Citations

Abstract Background The Joint Propagation Model (JPM)‐based CenTauR scale was recently introduced to harmonize tau‐PET quantification across different radiotracers. This study examined how CenTauR harmonization enhances the comparability of tau‐PET quantification across matched cohorts using different tracers. The evaluation focused on three key aspects: (1) comparing tau‐PET positivity rates as defined by CenTauR, (2) evaluating its diagnostic accuracy for symptomatic AD, and (3) analyzing longitudinal changes in tau‐PET rates over time. Method The JPM, developed by the CPAD‐led Tau PET Harmonization Working Group (Leuzy et al., Alzheimers Dement. 2024; Figure 1A), models relationships between anchor point subjects and head‐to‐head tau‐PET SUVR data onto the CenTauR scale, providing conversion equations for multiple tracers. JPM equations were applied to [¹⁸F]flortaucipir SUVR (Meta‐temporal ROI) data from 561 cognitively impaired participants in the ADNI and OASIS‐3 studies. Using ROC analysis, we determined the CenTauR cut‐off for positivity (T+) that maximized the Youden index for discriminating between FDA‐approved positive/negative visual reads. Three separate cohorts, scanned using [¹⁸F]flortaucipir (ADNI), [¹⁸F]MK‐6240 (CPAS), and [¹⁸F]RO‐948 (BioFINDER‐2), were matched 1:1 by age, MMSE, amyloid‐β, and clinical diagnosis. CenTauR‐based metrics were compared across these cohorts. Result A cut‐off of 18 CenTauRs was found to optimally classify [ 18 F]flortaucipir PET visual reads (Figure 1B). The matching procedure identified 1089 participants (363 per cohort). The frequency of T+ using the 18 CenTauRs cut‐off for the Meta‐Temporal ROI was highly comparable across tracers across groups, except for the Aβ‐positive cognitively unimpaired group, where variability was more pronounced due to a smaller sample size (Figure 2A). Similarly, tau‐PET discriminative accuracy for symptomatic AD vs controls remained similar across [ 18 F]flortaucipir and [ 18 F]MK‐6240 (Figure 2B). In a separate sample of 212 matched participants from ADNI ([¹⁸F]flortaucipir) and AIBL ([¹⁸F]MK‐6240) with baseline and 1‐year follow‐up tau‐PET scans, 1‐year change in CenTauRs was comparable (Figure 2C). An exploratory voxelwise transformation, utilizing the Meta‐Temporal conversion equation in a representative case scanned with both [¹⁸F]flortaucipir and [¹⁸F]MK‐6240, demonstrates the potential for voxelwise CenTauR harmonization (Figure 3). Conclusion These analyses suggest that CenTauR harmonization increases the comparability of tau‐PET data acquired with different tracers. Additional validation analyses with larger cohorts including other radiotracers ([¹⁸F]PI‐2620) are underway.

Study Design. Modified Delphi consensus process Objective. To establish a standardized, consensus-driven definition for postoperative spine infection (PSI) for research, diagnosis, and management. Summary of Background Data. Postoperative infection is a devastating and common complication following spine surgery. Rates of PSI in the literature range from 0% to over 20% depending on surgical indication and invasiveness. Despite the implications of PSI, there is no universally accepted diagnostic standard or consensus definition for infection following spine surgery, hindering research and treatment of this challenging clinical condition. Methods. A multispecialty workgroup convened by the Musculoskeletal Infection Society (MSIS) conducted a systematic literature review. Using data from the systematic review, an expert panel completed a modified Delphi process to achieve consensus. The panel included nine fellowship-trained, board-certified physicians with expertise in infectious diseases, orthopaedic and neurologic spine surgery, and musculoskeletal radiology. Iterative rounds focused on criterion selection, importance ranking, categorical grouping, and final constellation development for PSI diagnosis. Consensus was defined as a 2/3 majority, with a target of 100%. Results. The workgroup achieved 100% consensus on a new PSI definition, which incorporates six clinical domains: wound features, microbiology, imaging, inflammatory biomarkers, intraoperative findings, and histology. A single microbiological stand-alone criterion—identification of a phenotypically indistinguishable organism from two or more deep operative site specimens—was established as pathognomonic for postoperative spine infection. Additional primary and secondary supporting criteria were defined, with specific combinations required to classify cases as definite or probable PSI. Final definitions were ratified by the boards of MSIS and the European Bone & Joint Infection Society (EBJIS) Conclusion. This consensus-based definition provides a standardized framework for diagnosing postoperative spine infection, facilitating research and clinical management. The criteria balance sensitivity and specificity across diverse clinical scenarios and represent the first multispecialty, society-endorsed definition for PSI.

Background: Patients with abdominal aortic aneurysms (AAA) often have comorbidities that make them poor candidates for open surgical repair (OSR). Endovascular aortic aneurysm repair (EVAR) circumvents the morbidity associated with OSR of AAA. Candidacy for EVAR is impacted by multiple factors, including the quality and size of vascular access vessels and involvement of visceral arteries, as seen in paravisceral abdominal aortic aneurysms (PVAAA). Additional challenges, such as obesity, can complicate vascular access during EVAR. PVAAA may be better suited for fenestrated EVAR (FEVAR) using a physician-modified endograft (PMEG). Materials and Methods: In this report, we describe the case of a 64-year-old female patient with a complex PVAAA in the setting of significant aortoiliac occlusive disease (AIOD) with intermittent claudication. We describe a successful staged FEVAR technique in which vascular access challenges were first addressed by recanalization of the iliac system with femoral conduit (FC) creation, followed by successful FEVAR using bilateral FC for deployment of the PMEG. Conclusion: Patients with PAAA have unique and complex pathology that are clinically challenging to address. It is not uncommon that these patients also have co-morbid conditions that make them less-than ideal candidates for open repair. Patients may also have other conditions such as AIOD which make EVAR complex. Staged approach with iliac recanalization and femoral conduit creation followed by FEVAR with PMEG is an effective treatment option for high-risk complex patients and can help avoid common complications such as groin infection and delay in FEVAR which may result in a catastrophic event such as interval AAA rupture.

Hearing loss is a highly prevalent disease state affecting almost 1 in 5 individuals globally. Growing research shows that untreated or undertreated hearing loss carries significant long-term sequelae, including increased risk of social isolation, depression, and cognitive decline, among other ramifications. Limited awareness and common misperceptions among the general US adult population and primary care providers contribute to low rates of referral to hearing specialty clinics and underutilization of hearing aids, cochlear implants, and other rehabilitative devices. Comprised of diverse membership, the Hearing Health Collaborative (HHC) was formed in May 2021 to identify and overcome challenges impacting good health care practices and public policy on hearing care in connection with healthy aging. This editorial documents a recent outcome of the HHC derived from a structured A3 process. Specifically, initiative 2, a proposal to develop a simple, clinically anchored staging system primarily for use by frontline providers and patients, is presented. Unlike other common disorders that harbor long-term health sequelae, a corresponding pragmatic clinical staging system—leveraging precedent disease staging convention, based on clinically meaningful outcomes and prognosis for acquired hearing loss—does not exist. The development of this staging system will potentially allow for improved communication across providers and patients, facilitate referral pathways, and ultimately enable patient access to timely and appropriate care.

Background: Adeno-associated viruses (AAVs) are widely used vectors for in vivo gene therapy, but their standard storage at −80 °C limits deployment in regions lacking ultracold infrastructure. Strategies enabling stable AAV storage at higher temperatures are needed to support global distribution. Methods: Nine AAV serotypes were lyophilized in simple sucrose-based buffers. Post-lyophilization vector integrity was assessed by measuring in vitro transduction efficiency using a luciferase reporter in cell-based assays. Stability of selected serotypes (AAV2.5 and AAV6) was further evaluated over 8 weeks under varying storage temperatures. Results: Lyophilization in sucrose preserved transduction activity for all tested serotypes (AAV1, AAV2, AAV2.5, AAV3, AAV4, AAV5, AAV6, AAV8, AAV9, and AAVrh10). Notably, AAV2, AAV2.5, and AAV6 exhibited 3- to 6-fold increases in transduction, an effect attributable to the sucrose excipient rather than the lyophilization process itself. Long-term stability of lyophilized vectors varied by serotype, temperature, and vial-seal integrity. AAV6 retained full activity for at least 8 weeks when stored at 4 °C or −20 °C. Conclusions: AAV vectors can be effectively lyophilized in simple sucrose solutions, enabling storage at standard −20 °C freezer temperatures while maintaining functional activity. Optimization of lyophilization buffers and excipients may further extend AAV stability at higher temperatures, improving feasibility for global gene therapy deployment.

Objective The incidence of hip osteoarthritis (OA) is increasing with the aging population, leading to interest in intra-articular orthobiologic injections to alleviate symptoms and potentially slow disease progression. This systematic review aims to evaluate the clinical outcomes associated with six orthobiologic therapies for hip OA: hyaluronic acid (HA), platelet-rich plasma (PRP), autologous cells therapy (ACT), microfragmented adipose tissue (MFAT), and bone marrow aspirate (BMA) and its concentration (BMAC). Methods We conducted a literature search according to the PRISMA guidelines. Studies were included in our review if they used at least one of the four orthobiologic therapies and reported on the clinical outcome using patient reported outcome measures (PROMs). Since there is a large variability among clinical outcomes, we focused on the three most utilized PROMs (VAS, WOMAC, and HHS) and the latest follow-up time point. Results Of the 716 studies reviewed, thirty-six studies (n=36) fit inclusion criteria. There were 21 studies examining HA, 11 on PRP, 3 for MFAT, 2 for ACT, and 3 on BMA/BMAC. Eight studies were randomized controlled trials and 28 were cohort studies. The mean age of the patient population ranged from 45 ± 17.0 to 74 ± 8.0. The baseline grade of osteoarthritis ranged from 1-4 but was most reported as moderate (2-3). Overall, there was an improvement in PROMs at the latest follow-up after receiving orthobiologic interventions. Discussion Orthobiologic injections have shown promise for improving PROMs in patients with hip OA. Future studies should evaluate long-term efficacy and include randomized trials to establish efficacy.

ABSTRACT Background and Aims Chronic inflammatory demyelinating polyradiculoneuropathy ( CIDP ) is a common, treatable, autoimmune, neuropathy frequently misdiagnosed. The complex electrodiagnostic ( EDX ) criteria required for diagnosis are challenging to apply in routine practice. This study evaluates the effectiveness of a machine‐assisted EDX tool in real‐time identification of demyelinating nerve conduction studies ( NCS ) stipulated by 2021‐ EAN / PNS CIDP criteria in conjunction with an online CIDP clinical probability calculator. Methods We prospectively evaluated 100 consecutive patients with referral or EDX diagnosis of polyradiculoneuropathy beginning January 1, 2024. Fifty patients were included, each from Jacksonville and Rochester Mayo Clinics. Routine electromyography ( EMG ) reports were compared to a machine‐assisted support tool applying 2021‐ EAN / PNS CIDP EDX criteria to NCS assessing demyelination. The EDX ‐assistant performance was compared to the final clinical diagnosis and our previously reported online CIDP clinical prediction tool ( https://news.mayocliniclabs.com/cidp‐calculator/ ). Results Among 100 patients (60% male; median age 64), 30 had a final clinical CIDP diagnosis with 29 having intravenous immunoglobulin follow‐up; 27 (93%) improved and 2 (7%) stabilized. Routine EMGs reported demyelination in 14 of 30 (47%), with 46% sensitivity and 79% specificity. The EDX ‐assistant identified CIDP demyelination in 28 of 30 (93%), with 93% sensitivity and 57% specificity. The clinical calculator detected CIDP in 30 of 30 (100%) with 86% specificity, increasing to 94% after excluding false positives lacking demyelinating features on the EDX tool. Interpretation A real‐time machine‐assisted EDX support tool, used with a clinical web‐based calculator, streamlines CIDP assessment by improving standardized identification of 2021‐EAN/PNS CIDP demyelinating NCS criteria and aiding clinical decisions.

Introduction Despite the identification of multiple susceptibility loci by genome-wide association studies (GWAS), considerable chronic obstructive pulmonary disease (COPD) heritability remains unexplained. Aim To identify interaction networks of airway epithelial cell DNA methylation in COPD and further explore potential correlations with airway bacterial composition, as potentially collective regulators of biological pathways influencing COPD severity. Methods Using DNA isolated from bronchial airway brushings of 67 ever-smokers (>20 pack-years) from the SubPopulations and InteRmediate Outcomes Measures in COPD Study (SPIROMICS), we assessed proportion of DNA methylation (β) by epigenome-wide association study (EWAS) and examined associations of differentially methylated CpG probes (DMPs) with risk for moderate-to-severe COPD (N=34) versus absent or mild COPD (N=33). We tested co-methylation modules generated by Weighted Correlation Network Analyses (WGCNA) for associations with moderate-to-severe COPD and with bacterial genus-level relative abundances (16S rRNA sequencing). Results EWAS-identified nominally significant DMPs enriched for lung function GWAS loci. Eigengenes in six WGCNA modules were associated with moderate-to-severe COPD (false discovery rate <0.05). Four of those modules were enriched for forced expiratory volume in 1 s/forced vital capacity GWAS loci, and five overlapped with DMPs from EWAS. Overlapping CpG loci in three COPD-associated modules were adjacent to mucin genes; one had 10 genes highly ranked by connectivity with MUC5B, including important pathway genes: B3GNT6 , DGKI and ITGA8 . CpGs in an independent COPD-associated module showed the most correlations with Rothia , with directionality suggestive of negative associations with moderate-severe COPD. Conclusions Bronchial epithelial DNA methylation modules enriched for lung function GWAS loci associate with COPD severity in SPIROMICS. Potential module relationships to bronchial bacterial composition require further validation.

Importance Molecular analyses of biospecimens collected from study participants are essential for identifying biomarkers that can tailor treatments to specific subsets of patients who are most likely to benefit. Sharing of data and biospecimens from clinical trials enables personalized, patient-centric use of cancer therapies and accelerates the development of new treatments. Objective To describe obstacles to sharing data and biospecimens and to propose strategies to enhance access and collaboration. Evidence Review This is a Special Communication authored by 53 academic investigators and patient representatives from the breast cancer community with extensive experience in conducting clinical and translational research. The article also evaluates the impact of biomarker research on specifying responsive subpopulations in the 29 registrational clinical trials that have led to approval of a new drug for treatment of breast cancer between 2017 and 2024. Findings Clinical trial participants are increasingly asked to provide tissue and/or body fluid biospecimens for biomarker research that is typically controlled by the sponsoring pharmaceutical company, but published biomarker studies are rare. Among 29 breast cancer registrational studies reported in the past 8 years, none resulted in biomarker research that restricted a drug’s approved indication. Herein, strategies to maximize the value of clinical data and biospecimens contributed by participants are proposed, thereby supporting the shared goals of the pharmaceutical industry and academia to improve patient care. These strategies include (1) establishing coleadership structures involving academia and patients in clinical trial design and conduct, (2) ensuring that informed consent forms state that data and biospecimens will be shared with academia for future research, (3) requiring the sharing of clinical data as a condition for regulatory approval, and (4) enabling access to biospecimens and translational research data for independent studies on biomarkers that may indicate drug efficacy and toxicity. Conclusions and Relevance Data and biospecimen sharing from registrational trials has been suboptimal. Improving clinical data, biospecimens, and biospecimens’ related data sharing requires concrete actions and a multidimensional stakeholder approach to accelerate the impact of clinical cancer research on the quality of patient care.