Citations

Abstract Background The past two decades have witnessed tremendous growth in the appreciation and treatment of sacroiliac joint (SIJ) complex pain, including anatomical dissections that shed light on innervation, an appreciation for the contribution of extra-articular components to SIJ complex pain, the advent of radiofrequency ablation (RFA) and a host of minimally invasive surgical techniques. Yet, there is no standardization on diagnosis and treatment paradigms. Methods In February 2023, the Boards of Directors for the American Academy of Pain Medicine (AAPM) and American Society of Regional Anesthesia & Pain Medicine (ASRA-PM) approved the development of multispecialty guidelines on SIJ complex pain. Thirty partner organizations with clinical and scientific interests in SIJ complex pain were identified, and formal letters of request-for-participation were sent to each, along with a request for nominees to serve on the committee. Twenty five organizations agreed to participate in addition to the Departments of Defense and Veterans Affairs. A steering committee developed 21 questions, which spanned criteria for diagnosis, non-interventional and interventional treatments including surgery, technical parameters on how to optimize results, and what constitutes positive outcomes. Questions were methodically assigned to specialized modules comprising 4-5 members with complementary expertise, who collaborated with the Subcommittee Lead and one of three Committee Chairs to develop preliminary drafts. Following thorough revisions, these drafts were subsequently submitted to the full committee for comprehensive review. A modified Delphi method was used in which the answers to questions were sent to the committee en bloc and comments were returned in a non-blinded fashion to the Chairs, who incorporated the comments and sent out revised versions until consensus was achieved. During a committee meeting before commencement, it was agreed that recommendations would be noted when there was >50% agreement among committee members, but that a formal recommendation would require ≥75% consensus. Results Twenty-one organizations formally endorsed the guidelines. The American Society of Anesthesiologists, and American Academy of Physical Medicine & Rehabilitation, and the North American Spine Society affirmed the benefit of the guidelines but did not officially endorse them. The American Academy of Neurology declined to affirm the benefit of the guidelines citing “lack of relevance to their membership.” Per policies, while the Departments of Defense and Veterans Affairs did not formally review the guidelines for endorsement, their representatives approved them. In addition to being endorsed or the benefit affirmed by all voting organizations, complete consensus from committee members was obtained on all 21 questions. On 2 recommendations, there were dissensions from 3 societies who thought that selecting patients for sacral lateral branch RFA and minimally invasive fusion should be based on ≥75% relief from 2 blocks instead of at least 50% relief from a single block before RFA, and greater than 50% pain relief with documented functional improvement after a single block before fusion. One additional society (Latin American Society of Regional Anesthesia) abstained on the statement that the evidence is stronger for extra-articular than intra-articular injections. The committee found that a battery of physical exam tests has reasonable sensitivity, but lower specificity, for identifying intra-articular but not extra-articular pathology, with negative tests having greater predictive value than positive ones. Intra-articular injections have diagnostic validity for SIJ intra-articular, but not extra-articular pain. There is unclear or negative evidence for imaging. The prevalence rates of intra-articular and extra-articular pathology are comparable, with both intra- and extra-articular steroid injections providing at least 4 weeks of relief in well-selected patients. However, the evidence is slightly stronger for extra-articular corticosteroid injections to provide short-term relief. The evidence base for non-interventional therapies is indirect, extrapolated mostly from low back pain studies. There is weak evidence supporting dextrose-based prolotherapy and platelet-rich plasma to provide at least 3 months of pain relief. There is strong evidence for sacral lateral branch RFA to provide relief for at least 6 months in individuals with extra-articular pathology, with face validity and indirect evidence from randomized trials supporting sacral lateral branch blocks as a prognostic tool. There is stronger evidence for larger lesions or more aggressive lesioning strategies than for less stringent techniques. There is weak evidence to support non-steroidal anti-inflammatory drugs to prevent neuritis after RFA, and in most cases anticoagulation does not require cessation in the periprocedural perioid. With an aggressive lesioning strategy, sensory stimulation provides minimal therapeutic benefit, with weak, extrapolated evidence that motor stimulation can provide safety benefit. The cutoff to designate diagnostic or prognostic blocks as positive is most commonly set at 50%, with higher values not shown to improve outcomes for more definitive procedures; for therapeutic treatment outcomes, the evidence supports a lower threshold of ≥30% pain relief or meaningful benefit on non-pain outcomes (eg, opioid cessation) for designation of a positive response. For carefully selected patients with intra-articular SIJ complex pain based on controlled blocks who have failed conservative therapies, there is weak or very weak evidence that minimally invasive SIJ fusion can provide benefit for at least one year. Conclusions SIJ complex pain remains an underappreciated source of chronic low back pain, affecting between 15% and 30% of patients with axial pain predominantly below L5. Answers to many questions were limited by low-quality evidence, indicating the need for better research. SIJ complex pain is a multifarious condition (ie, pain can be from different portions of both the intra- and extra-articular components of the joint) for which an interdisciplinary, multimodal treatment plan can optimize treatment outcomes.

Glioblastoma (GBM) is an aggressive brain tumor with a highly immunosuppressive microenvironment that promotes tumor progression and therapy resistance. Tumor-associated macrophages (TAMs), comprising up to 50% of the tumor mass, are recruited via chemokine axes such as CCL2/CCR2, CX3CL1/CX3CR1, and CXCL12/CXCR4 and adopt an M2-like immunosuppressive phenotype, facilitating immune escape and angiogenesis. Key signaling pathways, including CSF1R, STAT3, NF-κB, PI3K/Akt, and HIF-1α, regulate TAM function, making them promising therapeutic targets. Strategies such as TAM depletion, reprogramming, and immune checkpoint blockade (PD-1/PD-L1, and CD47-SIRPα) have shown potential in preclinical models. Emerging approaches, including CAR-macrophage (CAR-M) therapy, nanotechnology-based drug delivery, and exosome-mediated modulation, offer new avenues for intervention. However, clinical translation remains challenging due to GBM’s heterogeneity and adaptive resistance mechanisms. Future research should integrate multi-omics profiling and AI-driven drug discovery to refine TAM-targeted therapies and improve patient outcomes. This review provides a comprehensive analysis of TAM-mediated immune regulation in GBM and explores evolving therapeutic strategies aimed at overcoming its treatment barriers.

Abstract Error analysis is a critical step in evaluating and improving clinical concept extraction models, the most common clinical natural language processing (NLP) task. Unlike corpus annotation, which follows standardized protocols for creating gold-standard datasets, error analysis requires nuanced judgment grounded in both clinical expertise and NLP knowledge. This is especially important given the heterogeneity of clinical text, where variations in documentation style, note structure, and terminology can substantially influence model behavior. Despite its importance, there is currently no standardized, user-level framework to support systematic error analysis in clinical concept extraction task. In this study, we developed and validated MedError, a machine-assisted, human-in-the-loop framework designed to standardize and enhance error analysis for clinical concept extraction tasks. We collected and manually curated a corpus of 1,187 unique errors from a total of 4,237 notes across three different distinct hospitals. The error categories were defined using our previously validated error taxonomy and included 480 false negatives and 707 false positives across 25 error types and 48 clinical concept categories. We evaluated the performance of three proprietary and three open-source large language models (LLMs) in automatically classifying these errors into 26 and 15 predefined categories. We further developed a machine-assisted framework, MedError, which integrates best practices in error analysis, LLM-assisted classification and reasoning, and a user-friendly interface to enable more efficient, reproducible, and context-aware error analysis. The framework supports both single-site and federated multisite error analysis, facilitating the effective translation of clinical NLP systems into real-world settings.

Importance Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology. Objective To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]). Design, Setting, and Participants This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964). Exposures Plasma p-tau217 levels measured by immunoassay. Main Outcome and Measures Aβ status, determined by CSF or Aβ PET biomarkers. Results Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .001). Conclusions and Relevance The findings highlight the potential of plasma p-tau217 as a stand-alone test—or when used in a sequential 2-step approach alongside PET or CSF testing—as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.

The integration of mobile health (mHealth) technologies is transforming neurosurgery. Despite its potential, many uses remain unrealized due to the unique challenges and complexity of developing mHealth technology. While neurosurgeons bring invaluable clinical expertise and an understanding of patient needs, the technical intricacies of application development often require collaboration with developers and computer scientists, a process that can feel unfamiliar and difficult to navigate. The aim of this article was to demystify mHealth development by providing a guide for neurosurgeons seeking to develop disease-specific mHealth applications. We outline this process using the development of SynapTrack, an mHealth tool designed to provide objective assessments of degenerative cervical myelopathy, a chronic condition caused by symptomatic compression of the cervical spinal cord. This article offers neurosurgeons concrete guidance on navigating key considerations such as design decisions, algorithm integration, database architecture, and data security. By grounding these insights with SynapTrack, this guide offers a transparent view into the development process and provides a practical framework that can be adapted to the development of other mHealth tools. The aim of this work was to foster interdisciplinary collaboration and enable neurosurgeons to develop mHealth applications tailored to the specific needs of their specialty.

Abstract Repetitive head impacts are associated with structural brain changes and an increased risk for chronic traumatic encephalopathy, a progressive neurodegenerative disease that can only be diagnosed after death. Chronic traumatic encephalopathy is defined by the abnormal accumulation of phosphorylated tau protein, particularly at the depths of the superior frontal sulci, suggesting that sulcal morphology may serve as a relevant structural biomarker. Contact sport athletes, such as former football players, are at elevated risk due to their prolonged exposure to repetitive head impacts. Cortical atrophy linked to underlying tau accumulation may result in shallower and wider sulci, potentially making sulcal morphology an imaging marker for identifying individuals at risk for this disease. This study investigated sulcal morphological differences in former football players and examined associations with age, football-related exposure, clinical diagnosis of traumatic encephalopathy syndrome, levels of certainty for chronic traumatic encephalopathy pathology, neuropsychological performance, and positron emission tomography imaging using flortaucipir. We analysed structural magnetic resonance imaging data from 169 male former football players (mean age 57.2 (8.2) years, range 45–74) and 54 age-matched, unexposed asymptomatic male controls (mean age 59.4 (8.5) years, range 45–74). Sulcal depth and width were quantified using the CalcSulc, focusing on two regions in each hemisphere commonly affected by chronic traumatic encephalopathy pathology: the superior frontal and occipitotemporal sulci. Generalized least squares models were used to assess group differences and interactions with age and football exposure variables, including age of first exposure, total years played, and cumulative head impact exposure. An analysis of covariance evaluated relationships between sulcal morphology, clinical measures, and flortaucipir uptake, adjusting for age, race, body mass index, education, imaging site, apolipoprotein E4 status, and total intracranial volume. Former football players demonstrated significantly shallower sulcal depth in the left superior frontal sulcus compared to unexposed controls. Earlier age of first exposure and longer football careers were associated with greater widening of the left occipitotemporal sulcus. Higher cumulative head impact exposure was linked to reduced sulcal depth in the left superior frontal region. However, sulcal morphology was not associated with clinical diagnosis, levels of certainty, neuropsychological test performance, or flortaucipir imaging. These findings suggest that sulcal morphology may reflect cumulative exposure to repetitive head impacts, particularly in brain regions vulnerable to chronic traumatic encephalopathy pathology. Future ante- and post-mortem validation studies are needed to determine whether sulcal morphology can serve as a reliable in vivo biomarker of risk.

Abstract Objective Gastrointestinal (GI) symptoms are common in systemic mastocytosis (SM). We hereby report the clinicopathologic and molecular features of GI mastocytosis. Methods The study includes 104 patients with suspected SM. Of 258 GI biopsy ­specimens, 33 (20 patients, 19%) were mastocytosis-positive, with 19 (16 patients) initially missed. Results Tryptase (n = 29) was weakly positive/negative in two-thirds of the mastocytosis-positive GI biopsy specimens. Additional immunohistochemistry (n = 23) showed positive mast cell expression for CD30 (n = 2), CD123 (n = 7), and PD-L1 (n = 12), as well as increased PD-1–positive cells (n = 4). Sixty patients had positive bone marrow (BM) for SM (SM-BM+), including 19 with positive GI biopsy specimens (SM-GI+). Almost all (43/44) SM-BM– patients were SM-GI–. The SM-GI vs SM-BM status showed high positive predictive value (95%) and specificity (98%). Patients with SM with mastocytosis-positive vs mastocytosis-negative GI biopsy specimens had higher serum tryptase levels (P = .04). KIT D816V mutation was detected in 7 of 13 and 12 of 13 mastocytosis-positive GI biopsy specimens using allele-specific polymerase chain reaction and droplet digital polymerase chain reaction (ddPCR), respectively. Conclusions GI mastocytosis is highly predictive of SM in BM; however, most SM-BM+ patients are SM-GI–. The SM-BM– patients are very unlikely to be SM-GI+. Because GI neoplastic mast cells are often tryptase negative, diagnostic evaluation should include CD117 and CD25 immunohistochemistry, as well as KIT D816V mutation analysis by ddPCR as needed.

Abstract Background & Aims Pregnancy can be a complex and risk-filled event for women with inflammatory bowel disease (IBD). High-quality studies in this population are lacking, with limited data on medications approved to treat IBD during pregnancy. For patients, limited knowledge surrounding pregnancy impacts pregnancy rates, medication adherence, and outcomes. Limited provider knowledge leads to highly varied practices in care affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus. The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike. The Global Consensus Consortium is a group of 39 IBD and content experts and 7 patient advocates from 6 continents who convened to review and assess current data and come to an agreement on best practices based on these data. Methods The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) process was used when sufficient published data were available and the RAND (Research and Development) process in those instances where expert opinion was needed to guide consistent practice. Recommendations were informed by the guiding principle that maternal health best supports infant health. Results The topics were divided into ten categories with 34 GRADE recommendations and 35 consensus statements. Conclusions Overall, the goal of the group was to provide data-driven and practical guidance to improve the care of women with IBD around the globe based on the best available research.

ABSTRACT Nonsteroidal anti‐inflammatory drugs (NSAID)‐exacerbated respiratory disease (N‐ERD) is a mainly type 2 inflammatory condition that combines asthma, nasal polyps, and hypersensitivity to NSAIDs. Its pathogenesis involves both upper and lower airways, yet most studies to date have examined these compartments separately. It remains unclear whether the molecular mechanisms in the nose, sinuses, and lungs are distinct or overlapping—an important gap, given that clinical manifestations of N‐ERD involve both sites. In this review, we summarize available omics studies—transcriptomics, proteomics, metabolomics, and epigenomics—performed on upper and lower airways in patients with N‐ERD. While omics approaches have revealed new molecular insights, comparisons across studies are limited by heterogeneity in design, controls, and methodology. We emphasize the need for integrated multi‐omics analyses and standardized frameworks to better characterize the disease across airways. Such efforts are essential for identifying robust biomarkers and therapeutic targets and for moving toward a systems‐level understanding of N‐ERD.

Abstract We investigated the influence of 55 583 autophagy-related single-nucleotide polymorphisms (SNPs) on chronic lymphocytic leukemia (CLL) risk across 4 independent populations comprising 5472 CLL cases and 726 465 controls. We also examined their impact on overall survival (OS), time to first treatment (TTFT), autophagy flux, and immune responses. A meta-analysis of the 4 populations identified, to our knowledge, for the first time, significant associations between CDKN2A (rs3731204) and BCL2 (rs4940571, rs12457371, and rs1026825) SNPs and CLL risk, with CDKN2A showing the strongest association (P = 1.57 × 10−12). We also validated previously reported associations for FAS, BCL2, and BAK1 SNPs with CLL risk (P = 4.73 × 10−21 to 3.39 × 10−9). The CDKN2Ars3731204 and FASrs1926194 SNPs associated with increased CDKN2A and ACTA2 messenger RNA expression levels in the whole blood and/or lymphocytes (P = 5.1 × 10−7, P = 1.58 × 10−21, and P = 7.8 × 10−41), although no significant effect on autophagy flux was observed. However, associations were found between CDKN2A, BCL2, and FAS SNPs and various T-cell subsets, cytokine production, and circulating concentrations of interferon gamma, tumor necrosis factor–related apoptosis-inducing ligand, CD40, chemokine ligand 20, and interleukin-2 receptor subunit β proteins (P ≤ .005). No significant association was detected between autophagy variants and OS or TTFT, suggesting that these variants drive disease initiation rather than progression. In conclusion, this study identified 4 novel associations for CLL and provided insights into the biological pathways that influence CLL development.