evaluated. RESULTS: Among 472 participants (54% male), each 10 mm Hg greater individual SBPs at 36 to 69 years were associated with 6% to 11% greater LV LGE calculated using the 3-SD method (all P ≤0.033), whereas each 10 mm Hg sustained greater SBPs on any age interval from 36 to 69 associated with 16% to 24% greater LGE calculated using the 3-SD method at 77(all P ≤0.005), independent of SBP at 77 years. Each 1 mm Hg/y steeper SBP rise during age intervals 36 to 43, 43 to 53, and 53 to 63 was associated with 6% to 12% greater LGE calculated using the 3-SD method at 77 years. LGE presence was associated with greater major adverse cardiovascular event rates (hazard ratio, 2.5 [95% CI, 1.2–5.2]). CONCLUSIONS: Higher life-course BPs, cumulative burden, and steeper increases were associated with greater older-age LV LGE, which was linked to incident major adverse cardiovascular events. BP trajectories, beyond single-point BP measurements, warrant further investigation as tools to guide BP management strategies.

Klippel-Trénaunay syndrome (KTS) is a rare congenital vascular-overgrowth disorder within the broader spectrum of PIK3CA -related overgrowth syndromes. Although clinical, radiologic, and orthopedic manifestations are well described, the histologic spectrum of KTS-associated pathology remains under-characterized. Clinicopathologic findings from 21 patients with clinically established KTS were reviewed, including 18 with longitudinal clinical follow-up and 3 consultation cases of rare malignant mesenchymal neoplasms. Cases were identified from institutional pathology and clinical databases, and available hematoxylin and eosin-stained sections and ancillary studies were reviewed. The cohort included 11 males and 10 females. Among the 18 clinically followed patients, 12 had limb length discrepancy or asymmetric limb overgrowth, 9 had documented deep vascular malformations, 4 had intra-articular/synovial malformations, and 10 underwent initial orthopedic evaluation or intervention before age 18. Orthopedic morbidity clustered into mechanical overgrowth-related, vascular malformation-related, and soft tissue/wound-related complications. Histologic findings included superficial and/or deep slow-flow vascular malformations, ulceration and granulation tissue, hemosiderin-laden reactive synovium, and destructive hemorrhagic arthropathy. Intra-articular disease recapitulated a hemophilic arthropathy-like pattern, with hemosiderotic synovitis, papillary synovial hyperplasia, and progressive joint destruction with loss of articular cartilage, exposed subchondral bone destruction and remodeling, all attributable to long-standing intra-articular hemorrhage. Three consultation cases showed malignant mesenchymal neoplasia, including 2 angiosarcomas. Recognition of these patterns is important for pathologists evaluating specimens from patients with known or suspected KTS, particularly when findings mimic hemophilic arthropathy, diffuse-type tenosynovial giant cell tumor, nonsyndromic vascular malformation, and/or end-stage destructive arthropathy.