Citations

Abstract Background Healthy aging and cognitive decline in Alzheimer's Disease (AD) and its precursor, Mild Cognitive Impairment (MCI), are linked to changes in resting‐state EEG power spectral density (PSD). Theta band (3‐7 Hz) power decreases with normal aging but increases with cognitive decline. However, frequency content does not always indicate true oscillatory activity. Oscillations reflect power concentration at a specific frequency, appearing as peaks in the frequency domain and visible rhythms in the time domain. Rhythmicity analysis quantifies oscillation persistence (percentage of time observed) independently of power. This study examined Theta power and Theta rhythms in healthy controls (HC) versus individuals with MCI/AD. Method Participants included 32 AD, 88 MCI, and 115 and age‐ matched HC, who completed 5‐minutes of resting‐state eyes‐closed EEG at their baseline visit. PSD was computed for one‐second epochs. Relative Theta power was defined as the proportion of total power in the Theta band, averaging across epochs. Theta rhythm duration was defined as the percentage of epochs with Theta oscillations. Baseline differences and longitudinal changes were analyzed for a subset of participants: 28 MCI and 5 AD with at least one follow‐up visit, and 25 HC with at least two follow‐ups. Result At baseline, the MCI/AD group exhibited significantly higher relative Theta power ( p <0.01, df=233, ES=0.35 at T6) and a greater Theta rhythm duration ( p <0.01, df=231, ES=0.41 at T6) compared to HC. Longitudinally, HC exhibited a significant reduction in Theta power by the second follow‐up ( p <0.05, df=24, ES=0.51 at Cz), with no significant changes in Theta rhythms duration. In contrast, MCI/AD showed a significant increase in Theta rhythm duration (and not power) at first follow‐up visit ( p < 0.05, df =32, ES=0.30 at T3). Conclusion Theta power and Theta rhythm duration are both linked to cognitive decline in MCI and AD but differ from healthy aging patterns. While Theta power reflects age‐related changes, Theta rhythms duration may serve as a specific biomarker for disease progression in MCI and AD. These findings support the value of Rhythmicity analysis in EEG‐based biomarkers of cognitive decline.

Abstract Background Clinicians’ views on clinical readiness of Alzheimer's disease (AD) blood biomarkers (BBM) are not well understood. Method The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment Biofluid‐Based Biomarkers Professional Interest Area conducted a survey to elicit clinician opinions on AD BBM implementation, including contexts of use, assay selection, reporting and result interpretation. Result Clinician respondents ( n = 212) practiced in Europe (56%), North America (24%), Caribbean and Central or South America (11%) and other continents (9%). Most respondents were medical doctors (80%) practicing in secondary or tertiary care (88%) (Table 1). For 56% of respondents, CSF AD biomarkers or amyloid PET were accessible, but 48% agreed and 52% disagreed with implementation of AD BBM in any clinical context (Table 2). Respondents emphasized the need for data from diverse populations and educational resources to support test interpretation. Conclusion Surveyed clinicians generally agreed with published appropriate use recommendations but were divided on AD BBM readiness for clinical use.

Background: Carriers of a pathogenic variant (PV) in BRCA1 face a high risk of breast cancer. This study estimated the risk of developing breast cancer according to mutation type and location. Methods: BRCA1 carriers with no personal history of breast cancer or bilateral mastectomy were included. Detailed information on clinical and family history was collected by questionnaire. Survival analysis was used to estimate 15-year cumulative risk according to PV type and location. Results: A total of 3677 BRCA1 carriers were followed for a mean of 7.2 years (range 0.1–15.0 years); 481 incident breast cancers were documented. Overall, the 15-year cumulative incidence was 25%. Risk estimates varied by exon, ranging from 9% (exon 21) to 19% (exon 12) to 36% (exon 15); however, strata were small. Carriers of four founder mutations common in Eastern Europe (c.5263_5264insC, c.181T > G, c.66_67delAG and c.4034delA) experienced a lower-than-expected cancer risk (15.9–24.4%) compared to other PVs (28.8%) (p = 0.02). Conclusions: Although our data suggests some variability in penetrance based on specific BRCA1 PV, this was based on a large number of founder mutations. Breast cancer management strategies should continue to be based on comprehensive risk assessment.

ABSTRACT The concentration of cells is a key component of modern blood tests. Given the biomarker potential of extracellular vesicles (EVs) in blood, we aimed to establish reference ranges for blood cell‐derived EVs using flow cytometry. To address the orders‐of‐magnitude variability in reported EV concentrations between different flow cytometers (FCMs), we first validated a calibration methodology to enable reproducible EV concentration measurements. The methodology was evaluated in an interlaboratory comparison study and shows that calibration reduces the median absolute deviation of EV concentrations measured on 25 different FCMs from 67 % to 25 %–31 %. The calibration methodology was then used to determine reference ranges of erythrocyte‐, leukocyte‐, and platelet‐derived EVs in human blood plasma in a cohort of healthy individuals ( n = 224). This study demonstrates that calibration enables comparable concentration measurements of blood cell‐derived EVs, thereby bringing EVs one step closer to clinical applications.

Abstract Background Women with a pathogenic variant in BRCA1 or BRCA2 are at high risk of developing ovarian cancer, and it is often recommended that they undergo bilateral salpingo-oophorectomy at an early age, resulting in surgical menopause. Menopausal hormone replacement therapy (HRT) is an effective way to mitigate the adverse outcomes of early menopause; however, the safety of menopausal HRT on breast cancer risk in this population has not been established. Methods We conducted a prospective matched analysis of HRT use following menopause and breast cancer risk in BRCA carriers. Women who initiated HRT were matched one-to-one with women who had not initiated menopausal HRT by gene, year of birth, and age at menopause, resulting in 676 matched pairs. Menopausal HRT use collected by questionnaire included formulation and mode of administration. Results After a mean of 5.6 years, there were 87 (12.9%) incident breast cancer cases in the 676 exposed women and 128 (18.9%) cases in the 676 unexposed women (P = .002). Compared with unexposed matched control individuals, women who used estrogen alone experienced a statistically significantly decreased risk of breast cancer (hazard ratio = 0.37, 95% CI = 0.24 to 0.57). No protective or adverse effect was associated with the use of estrogen plus progestogen (hazard ratio = 0.94, 95% CI = 0.54 to 1.63). Conclusions Our findings suggest no substantial increase in the risk of breast cancer in BRCA carriers with the use of HRT and that estrogen alone might be protective.

Summary Central obesity is a risk factor for esophageal adenocarcinoma (EAC) independent of acid reflux. However, about a quarter of patients with Barrett’s esophagus (BE) and EAC have a normal body mass index (BMI). One hypothesis is that chronic systemic inflammation is as critical to the cancer pathway than the BMI alone. Therefore, we hypothesized that lean patients with BE/EAC would have a high prevalence of metabolic diseases. We aimed to compare metabolic diseases among lean patients with BE/EAC and overweight/obese BE/EAC and lean control without BE/EAC. We performed a propensity score–matched case–control study including patients with BE/EAC and a control group without BE/EAC from the Rochester Epidemiology Project (REP). The groups were compared using chi-square χ 2 and Student t-test as appropriate. Adjusted logistic regression models were used to compare the association with metabolic diseases. We included a total of 2504 patients (631 EAC, 621 BE, and 1252 controls). A quarter of patients (24.6%) with BE/EAC were lean. When compared to controls without BE/EAC, lean patients with BE were more likely to have diabetes (32.2% vs. 11.2%, P &lt; 0.001) and hyperlipidemia (76.2% vs. 53%, P &lt; 0.001). When comparing lean EAC patients to controls without BE/EAC, lean patients had a higher association with smoking (73.3% vs. 58.6%, P: 0.002) and diabetes (18.7% vs. 11.2%, P: 0.03). When compared to overweight/obese BE patients, lean BE were less likely to have NASH (7.7% vs. 20.3%, P: 0.001), diabetes (32.3% vs. 42.1%, P: 0.03), hyperlipidemia (77.2% vs. 87%, P: 0.003), and metabolic syndrome (24% vs. 54%, P &lt; 0.001). Similarly, when compared to overweight/obese patients with EAC, lean EAC patients were less likely to have NASH (0% vs. 15.5%, P &lt; 0.001), diabetes (18.7% vs. 34.1%, P &lt; 0.001), hyperlipidemia (37.3% vs. 51.8%, P: 0.002), hypertension (37.3% vs. 55.3%, P &lt; 0.001), and metabolic syndrome (8% vs. 37.6%, P &lt; 0.001). A quarter of patients with BE/EAC are lean. Although lean BE/EAC patients have a more favorable metabolic profile compared to overweight/obese BE/EAC patients, diabetes and smoking are more common among lean patients with EAC compared to lean controls. The higher association with smoking and diabetes among lean EAC challenges traditional risk factor paradigms, suggesting a significant role for insulin resistance and chronic inflammation in EAC pathogenesis, especially in patients without typical risk factors. BMI-determined obesity may need to be supplemented with inflammatory metabolic diseases to improve assessment of BE/EAC risk in lean patients.

Background: Endometriosis affects an estimated 10% of reproductive-aged women and is associated with increased ovarian cancer risk. While BRCA1/2 mutations are established risk factors for ovarian cancer, their association with endometriosis remains unclear. This study aimed to characterize the prevalence and clinical features of endometriosis within a large cohort of BRCA mutation carriers. Methods: A descriptive analysis was conducted using data from a multi-center longitudinal cohort of women with pathogenic BRCA variants. Reproductive history and related factors were collected through self-reported questionnaires and compared. Results: Among 16,950 BRCA carriers, the prevalence of endometriosis was 2.4%. Compared to BRCA carriers without endometriosis, those with endometriosis were more likely to carry a BRCA2 mutation, have post-secondary education, and experience earlier menarche. BRCA carriers with endometriosis had a lower ovarian cancer prevalence than those without (10% vs. 15%, p < 0.001). Conclusions: This is the first study of this scale to report the prevalence of endometriosis among BRCA mutation carriers, which was lower than previously reported in the general population. The association between endometriosis and ovarian cancer does not appear to be generalizable to this population. Further prospective studies are warranted to clarify this association among BRCA mutation carriers.

Objective To assess the impact of renal replacement therapy in people with lupus nephritis (LN)–associated end‐stage kidney disease (ESKD) and support the development of the 2024 American College of Rheumatology LN treatment guidelines. Methods We conducted a systematic literature review and meta‐analysis to address three Population, Intervention, Comparison, and Outcome (PICO) questions related to renal replacement therapy for ESKD due to LN, including comparisons of kidney transplant versus dialysis, hemodialysis versus peritoneal dialysis, and preemptive kidney transplant versus no preemptive kidney transplant. Outcomes of interest included mortality, cardiovascular (CV) events, infections, lupus flares, disease‐related damage, graft failure, and quality of life. We conducted a meta‐analysis and analyzed hazard ratios for time‐to‐event analyses and risk ratios for dichotomous outcomes, as well as absolute risk estimates. Results Sixteen comparative observational studies addressed at least one of the three PICO questions. Kidney transplant was found to reduce the risks of all‐cause mortality, CV mortality, infection‐related mortality, and CV events compared with dialysis (high certainty). Dialysis modality (peritoneal vs hemodialysis) was not associated with mortality (high certainty) or with other outcomes of infection, CV complications, and systemic lupus erythematosus flares (low certainty). Preemptive kidney transplant was associated with lower risks of graft failure and mortality (low certainty). Conclusion This systematic review identified improved outcomes with kidney transplant versus dialysis for people with LN‐associated ESKD and potential benefits of preemptive kidney transplant. This evidence supports the use of kidney transplant as a preferred renal replacement therapy for people with LN‐ESKD.

The treatment landscape of invasive early-stage and metastatic breast cancer is evolving constantly. These NCCN Guidelines Insights focus on recent updates included in the most recent version (version 5.2025) of the NCCN Guidelines for Breast Cancer specific to workup, locoregional therapy, surveillance, and systemic neoadjuvant/adjuvant therapy recommendations for invasive, nonmetastatic breast cancer.

Objective To provide evidence‐based and expert guidance for the treatment and management of non‐renal systemic lupus erythematosus (SLE); treatment and management of lupus nephritis are addressed in a separate guideline. Methods Clinical questions for treatment and management of SLE were developed in the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were developed for each PICO question, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess evidence quality and formulate recommendations. The Voting Panel achieved a consensus of ≥70% agreement on the direction (for or against) and strength (strong or conditional) of each recommendation. Results We present recommendations and ungraded, consensus‐based good practice statements for the treatment and management of SLE that are applicable to pediatric and adult patients. Recommendations emphasize uniform treatment with hydroxychloroquine, limiting duration of glucocorticoid use, and early introduction of conventional and/or biologic immunosuppressive therapies to achieve and maintain control of SLE inflammation (remission or a low level of disease activity), reduce SLE‐related morbidity and mortality, and minimize medication‐related toxicities. Conclusion This guideline presents direction regarding treatment and management of SLE and provides a foundation for well‐informed, shared clinician–patient decision‐making. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each person with SLE.