Citations

Abstract Background The diagnosis of monoclonal gammopathies relies on the detection of monoclonal immunoglobulins (M-proteins) in serum or urine. Mass-Fix utilizes matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) to detect and quantify M-proteins. This method employs immunoaffinity enrichment using antibodies against heavy chains (HC) and light chains (LC), followed by MS analysis to determine M-protein isotypes. Mass-Fix has also revealed novel M-protein characteristics, including LC glycosylation and fragmentation, facilitated by measuring the mass of LC. LC glycosylation is as an independent risk factor for disease progression of monoclonal gammopathy of undetermined significance (MGUS), while light chain fragments have been postulated as the origin of amyloid light chain (AL) plaques. Since Mass-Fix enriches intact immunoglobulins before dissociating LCs, it potentially enhances fragment detection. However, the precise nature and clinical significance of these fragments remain to be fully elucidated. Methods Mass-Fix serum results from Mayo Clinic patients tested from September 10, 2018, to October 1, 2024, were reviewed for the presence of M-protein and LC fragments. The frequency and the isotype of fragment LC fragments was determined in the M-protein positive cohort (n=15410). Patients diagnosed with either MGUS (n=6996), AL amyloidosis (n=315), or both (n=32) who had positive M-protein results on Mass-Fix, either prior to or within one month after the diagnosis, were included for a retrospective clinical association study of LC fragments and disease. To validate that these fragments were not artifacts of MS analysis, PAGE gel analysis and Western blots were performed using clinical residual serum from 9 patients: 2 IgG/kappa and 3 IgG/lambda patients with detectable LC fragments and 2 IgG/kappa and 2 IgG/lambda patients without fragments. Samples were purified using antibodies against gamma heavy chains and reduced with TCEP prior to gel electrophoresis and Western blot. Results Of the 15410 patients with monoclonal proteins detected by Mass-Fix, 2896 (18.7%) had detectable LC fragments; kappa fragments in 1533 and lambda fragments in 1363. Most often, the fragments were observed in pairs, with combined molecular weight typically equaled that of the full-length monoclonal LC present in the same sample. LC fragments were observed more frequently among patients diagnosed with AL amyloidosis (118/347=34%) compared to those without the diagnosis (685/6996=10%), with an odds ratio of 4.75 (95% CI, 3.75-6.01). PAGE with Coomassie blue staining revealed bands with sizes representing LC fragments in the five M-protein samples with detectable LC fragments on Mass-Fix, while no such bands observed in those without LC fragments. Western blot using anti-kappa or anti-lambda antibodies confirmed the identity of the bands with higher molecular weight as a fragment of LC in each of the IgG/kappa and IgG/lambda samples. Conclusion Mass-Fix is able to discriminate LC fragments from intact LC based on their sizes. The detection of LC fragments with Western blot without ionization suggests a biological origin rather than analytical artifacts from MS. The clinical association study suggests that LC fragments may have utility in increasing the suspicion of AL amyloidosis in M-protein positive patients with LC fragments, potentially facilitating earlier intervention and improving patient outcomes.

Abstract INTRODUCTION In multicenter Alzheimer's disease studies, amyloid positron emission tomography (PET) visual reads are typically performed centrally by a few experts. Incorporating a broader reader network enhances scalability and generalizability. METHODS Ten neuroimaging experts from eight Alzheimer's Disease Research Centers (ADRCs) visually read 180 amyloid PET scans (30 scans and 15 duplicate scans for each of four tracers, imaged across a wide variety of scanners), using preferred reading software without anatomical imaging or quantitation. Scans were classified as elevated or non‐elevated per tracer‐specific criteria. Inter‐ and intra‐rater agreement was assessed. RESULTS Inter‐rater agreement was substantial (Fleiss’ κ = 0.78), with full consensus on 69% of scans. Inter‐rater reliability was substantial to perfect across tracers (Fleiss’ κ = 0.70–0.87). Intra‐rater agreement was substantial to perfect (Cohen's κ = 0.79‐1). Scans with intermediate (10–40 Centiloid) quantitation had lower reader agreement. DISCUSSION A multicenter expert network achieved substantial agreement classifying amyloid PET scans. These scans provide a standard for reader training and reliability assurance in future studies. Highlights Calibration methods ensure reliable amyloid positron emission tomography (PET) visual reads across multiple raters. Substantial agreement is possible across readers using their preferred tools. Agreement is also substantial regardless of the amyloid PET tracer used. Scans with intermediate (10–40 Centiloid) quantitation have lower reader agreement. The calibration set will become a training tool for amyloid PET visual read studies.

Background: Cirrhosis and cirrhosis-related deaths have risen in the United States in recent years. Ascites is a common complication, often requiring large-volume paracentesis (LVP). The American Association for the Study of Liver Diseases (AASLD) recommends the administration of albumin in conjunction with LVP to prevent further complications of cirrhosis. Emerging research in cirrhosis care reveals significant variations in outcomes among different demographics. Therefore, we assessed the use of guideline-adherent albumin and outcomes in U.S. patients undergoing LVPs, particularly at the intersection of race, ethnicity, socioeconomic disparities, and cirrhosis. Methods: This retrospective study utilized Cerner Real World Data to identify adults with cirrhosis and ascites undergoing LVP between January 2016 and June 2022. We assessed albumin utilization patterns across racial and ethnic groups and payor types, and their overall impact on acute kidney injury (AKI)-related hospitalization using an adjusted generalized linear model (aGLM). Results: We identified 736 patients: 301 in the LVP + albumin group and 435 in the LVP-only group. Despite clinical recommendations, only 41% undergoing LVPs received albumin. White patients and commercially insured patients received albumin at higher rates (p=0.042 and p=0.009, respectively). The overall rate of AKI-related admissions within the 30-day post-procedure period was 26%. However, patients who received albumin during LVP had a 36% lower risk of short-term AKI-related hospitalization (OR: 0.64; p=0.03). Conclusions: These findings indicate a potential for broader albumin utilization in U.S. patients with refractory ascites undergoing repeated LVPs to reduce AKI-related admissions.

Abstract Background Physical activity is associated with lower colorectal cancer (CRC) risk, but its association with molecular subtypes defined by genetic and epigenetic alterations of the disease is unclear. Such information may enhance the understanding of the mechanisms related to the benefits of physical activity. Methods Pooled observational (cases: n = 5386; controls: n = 6798; studies n = 5) and genome-wide association data (cases: n = 8178; controls: n = 10 472; studies n = 5) were used. We used multivariable logistic regression models and Mendelian randomization to assess the association between physical activity and the risk of CRC subtypes defined by individual tumor markers (and marker combinations), namely microsatellite instability status, CpG island methylator phenotype status, and BRAF and KRAS mutations. We used case-only analysis to test for differences between molecular subtypes. We applied Bonferroni correction to account for multiple tests. Results In the pooled observational analysis, higher levels of physical activity were associated with lower CRC risk (Obs-per 1SD, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.90 to 0.97), with an association that was stronger in males (Obs-per 1SD, OR = 0.91, 95% CI = 0.87 to 0.96) than in females (Obs-per 1SD, OR = 0.97, 95% CI = 0.91 to 1.03; Pinteraction = .04). Higher physical activity was associated with a lower risk of CRC across all molecular subtypes, especially in males. There was no difference in the associations by subtypes by pooled observational or Mendelian randomization analyses. The findings did not differ by study design, anatomical site, and early or late age onset of CRC. Conclusions Our findings suggest that physical activity is not differentially associated with the 4 major molecular subtypes involved in colorectal carcinogenesis, indicating that its benefits extend broadly across colorectal cancer pathogenesis.

Background: Lithium is a mainstay treatment for bipolar disorder, but its narrow therapeutic index and susceptibility to pharmacokinetic interactions make appropriate monitoring crucial. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, are increasingly prescribed for type 2 diabetes and weight management. Scarce evidence exists on the potential interaction between semaglutide and lithium. Methods: We present 3 cases involving patients on stable lithium regimens who were initiated on semaglutide, reviewing potential mechanisms underlying the interaction between them. Findings: In 2 cases, lithium levels increased significantly, leading to toxicity despite stable renal function and no changes in concurrent medications. In the third case, preemptive reductions in lithium dosage mitigated toxicity, although lithium levels remained higher than anticipated. Mechanistic hypotheses that might contribute to semaglutide-associated elevated lithium levels include altered kidney function, dehydration from reduced oral intake, vomiting, or diarrhea, and delayed gastric emptying. Conclusions: To our knowledge, this is one of the first documented case series describing a potential interaction between semaglutide and lithium in the medical literature. These cases underscore the importance of vigilant monitoring when combining lithium with semaglutide, and potentially other GLP-1 RAs. Baseline renal function, hydration status, and lithium levels should be assessed before initiating semaglutide, and lithium levels should be monitored more frequently during therapy. Clinicians prescribing semaglutide to patients on lithium should exercise caution, monitor for signs of toxicity, and provide appropriate patient education. Further research is needed to elucidate the mechanisms of this potential interaction and its clinical significance.