Citations

Abstract BACKGROUND This systematic review and meta‐analysis aimed to assess the diagnostic test accuracy of blood‐based biomarkers (BBMs) for detecting Alzheimer's disease (AD) pathology in cognitively impaired individuals in specialized care settings. The overarching goal is to inform the development of a clinical practice guideline, led by the Alzheimer's Association, for use in clinical practice. METHODS A systematic search of MEDLINE, Embase, and Cochrane Library was conducted from January 2019 to November 2024. Studies evaluating the diagnostic test accuracy of plasma phosphorylated tau (p‐tau) and amyloid beta (Aβ) tests (p‐tau217, %p‐tau217, p‐tau181, p‐tau231, and Aβ42/Aβ40) compared to reference standard tests (cerebrospinal fluid [CSF] AD biomarkers, amyloid positron emission tomography [PET], or neuropathology) in individuals with cognitive impairment (mild cognitive impairment or dementia) in specialized care settings were included. Pooled diagnostic test accuracy measures were calculated, including sensitivity, specificity, and likelihood ratios. Across a range of pre‐test probabilities, we evaluated how much a positive or a negative test result would lead to a change in the probability of having amyloid positivity (post‐test probability). All analyses were conducted for each test within each biomarker. The Quality Assessment of Diagnostic Accuracy Studies 2 tool was used to evaluate the risk of bias, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS Across 49 observational studies meeting eligibility criteria, 31 different BBM tests were examined. When evaluated using a single cut‐point, the diagnostic test accuracy varied considerably across tests: the pooled sensitivity ranged from 49.3% (95% confidence interval [CI]: 41.2–57.4) to 91.4% (95% CI: 86.6–94.6), and the pooled specificity ranged from 61.5% (95% CI: 45.6–75.3) to 96.7% (95% CI: 87.8–99.2). Differences in post‐test probability based on a range of pre‐test probabilities varied greatly across tests. Furthermore, the certainty of evidence across tests ranged from moderate to very low. Most included studies were judged to be at high risk of bias, particularly in domains related to patient selection, index test conduct, and reference standard. CONCLUSION This systematic review provides a comprehensive synthesis of the current evidence on the diagnostic accuracy of BBMs for detecting AD pathology in cognitively impaired individuals in specialized care settings. The findings serve as a foundation for an accompanying clinical practice guideline that provides evidence‐based recommendations for BBM use in the clinical diagnostic pathway. Given continuous developments in this rapidly evolving field, ongoing evaluation will be critical to ensure the synthesized evidence and clinical guidelines remain up to date and maintain clinical relevance. Highlights This is the first comprehensive systematic review and meta‐analysis to evaluate the diagnostic accuracy of blood‐based biomarker (BBM) tests specifically in individuals with objective cognitive impairment seen in specialized care settings. Across 49 studies, BBM test performance varied widely. Pooled sensitivity ranged from 49.3% to 91.4% and specificity from 61.5% to 96.7%, depending on the analyte and assay platform. This review followed the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy, the Grading of Recommendations, Assessment, Development, and Evaluation approach to assess the certainty of evidence. This review served as the evidence base for the Alzheimer's Association's new clinical practice guidelines on BBMs, providing structured, evidence‐based guidance for implementing BBMs in the diagnostic workup of suspected Alzheimer's disease. The review underscores that BBM test performance is assay‐ and platform specific and advises clinicians and laboratory directors to interpret results in the context of the specific test used and integrate the results with a comprehensive clinical assessment.

Background Peripheral nerve stimulation (PNS) has emerged as a promising neurostimulation modality, yet its effectiveness and durability for chronic pain remain uncertain. We conducted a systematic review and meta-analysis to evaluate changes in pain intensity following implantable PNS therapy. Methods Eligible studies included adults (≥18 years) with chronic pain treated with an implantable PNS system, and pain intensity was assessed at baseline and follow-up time points. The primary outcome was change in pain intensity from baseline to 6 months after PNS implantation. Secondary outcomes included changes in pain intensity at 3, 12 and 24 months after PNS implantation. Standardized mean differences (Hedges’ g ) were pooled using a random-effects model. Results A total of 106 studies comprising 9272 patients were included. PNS was associated with large, statistically significant reductions in pain intensity from baseline to all time points: 3 months (Hedges’ g 2.92; 95% CI 2.62 to 3.21), 6 months (Hedges’ g 3.08; 95% CI 2.68 to 3.48), 12 months (Hedges’ g 2.68; 95% CI 2.30 to 3.05) and 24 months (Hedges’ g 2.08; 95% CI 1.68 to 2.48) (all p<0.001). However, the certainty of evidence as assessed by the Grading of Recommendations Assessment, Development and Evaluation criteria was rated as low for the primary outcome, due to pooling from observational studies, risk of bias, and heterogeneity (statistical, clinical and methodological). Subgroup analyses revealed no differences by study design or device type, while smaller effect sizes were reported in industry-funded studies and those with declared conflicts of interest. The largest effect sizes were observed in pelvic and upper extremity pain, whereas the smallest in truncal pain. Conclusion Implantable PNS provides persistent and clinically meaningful analgesia for chronic pain, with benefits sustained up to 24 months. These findings support broader clinical adoption and provide evidence to inform pay0r coverage and policy decisions.

ABSTRACT Objective Fetal surgery (FS) for spina bifida (SB) repair improves infant outcomes; however, spontaneous preterm birth (sPTB) is common. We aimed to evaluate maternal and fetal immune responses following FS for SB repair. Method Pregnant participants undergoing fetoscopic SB repair at 24–26 weeks of gestational age (GA) were prospectively recruited and compared to GA matched low‐risk controls. Blood samples were collected at baseline, 2‐week post‐surgery (POD14), and delivery. Cytokine analysis, flow cytometry, and T cell receptor (TCR) sequencing were performed. Results sPTB occurred in 5/6 of the FS group (0/6 of controls). Maternal blood in the FS group demonstrated increased alpha‐fetoprotein (AFP) and anti‐inflammatory IL‐1RA at baseline and POD14, increased pro‐inflammatory IL‐8 only post‐operatively, and elevated growth factors throughout. T cell phenotypes following FS revealed reduced TH17 frequency but increased activation receptors on cytotoxic T cells. At delivery, the FS cohort had reduced Th2 and Th17 helper T cells and CD4+ memory T cells, but CD8 T cells still showed increased activation. No TCR expansion was detected post‐surgery, suggesting antigen‐independent activation. Cord blood in FS repaired neonates had increased AFP, IL‐8, IL‐1RA. Conclusion Systemic immune changes following FS, particularly T cell maturation and activation, were observed. Further characterization of these mechanisms may help predict and prevent surgery‐induced PTB, improving outcomes.

PURPOSE Immunotherapy has demonstrated limited efficacy in the treatment of microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) to date. We evaluated whether an off-the-shelf, multipeptide vaccine, PolyPEPI1018, in conjunction with standard chemotherapy can induce broad antitumor immune responses, potentially improving disease control in refractory mCRC. PATIENTS AND METHODS This single-arm, open-label study enrolled adults with MSS mCRC who had progressed after ≤2 previous lines of therapy for metastatic disease. PolyPEPI1018 was administered subcutaneously to four anatomical sites on days 1 and 15 and TAS-102 orally twice a day on days 1-5 and 8-12 of a 28-day cycle. Patients were treated for seven cycles or until disease progression. The primary end point was safety. Secondary end points were overall response rate, progression-free survival (PFS), overall survival (OS), and immune and genetic correlates. RESULTS Fifteen patients were enrolled; 80% had liver metastases and 67% had KRAS mutations. Adverse events (AEs) related to PolyPEPI1018 were grade 1 and 2 local skin reactions (n = 14). Grade 3 AEs (n = 15) at least possibly related to treatment were fatigue, decreased lymphocyte and neutrophil counts, and diarrhea. None had objective tumor response; the disease control rate was 53.3%. The median PFS (mPFS) was 4.0 (95% CI, 2.2 to 6.1) months and the median OS (mOS) was 8.7 (95% CI, 6.4 to 15.2) months. In post hoc subgroup analyses, patients without active liver metastasis had improved mPFS of 9.7 months and mOS of 14.8 months. In addition, patients who were predicted to have broader immune responses to vaccine based on human leukocyte antigen genotype had longer mOS (10.3 v 4.6 months, hazard ratio, 0.29 [95% CI, 0.07 to 1.17]). CONCLUSION The addition of PolyPEPI1018 to TAS-102 was safe and induced immunological responses that were associated with improved clinical outcomes. Further investigation of this chemo-immunotherapeutic is warranted.

Background: Hip decompression effectively treats early-stage osteonecrosis of the femoral head (ONFH) by slowing disease progression and potentially delaying joint replacement. Biological adjuvants like bone marrow aspirate concentrate (BMAC) and platelet-rich plasma (PRP) support bone regeneration and improve outcomes 1–7 . The present video article demonstrates a simple, coreless hip decompression technique with BMAC and PRP injection for early-stage ONFH. Description: The procedure is performed in the same operating room setting as traditional core decompression, with the patient supine on a radiolucent table for fluoroscopic guidance. One or both legs are draped free for access to the iliac crests. Bone marrow is harvested percutaneously from the anterior superior iliac crest with a trocar needle kit, centrifuged, and prepared for injection. We recommend precoating needles and syringes with 1:1,000 heparin to prevent clotting. The BioCUE System (Zimmer Biomet) is typically utilized for centrifugation. Hip decompression is performed with use of a trocar and cannula (PerFuse System; Zimmer Biomet), with subsequent injection through the cannula into the femoral head. A 0.5-cm skin incision is made. The trocar is placed lateral to the femur and advanced percutaneously through the lateral femoral cortex, with a starting point proximal to the lesser trochanter. The trocar is then advanced along the femoral neck into the necrotic region by performing mallet strikes on the instrument’s strike cap. Anteroposterior and frog-leg lateral views assist in positioning the trocar within the necrotic area. Internal leg rotation, which aligns the patella upward, helps position the trocar horizontally parallel to the floor. Positioning is adjusted using repeated imaging as needed. Once the patient is positioned, the trocar is removed, leaving the cannula in place. With the cannula retracted 1 cm, a 30-mL syringe is utilized to inject BMAC and PRP into the necrotic lesion. Because of sclerotic resistance, substantial pressure is needed, but retraction of the cannula helps. Following injection, the cannula is withdrawn another 1 cm, and demineralized bone matrix is injected to prevent escape of the BMAC. Alternatives: Alternative treatments for ONFH include traditional core decompression with a sliding hip screw drill or an X-REAM device (Stryker), both of which carry a higher risk of fracture because of the larger diameter of the tract and require limited weightbearing postoperatively. Bone-cement injection can stabilize the femoral head but lacks regenerative properties. Core decompression with either BMAC or PRP alone, rather than in combination, also serves as an alternative treatment strategy. Open approaches, like osteotomy, are more invasive, have longer recovery times, and may complicate future hip arthroplasty if unsuccessful. Rationale: This technique enables minimally invasive hip decompression and delivery of adjuvant cell therapy or grafting, typically without the use of power instruments. This approach avoids the risk of injuring the bone due to the heat from power tools, protecting the BMAC injection site. Patients are generally discharged the same day and permitted full weight-bearing immediately, even in bilateral surgeries. Expected Outcomes: Hip decompression for ONFH has shown variable rates of success 8,9 , but adding BMAC or PRP may improve outcomes 1–3 . Houdek et al. reported that among 35 hips treated with decompression plus BMAC and PRP for corticosteroid-induced ONFH, 88% avoided THA at 3 years 2 and 70%, at 7 years 3 . Patients with grade-1 or 2 Kerboul angles had a 90% survivorship rate, underscoring the benefits of BMAC and PRP. Important Tips: Insert the trocar into the lateral cortex, positioned distal to the vastus ridge and proximal to the lesser trochanter, to reduce iatrogenic subtrochanteric fracture risk. Avoid advancing closer than 5 mm to the subchondral cortex to prevent joint-surface disruption or collapse, especially with eccentric lesions. If resistance occurs during injection, retract the cannula a few millimeters laterally to increase delivery space and reduce pressure. Acronyms and Abbreviations: BMAC = bone marrow aspirate concentrate ONFH = osteonecrosis of the femoral head PRP = platelet-rich plasma AP = anteroposterior THA = total hip arthroplasty ARCO = Association Research Circulation Osseous classification MRI = magnetic resonance imaging

Decades of research on biomarker identification and integration in Alzheimer’s disease (AD) have helped to advance biologically driven disease models, disease subtypes, and disease-modifying treatments. Key lessons learned from AD biomarker development include the need for integration of new biological insights, investment in large cross-sectional and longitudinal studies, a multicomponent biomarker approach, and recruitment of clinical trial cohorts and biosamples that are representative of the target population. We describe how these lessons are being applied in Parkinson’s disease, Huntington’s disease, multiple sclerosis, and psychotic disorders as use cases to inform biomarker-based approaches across central nervous system disorders.

Background Robotic-assisted TKA may allow for more reproducible balancing and implant positioning. However, few RCTs have directly compared modern robotic-assisted TKA to conventional TKA. Questions/purposes (1) Do patients undergoing robotic-assisted TKA perform better on the Timed Up and Go (TUG) test and Stair Climb test (SCT) than patients undergoing conventional TKA at 1 and 6 months after surgery? (2) Do patients undergoing robotic-assisted TKA demonstrate better patient-reported outcomes, including Knee Injury and Osteoarthritis Outcome Score (KOOS), EQ-5D, and VAS scores, than patients undergoing conventional TKA at 1 and 6 months after surgery? (3) Do patients undergoing robotic-assisted TKA demonstrate better radiographic alignment and position than patients undergoing conventional TKA? Methods In this double-blind RCT, 60 patients were randomized to robotic-assisted TKA (n = 30) or conventional TKA (n = 30) without the use of a tensioning device. All care was otherwise standardized, using mechanical alignment guides. The primary outcome measures were the TUG and SCT tests; results were collected by a blinded observer at 6 months postoperatively. These time points were chosen based on the maximal early improvement in patient-reported outcomes and bimodal distribution of the TUG and SCT tests, worsening in the immediate postoperative period, and improving within the first 6 months. Secondary outcome measures were KOOS, EQ-5D, and VAS scores; radiographic measurements; and operative time. Standard bivariate statistical analysis was conducted. The mean ± SD age of the cohort was 66 ± 7 years, with no differences between groups (p = 0.21). Ninety-three percent (28 of 30) of patients in the robotic-assisted group were White versus 97% (29 of 30) in the conventional TKA group (p > 0.99). Women made up 57% (17) of the robotic-assisted cohort and 60% (18) of the conventional TKA cohort. No differences were noted between the robotic-assisted and conventional TKA groups in BMI, Charlson comorbidity index, or American Society of Anesthesiologists (ASA) classification. Results Patients undergoing robotic-assisted TKA did not perform better than those who underwent conventional TKA on the TUG (11 versus 11 seconds; p = 0.88) or SCT (15 versus 15 seconds; p = 0.93) tests. Patients undergoing robotic-assisted TKA did not demonstrate better mean ± SD scores on the KOOS pain subscale than patients undergoing conventional TKA (86 ± 14 versus 80 ± 17; p = 0.15). Patients undergoing robotic-assisted TKA did not demonstrate better radiographic alignment and position than patients undergoing conventional TKA based on hip-knee-ankle angle (178° versus 178°; p = 0.89). No differences between the two groups were noted at the 1-month follow-up in TUG and SCT test results. Conclusion In this study, patients who underwent robotically assisted TKA did no better in terms of function, patient-reported outcomes, or radiographic measures than did patients who underwent conventional TKA. Until or unless future studies demonstrate benefits of robotically assisted TKA that are large enough for patients to perceive, we recommend against its use. Level of Evidence Level I, therapeutic study.

Abstract Arthroscopic posterior labral repair is an effective surgical technique for managing patients with posterior labral tears and symptomatic unidirectional posterior shoulder instability. It is well documented that a curved liberator from the mid‐glenoid (anterior‐inferior) portal passed from anterior to posterior provides an effective trajectory for liberation and mobilization of the posterior and posterior‐inferior labral tear. However, biologic preparation of the posterior and inferior glenoid rim with a shaver can be challenging because the anterior mid‐glenoid portal and the posterior portal do not provide an adequate trajectory for instruments to be parallel to the posterior glenoid rim. The purpose of this technical note is to describe a simple efficient procedure for biologic preparation of the posterior and inferior glenoid rim in the setting of arthroscopic posterior labral repair. Technique Video video See video under supplementary data.