Citations

ABSTRACT Current laboratory testing for Lyme disease (LD) relies on serology. We evaluated the performance of standard two-tiered testing (STTT) and modified two-tiered testing (MTTT) algorithms using samples obtained from well-characterized patients with early LD in the U.S. East Coast and Upper Midwest. Participants with signs and symptoms of early LD (cases) and controls were enrolled by Lyme Disease Biobank. We compared the performance of four FDA-cleared STTT or MTTT algorithms using serum samples from 251 participants (107 cases, 69 with a convalescent draw; 144 endemic controls). At the initial blood draw, algorithm sensitivity ranged from 22% to 36%, with specificity ranging from 98% to 100%. MTTT algorithms showed higher sensitivity compared with STTT algorithms ( P ≤ 0.05). One STTT algorithm was less sensitive than the other ( P = 0.035), and there was no significant difference in sensitivity between MTTT algorithms. There was also discordance between algorithms; only 22 of the 45 samples classified as laboratory confirmed by Lyme Disease Biobank testing were positive using all algorithms evaluated. Likelihood of positive two-tiered serology among cases with a suspected erythema migrans (EM) skin lesion increased with longer lesion duration and/or when presenting with >1 constitutional symptom. Participants with suspected EM without constitutional symptoms were unlikely to test positive by any algorithm evaluated. Testing convalescent samples did not improve LD detection, and seroconversion was rare. While MTTT confirmed more early LD cases than STTT, all two-tiered algorithms evaluated were insensitive in this population. Novel diagnostics that improve laboratory confirmation for early LD are urgently needed. IMPORTANCE This study confirms that two-tiered serologic testing algorithms are insensitive in early Lyme disease, particularly within the first 2 weeks after symptom onset or when erythema migrans is not accompanied by constitutional symptoms. It also demonstrates that seroconversion is rare after antibiotic treatment. These results highlight the need for novel diagnostics for early Lyme disease that do not rely on serologic testing.

ABSTRACT Vancomycin is broadly used to treat gram-positive infections in both inpatient and outpatient settings. Its use is primarily for the treatment of methicillin-resistant Staphylococcus aureus (MRSA), which is a common cause of pneumonia, skin and soft tissue infections, and bloodstream infections. Vancomycin therapy requires close clinical monitoring to maintain therapeutic efficacy and, importantly, patient safety. Vancomycin use is associated with acute kidney injury in up to 20% of cases, a number that can be driven down by pharmacokinetic dosing protocols. However, the best mitigation against adverse outcomes associated with vancomycin is to ensure it is only used when needed and rapidly de-escalated when not. As such, many stewardship programs, who are tasked with the safe and effective use of antimicrobial agents, have focused on optimizing vancomycin use. There is a strong correlation with MRSA colonization and infection, and a negative MRSA nares screen has a good negative predictive value for MRSA pneumonia (although this association is less well documented for other infections). As such, detection of MRSA in nares swabs, by nucleic acid amplification tests (NAATs) or culture, is a logical tool for stewarding vancomycin. However, the application of MRSA screening tests as MRSA diagnostics is complex, as these tests are cleared by the U.S. Food and Drug Administration for the detection of MRSA colonization, and not for therapeutic decision making. In this issue of the Journal of Clinical Microbiology, the issue of MRSA nares tests is debated by a clinical pharmacy team and the laboratory. The authors review the clinical evidence and regulatory background in which an MRSA nares NAAT may be used to inform treatment decisions.

BACKGROUND AND OBJECTIVES: Perioperative protocols facilitate earlier discharge without compromising safety in nonfunctioning pituitary adenomas, but no large multicenter studies in the United States have investigated protocols regarding Cushing disease (CD). We sought to characterize perioperative protocols and how their implementation influences clinical outcomes in patients with CD. METHODS: A retrospective analysis was conducted using data from the Registry of Adenomas of the Pituitary and Related Disorders consortium comprising 13 US academic pituitary centers. Institutions were surveyed regarding perioperative procedures for patients undergoing transsphenoidal tumor resection for CD. The impacts of institutional procedures and approaches to implementation on length of stay (LOS) and unplanned 90-day readmission were evaluated. RESULTS: Thirteen institutions contributed survey responses and clinical data for a total of 832 patients meeting inclusion criteria. Ten (76.9%) institutions reported having a postoperative protocol, 9 (69.2%) used a formal document to outline their protocol, and 3 (23.1%) had protocols implemented into hospital policy. Mean LOS was significantly reduced in centers with an established protocol (3.14 vs 3.42 days, P = .032), and more so with a formal document (3.10 vs 3.48 days, P = .001) or hospital policy (2.72 vs 3.36 days, P < .001). Patients treated after protocol implementation experienced shorter LOS ( P < .001). Other factors associated with reduced LOS were presence of a separate CD pathway, intraoperative checklist specific to pituitary surgery, non-narcotic pain regimen, Foley removal order, dedicated outpatient advanced practice provider follow-up, and target discharge date ≤2 days. Intraoperative checklist ( P = .045), non-narcotic pain regimen ( P = .048), nasal packing ( P = .005), and 1-day target discharge date ( P = .032) were important factors against readmission. Compared with microscopic surgery, endoscopic surgery was associated with shorter LOS but increased readmission odds. CONCLUSION: This is the first multicenter study to illustrate that implementation of perioperative protocols is associated with a reduction in LOS and readmission risk in patients with CD.

Submucosal lesions of the esophagus and stomach are commonly discovered as incidental findings during routine endoscopy. These lesions arise from varying layers of the gastrointestinal wall, primarily from the submucosa or the muscularis propria, and can range from benign to malignant. This review provides an overview of common submucosal lesions including gastrointestinal stromal tumors (GIST), leiomyomas, duplication cysts, varices, glomus tumors, lipomas, granular cell tumors, neuroendocrine tumors, pancreatic rest, and schwannomas. We focus on their clinical presentation, endoscopic characteristics, radiologic features, and histopathologic findings to aid in diagnosis.

Background: Little is known about how silicone metacarpophalangeal (MCP) arthroplasty outcomes compare between rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Methods: Using our single institutional data from 2000 to 2022, we propensity matched 46 primary silicone MCP arthroplasties in 33 OA patients 1:2 to 92 arthroplasties in 54 RA patients based on age, sex, body mass index, operative digit, and if the surgery was on the dominant hand. We used Kaplan-Meier estimates and cluster-robust Cox proportional hazard models to compare survival free from revision, all-cause reoperation, and development of coronal plane deviation >10°. Results: There was comparable 10-year survival free of revision (94% OA, 91% RA) and all-cause reoperation (91% OA, 87% RA), with no difference in risk for each outcome between groups. Revision in OA patients occurred early (mean 0.6 years) for recurrent deformity (n = 2) and periprosthetic joint infection (n = 1). Revision in the RA cohort occurred later (mean 6.3 years postoperatively) for recurrent deformity (n = 3) and dislocation (n = 1). Osteoarthritis patients had less coronal plane deviation at the final radiographic follow-up (6.5° vs 16.2°, P < .001), higher 10-year survival free from coronal deviation > 10° (79% vs 17%), and lower risk of progressive coronal deformity (hazard ratio 0.15, P < .001). Conclusions: Silicone MCP arthroplasty remains a durable option with low reoperation rates for RA and OA. Osteoarthritis patients experience less coronal deviation and late reoperation for deformity than RA patients, likely due to their more robust soft-tissue stabilizers and noninflammatory disease process.

Rotator cuff injuries are among the most common musculoskeletal conditions that affect shoulder function and can ultimately impact quality of life. While physical therapy is essential in the care of rotator cuff injuries, the ideal dose of therapeutic exercises continues to be a significant clinical dilemma because of the generalized nature of rehabilitation protocols. This pilot study proposes a machine learning approach to personalize rehabilitation using surface electromyography (sEMG) data collected from eight healthy individuals by testing four key shoulder movements: scaption, internal rotation, external rotation, and external rotation at 90° abduction. In this research, the XGBoost algorithm was used to model muscle activation patterns by achieving a high predictive accuracy (R2 = 0.5325; MSE = 0.0084 μV2). Because sEMG reliably measures superficial muscle activity, a linear programming model was used to divide a 60 min therapy session in a way that increases activation of superficial muscles (such as deltoid and trapezius) while reducing strain on deep muscles (such as supraspinatus and infraspinatus). Three optimization scenarios were tested by reflecting a different clinical goal: prioritizing superficial muscles, minimizing deep muscle strain, or balancing both. Optimized time allocations assigned more time to external rotation at 90° abduction and scaption. This research demonstrates the potential for data-driven methods to transform rotator cuff rehabilitation through personalized and evidence-based treatment plans. The results enhance clinical practice by enabling adaptive rehabilitation planning and show that machine learning can support decision-making in complex muscle activation analysis with strong performance and low latency.

Abstract Alzheimer’s disease (AD) emerges from multi-scale interactions between molecular pathology and disruptions in large-scale brain network dynamics. Understanding how these processes co-evolve and relate to disease stages is essential for advancing complex systems models of aging and AD, and for developing system-informed interventions. However, progress has been limited by a lack of large-scale longitudinal data. To address this, we examined the longitudinal relationship between subsystems of the default mode network (DMN) (posterior DMN, ventral DMN, anterior dorsal DMN) using task-free functional MRI (fMRI) and amyloid positron emission tomography (PET) imaging in a large longitudinal cohort spanning the clinico-biological spectrum of AD (n = 1,451; 2,763 time points) using mixed-effect models. We also assessed whether patterns of DMN connectivity predicted conversion to amyloid positivity, mild cognitive impairment (MCI), and dementia using Cox proportional hazards models. Our findings reveal a dynamic interplay between amyloid accumulation and connectivity within and between DMN subsystems, with both hyper- and hypoconnectivity emerging across DMN subsystems in association with increasing amyloid burden. Importantly, survival models showed that DMN connectivity patterns predicted conversion to critical stages of the disease, including not only conversion to MCI and dementia, but also conversion to amyloid positivity in otherwise clinically unimpaired individuals who were amyloid negative at baseline. These associations were independent of age, APOE4 status, sex, education, and in-scanner motion. These results support a model in which breakdowns in tightly regulated feedback loops governing DMN physiology represent a core systems-level pathophysiology of AD. Notably, this functional dyshomeostasis precedes detectable amyloidosis on imaging. Future studies should focus on the development of robust biomarkers of brain function that can be applied at the individual level, which could in turn help support the development of therapeutic approaches targeting system-level pathophysiology.

Abstract Background Alveolar macrophages (AMs) are central to host defense against Pneumocystis, mediating organism clearance while also contributing to lung inflammation. EphA2, a transmembrane receptor that binds fungal β-glucans, has emerged as a regulator of host–pathogen interactions, but its role in AM responses during Pneumocystis pneumonia (PCP) is unknown. Methods We evaluated AM inflammatory responses to Pneumocystis β-glucans in the presence and absence of EphA2. In vivo studies used a CD4-depleted mouse model of PCP comparing wild-type and EphA2-deficient (EphA2−/−) mice. Lung cytokine responses and organism burden were assessed. Additionally, EphA2 signaling was pharmacologically inhibited using ALW-II-41-27 during trimethoprim-sulfamethoxazole treatment. Results EphA2 deficiency significantly reduced AM proinflammatory cytokine responses to Pneumocystis β-glucans. In CD4-depleted PCP mice, EphA2−/− animals demonstrated decreased lung inflammatory cytokines, but increased organism burden compared to controls. Pharmacologic inhibition of EphA2 during antimicrobial therapy significantly suppressed lung inflammation. Conclusions EphA2 signaling plays a critical role in AM-mediated host defense against Pneumocystis by promoting inflammatory responses necessary for organism control. However, this pathway also contributes to lung inflammation. Targeting EphA2 may represent a novel strategy to modulate inflammation during severe PCP while preserving antimicrobial defense.

Abstract Skin biopsies analyzed with α-synuclein seed amplification assays (SAAs) are a simple way to clinically interrogate the presence of α-synuclein aggregates. We determined the accuracy of skin biopsy SAA in predicting the clinical diagnoses of Parkinson disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB). Blinded SAAs were performed in 3 independent laboratories. Subjects diagnosed with PD, PDD and DLB were analyzed together as group 1, clinically unaffected subjects as group 2 and those with risk factors for LBD as group 3. Punch biopsies were taken from the posterior neck and analyzed by the 3 labs in 6 separate SAAs. Pairwise agreement between labs and assays ranged from excellent (kappa 0.82) to moderate (kappa 0.40-0.68). Sensitivity across assays ranged between 50.0% and 61.3%; specificity ranged between 68.6% and 100%. Comparisons of group 1 vs group 2 produced the greatest specificities, between 77.3% and 100%. In 17 cases that subsequently came to autopsy, 93% of SAAs were positive in those at the neocortical LBD stage but in only &lt;10% of those at lower stages. Skin biopsy α-synuclein SAA may be useful as a diagnostic and progression biomarker in Lewy body dementia clinical trials.