Citations

Abstract BACKGROUND Tau‐derived cerebrospinal fluid (CSF) biomarkers correlate with amyloid‐beta (Aβ) plaques or tau tangles in Alzheimer's disease (AD). This study assessed the effects of long‐term anti‐Aβ antibodies on amyloid plaques, tau tangles, and CSF tau species to determine the relationships between them. METHODS A post‐hoc analysis of the DIAN‐TU‐001 trial (NCT01760005) examined 142 participants at risk for dominantly inherited AD randomized to solanezumab ( n = 50), gantenerumab ( n = 52), or placebo ( n = 40). High‐resolution mass spectrometry quantified CSF tau species over four years. RESULTS Phosphorylated tau (p‐tau) species (153, 181, 217, 231) increased early in preclinical AD but were reduced with gantenerumab‐mediated Aβ plaque reduction. Nearly a decade later, MTBR‐tau243 and p‐tau205 increased, showing no association with Aβ reduction, aligning with tau tangle pathology progression. DISCUSSION Initially changing soluble p‐tau species track Aβ plaque reduction, while ptau205 and MTBR‐243 reflect tau tangle pathology, informing different pathways of therapeutic strategies. Highlights p‐tau217 and p‐tau231 correlate with Aβ‐PET and respond to Aβ‐plaque lowering therapies. Aβ immunotherapy trials support a direct link between p‐tau changes and Aβ plaques Gantenerumab reduces Aβ plaques but does not affect tau NFT‐related biomarkers. Blood‐based p‐tau217 assays may provide a non‐invasive tool to monitor Aβ therapies. MTBR‐tau243 strongly correlates with tau PET and tracks NFT pathology progression. Further studies are needed to validate tau biomarkers for tracking NFT‐targeting therapies.

AbstractObjectiveTo evaluate the diagnostic performance of multiparametric MRI (mpMRI), mpMRI combined with PSA density (PSAd) and combined biopsy (CBx) in detecting clinically significant prostate cancer (csPCa) in men undergoing active surveillance, using radical prostatectomy (RP) specimens as the reference standard.Patients and MethodsIn this prospective single‐centre study, 91 patients with low‐risk prostate cancer under active surveillance underwent mpMRI, PSAd measurement, CBx and ultimately RP. mpMRI was reported using PI‐RADS v2.0, and PSAd was dichotomised at 0.12 ng/ml/cm3. Diagnostic accuracy was compared using ISUP grade ≥2 and ≥3 thresholds. Radical prostatectomy pathology served as the reference standard.ResultsFor detecting ISUP ≥3 cancer, mpMRI combined with PSAd achieved the highest sensitivity (93.3%) and negative predictive value (94.4%). CBx demonstrated the highest specificity (88.2%) and overall diagnostic balance (Youden index = 0.348). mpMRI alone showed intermediate performance. Differences in classification between strategies were statistically significant (McNemar p < 0.001).ConclusionsmpMRI combined with PSAd provides high sensitivity and negative predictive value for ruling out aggressive prostate cancer, supporting its use as a non‐invasive triage tool in active surveillance. CBx remains the most specific method for histological confirmation. These strategies should be used complementarily to optimise decision‐making in active surveillance protocols.

Abstract Introduction: The purpose of this study is to evaluate the effectiveness of opportunistic salpingectomy (OS), a procedure that aims to remove only the fallopian tubes of general population risk women, for the prevention of epithelial ovarian cancer. Currently, the method of prevention for individuals at high risk of ovarian cancer involves a bilateral salpingo-oophorectomy (BSO), a procedure that removes both the fallopian tubes and ovaries. However, this procedure is not recommended for individuals of the general population, who make up about 80% of ovarian cancers, due to negative health implications to the cardiovascular and skeletal systems because of surgically induced menopause. The effectiveness of the OS in preventing ovarian cancers and how the procedure impacts the histotype distribution of ovarian cancers remains unknown. Study Methods: This study uses a population-based approach and a case-based approach to determine the effectiveness of OS and its impact on histotype distribution, respectively. For the population-based analysis, we will search through clinical databases to acquire cases of individuals who have had an OS and a tumor. A control population who have their fallopian tubes in-tact will also be acquired. A cox-proportional hazard analysis will be performed to determine the effectiveness of the procedure. Using pathological records, the case-based ascertainment of tumors from individuals who have had an OS will be selected and reviewed for histotype confirmation. Fallopian tubes of these patients will also be reviewed for precursor lesions. This cohort will be compared to a historical histotype distribution of ovarian cancers. Results: For the population-based approach, we have to date, identified less than five serous ovarian cancers in individuals who have had an OS (n=40, 477). A comparator surgery was used as a control and showed 21 cancers. For the case-based approach, we have partnered with 23 collaborating institutions from around the world to identify tumors in individuals who have had an OS. We have identified 26 epithelial ovarian cancers, with the most lethal gynecological histotype, high grade serous carcinoma (HGSC), accounting for 23.1% of the total proportion of epithelial ovarian cancer cases (n=6/26). This is significantly less than the historical histotype distribution of HGSC, which is 69.3% (Fisher’s exact test, p&lt;0.0001). One HGSC case had a precursor lesion called a serous tubal intraepithelial carcinoma (STIC) while reviewing fallopian tubes of this individual. TP53 mutation analysis on one HGSC tumor sample showed a frameshift mutation in TP53 (c229fs) with the tumor and the corresponding STIC staining negative for p53 protein expression by immunohistochemistry. Conclusion: This evidence demonstrates the effectiveness of opportunistic salpingectomy for the prevention of ovarian cancer and shows a histotype distribution shift, with the most lethal gynecological malignancy having a significant reduction in cases following the procedure. Citation Format: Ramlogan Sowamber, Alice J. Mei, Paramdeep Kaur, Julianne McLeod, Emily McKay, Alex Lukey, Jamie Bakkum-Gamez, Natalia Buza, Paul Cohen, Kyle Devins, Rhonda Farrell, Christine Garcia, Blake Gilks, Ellen Goode, Anjelica Hodgson, Brooke Howitt, Pei Hui, Jutta Huvila, Anthony Karnezis, Kianoosh Keyhanian, Mary Kinloch, Martin Köbel, Felix KF. Kommoss, Lawrence Kushi, Janice S. Kwon, Kara Long-Roche, Anais Malpica, Jessica N. McAlpine, Dianne Miller, Esther Oliva, Andrea Palicelli, Aleksandra Paliga, Carlos Parra-Herran, Celeste Leigh Pearce, Sharnel Perera, Jurgen M. Piek, Haiyan Qiu, Joseph Rabban, Robert Rome, Miranda Steenbeek, Rebecca Stone, Aline Talhouk, Kristin M. Tischer, Britton Trabert, Penelope M. Webb, John R. Zalcberg, Gillian E. Hanley, David G. Huntsman. Evaluating the effectiveness of opportunistic salpingectomy (OS) for the prevention of epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B045.

ABSTRACT Objective The optimal treatment for neurosarcoidosis myelitis is uncertain. We characterize incident neurosarcoidosis myelitis and assess treatment response by MRI and clinical scales. Methods Incident probable or definite neurosarcoidosis myelitis in adults was retrospectively identified from 13 academic medical centers. Cases were analyzed by initial treatment. The primary outcome was T1 post‐contrast gadolinium enhancement resolution at 6 months post‐treatment. Secondary outcomes were changes in modified Rankin scale (mRS) and Expanded Disability Status Scale (EDSS) from nadir to final follow‐up. Results Two hundred two patients were identified (median diagnosis age: 47 years (IQR 39–55); male: female 1.3:1). Median nadir mRS and EDSS were 2 (IQR 2–3) and 4 (IQR 2.5–6). At initial treatment, 129 (63.9%) received prolonged corticosteroids ≥ 4 weeks (group A 1 ), 36 (17.8%) received corticosteroids < 4 weeks (B 1 ), 21 (10.4%) received corticosteroids plus sarcoidosis‐directed immunosuppressant (E), and 16 (7.9%) received corticosteroids plus non‐sarcoidosis‐directed agents (F). In 167 cases with sufficient imaging, there were no significant differences in contrast enhancement resolution at 6 months (A 1 27/106 (25.5%), B 1 9/28 (32.1%), E 5/19 (26.3%), F 5/14 (35.7%); Fisher's exact p = 0.76). There were no significant differences in changes in mRS or EDSS among treatment groups (Kruskal–Wallis p = 0.69 and 0.63, respectively) after median follow‐up of 46.5 months (IQR 18–91.3). Interpretation Different initial immunosuppression strategies did not correlate with MRI contrast enhancement resolution at 6 months or clinical scales (mRS, EDSS). However, conclusions are limited by retrospective design, imbalanced cohorts, and insensitivity of binary MRI outcomes and available clinical scales for treatment response in neurosarcoidosis.

ImportanceStudies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.ObjectiveTo evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant.Design, Setting, and ParticipantsMulticenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023.InterventionsParticipants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months.Main Outcomes and MeasuresThe primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder.ResultsAmong 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, −0.32; 95% CI, −0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, −0.40; 95% CI, −1.81 to 0.93), meeting the success criterion for safety (noninferiority margin &amp;lt;3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).Conclusions and RelevanceAmong 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection.Trial RegistrationClinicalTrials.gov Identifier: NCT03386539

OBJECTIVE The Centers for Medicare & Medicaid Services (CMS) requires a low C-peptide level for insulin pump coverage unless the individual is β-cell autoantibody positive, which precludes coverage of automated insulin delivery (AID) systems for many people with type 2 diabetes. RESEARCH DESIGN AND METHODS In the Randomized Trial Evaluating the Efficacy and Safety of Control-IQ+ Technology in Adults With Type 2 Diabetes Using Basal-Bolus Insulin Therapy study evaluating the t:slim X2 insulin pump with Control-IQ+ technology, adults with insulin-treated type 2 diabetes were categorized into high C-peptide (n = 195) and low C-peptide (n = 59) groups based on CMS criteria. RESULTS In the AID group, mean HbA1c decreased from baseline by 0.8%, which was significantly greater than in the control group with both high (P &lt; 0.001) and low (P = 0.02) C-peptide levels. Results were similar in participants ≥65 years old. CONCLUSIONS The benefit of AID is present with high and low C-peptide levels. Thus, requiring a low C-peptide level as a prerequisite for AID therapy is not warranted.

Importance Multiparametric magnetic resonance imaging (MRI), with or without prostate biopsy, has become the standard of care for diagnosing clinically significant prostate cancer. Resource capacity limits widespread adoption. Biparametric MRI, which omits the gadolinium contrast sequence, is a shorter and cheaper alternative offering time-saving capacity gains for health systems globally. Objective To assess whether biparametric MRI is noninferior to multiparametric MRI for diagnosis of clinically significant prostate cancer. Design, Setting, and Participants A prospective, multicenter, within-patient, noninferiority trial of biopsy-naive men from 22 centers (12 countries) with clinical suspicion of prostate cancer (elevated prostate-specific antigen [PSA] level and/or abnormal digital rectal examination findings) from April 2022 to September 2023, with the last follow-up conducted on December 3, 2024. Interventions Participants underwent multiparametric MRI, comprising T2-weighted, diffusion-weighted, and dynamic contrast–enhanced (DCE) sequences. Radiologists reported abbreviated biparametric MRI first (T2-weighted and diffusion-weighted), blinded to the DCE sequence. After unblinding, radiologists reported the full multiparametric MRI. Patients underwent a targeted biopsy with or without systematic biopsy if either biparametric MRI or multiparametric MRI was suggestive of clinically significant prostate cancer. Main outcomes and measures The primary outcome was the proportion of men with clinically significant prostate cancer. Secondary outcomes included the proportion of men with clinically insignificant cancer. The noninferiority margin was 5%. Results Of 555 men recruited, 490 were included for primary outcome analysis. Median age was 65 (IQR, 59-70) years and median PSA level was 5.6 (IQR, 4.4-8.0) ng/mL. The proportion of patients with abnormal digital rectal examination findings was 12.7%. Biparametric MRI was noninferior to multiparametric MRI, detecting clinically significant prostate cancer in 143 of 490 men (29.2%), compared with 145 of 490 men (29.6%) (difference, −0.4 [95% CI, −1.2 to 0.4] percentage points; P = .50). Biparametric MRI detected clinically insignificant cancer in 45 of 490 men (9.2%), compared with 47 of 490 men (9.6%) with the use of multiparametric MRI (difference, −0.4 [95% CI, −1.2 to 0.4] percentage points). Central quality control demonstrated that 99% of scans were of adequate diagnostic quality. Conclusion and relevance In men with suspected prostate cancer, provided image quality is adequate, an abbreviated biparametric MRI scan, with or without targeted biopsy, could become the new standard of care for prostate cancer diagnosis. With approximately 4 million prostate MRIs performed globally annually, adopting biparametric MRI could substantially increase scanner throughput and reduce costs worldwide. Trial registration ClinicalTrials.gov Identifier: NCT04571840

Background and importance Emergency airway management in the emergency department (ED) is a high-risk procedure associated with patient outcomes. First-attempt success is a widely recognized quality metric, as multiple attempts are associated with an increased risk of peri-intubation complications. In Brazil, where emergency medicine is a recently established specialty, many ED are staffed by physicians without formal emergency medicine training. The association between emergency medicine training and intubation outcomes in this setting has not been well characterized. Objective To assess the association of physician specialty with first-attempt success and immediate peri-intubation complications in Brazilian EDs. Design Secondary analysis of a multicenter, prospective cohort study from the Brazilian Airway Registry Cooperation. Setting and participants This study included adult patients who underwent tracheal intubation in EDs between March 2022 and April 2024. Patients were excluded if the intubation occurred outside the ED, during cardiopulmonary resuscitation, or for elective procedures. Intubations performed by medical students were also excluded. Physicians were categorized by specialty as emergency medicine or nonemergency medicine. Outcome measures and analysis The primary outcome was first-attempt success; secondary outcomes included peri-intubation complications (severe hypoxemia, hemodynamic instability, and cardiac arrest). Multivariable logistic regression was used to assess the association between physician specialty and outcomes. Main results Among 2582 patients, 1087 (42.1%) were intubated by emergency physicians and 1495 (57.9%) by other physicians (mainly internal medicine and surgery). Intubations by emergency physicians were associated with a higher rate of first-attempt success [80.4 vs. 70.9%, adjusted odds ratio [aOR]: 1.63, 95% confidence interval (CI): 1.34–1.97]. There was also a higher odds of intubations without major complications (aOR: 1.20, 95% CI: 1.01–1.42). Conclusion In this study, there was a higher rate of first-attempt success in intubations performed by board-certified emergency physicians compared with other physicians working in Brazilian EDs.

Objectives To evaluate whether patients with systemic lupus erythematosus (SLE) have different nailfold videocapillaroscopy (NVC) findings compared with healthy controls (HCs) and whether there is an association between NVC abnormalities and disease activity, clinical and/or laboratory features in SLE. Methods This is an observational, multicentre, international, matched case–control study. 381 subjects (203 patients with SLE and 178 HCs) were enrolled from 16 centres in 10 countries. Clinical and laboratory data were collected using ad hoc forms. 5861 NVC images were acquired, coded and uploaded for central blinded analysis. Results A normal NVC pattern was observed in most patients with SLE (86.6%) and, a significantly higher frequency of NVC abnormalities such as enlarged and giant capillaries, microhaemorrhages and irregular nail bed architecture (p<0.001) were found in the remaining patients. Multiple correspondence analysis outlined two NVC patterns, one of which, the more severe (cluster 2), present in 12% of patients, was characterised by a higher prevalence of lower capillary density, abnormally shaped and enlarged capillaries and irregular nail bed architecture. NVC cluster 2 had significantly higher disease activity compared with cluster 1 for both Systemic Lupus Erythematosus Disease Activity Index cut-off points ≥3 and ≥4 (p=0.016 and p=0.028, respectively). SLE with ‘more severe’ NVC pattern (cluster 2) have a significantly higher frequency of arthritis, renal involvement and ongoing glucocorticoid therapy, whereas serositis was significantly associated with ‘less severe’ NVC pattern (cluster 1). Conclusions This study has shown that changes in NVC patterns are associated with important aspects of SLE disease activity. Future prospective studies are needed to further support the use of NVC in SLE monitoring. Trial registration number NCT02801812.

Abstract Background Patients with end-stage heart failure and chronic kidney disease requiring dual-organ transplantation (DOT) face significant challenges in utilizing durable mechanical circulatory support due to the risks associated with renal replacement therapies (RRTs) and multi-organ failure. Given the limited options available for long-term support in this patient population, there remains a critical need for alternative strategies to optimize end-organ function and bridge patients safely to transplant. With prolonged waitlist times for DOT, we present our experience with the Impella 5.5 as temporary mechanical circulatory support, demonstrating its potential to provide hemodynamic stability and support as a bridge to transplantation (BTT) in this complex cohort. Methods A single-centre retrospective review was completed of all patients listed for single-organ transplantation or DOT between December 2019 and November 2022 at Mayo Clinic in Florida, supported by the Impella 5.5 intended as BTT. The focus of this analysis was patients requiring RRT or listed for heart/kidney transplantation. Data were extracted from the electronic health record at baseline and during their transplant episode of care after institutional review board approval as exempt status for retrospective data collection. Results A total of 41 patients were supported with Impella 5.5, intended as BTT. All patients underwent successful transplantation. We focus on the 10 patients with Impella support who underwent DOT. In the DOT group, the median age at transplantation was 63 years (59–66), with nine males and one female. The baseline median ejection fraction was 19% (15–22), with 50% Caucasian and 50% African American and an even split between ischaemic and non-ischaemic aetiology. Median body mass index was 30 kg/m2 (26–31), and 60% were in blood group O. The median time on the waitlist for DOT patients was 53 days (29–75). Perioperative management of DOT Impella patients demonstrated baseline haemodynamics of RA 11 mmHg (7–16), mean PA 36 mmHg (32–47), PCWP 29 mmHg (21–35), mixed venous saturation (SVO2%) 51 (46–61) and Fick CI 2.03 L/min/m2 (1.66–2.5). Post-Impella placement haemodynamics demonstrated significant improvements in RA pressure to 5 mmHg (4–8), P = 0.02, SVO2 to 70% (65–72), P = 0.002, and Fick CI to 5.5 (5.2–8), P = 0.03. The average duration of support was 44 days (range 10–94). The median glomerular filtration rate at baseline was 27 mmol/L (16–29). Twenty-four hour urine protein averaged 168 mg/24 h (range 87–328), with the 24 h creatinine clearance of 29 mg/24 h (range 24–35). Eight of the 10 patients required continuous or intermittent RRT before DOT. The median total duration of RRT (including Impella support) was 36 days (9–72). DOT recipients had a 1 year survival of 90%, with an average follow-up of 432 days. Conclusions Our findings demonstrate that prolonged use of the Impella 5.5 provides safe and effective haemodynamic support for patients with end-stage heart and kidney failure awaiting dual-organ transplantation. With a 1 year survival rate of 90%, our data suggest that Impella 5.5 can be a viable alternative to traditional support strategies, particularly in patients who are otherwise limited by RRTs. As dual-organ transplantation becomes more prevalent, the Impella 5.5 offers a promising bridge to transplant, improving both short-term and long-term outcomes in this complex patient population.