Citations

Abstract Background Data on respiratory syncytial virus (RSV) acute respiratory infection (ARI) among community-dwelling U.S. adults aged 18 to 64 years, particularly those with high-risk conditions (HRC), remain limited. This study estimated incidence and attack rates of RSV-ARI and RSV lower respiratory tract disease (LRTD) in adults with and without HRCs. Methods A multistate, community-based prospective cohort of adults aged 18 to 64 years with and without HRCs was followed from October 2022 to September 2024. Incidence rates and annual attack rates of RSV-ARI and RSV-LRTD were calculated by HRC presence and age group. Results Of 3375 adults with at least 1 HRC, the RSV-ARI incidence rate was 17.9 per 1000 person-years (attack rates: year 1, 1.87%; year 2, 1.56%), compared with 14.8 per 1000 person-years (year 1, 1.33%; year 2, 1.50%) among adults without HRCs. RSV-LRTD incidence was 10.0 per 1000 person-years in adults with HRCs versus 5.7 per 1000 person-years in those without. Asthma, congenital immunodeficiency, and immunosuppressive medication use were associated with increased incidence of RSV-ARI and RSV-LRTD; whereas adults with solid organ transplant and chronic kidney disease had a significantly higher incidence rate of RSV-LRTD compared to those without these conditions. Adults aged 18 to 49 years with HRCs had significantly higher RSV-LRTD incidence (9.6 vs 4.3 per 1000 person-years). After adjustment for age and sex, having ≥1 HRC was associated with a 62% increased RSV-LRTD risk, rising to 117% among adults aged 18 to 49 years. Conclusions Adults with HRCs—particularly asthma, congenital immunodeficiency, chronic kidney disease, immunosuppressive medication use, and solid organ transplant—experienced higher RSV-ARI and RSV-LRTD incidence. The elevated RSV-LRTD burden was most pronounced in adults aged 18 to 49 years with HRCs.

Abstract Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 and CXCR4 mutations, whose prognostic value in patients treated with chemoimmunotherapy remains unclear. Moreover, the typically prolonged progression-free survival (PFS) correlates inconsistently with overall survival (OS), underscoring the importance of examining other surrogates. Progression of disease within 24 months (POD24), an established early end point, delineates functionally high-risk patients in other indolent lymphomas. This international study evaluated 253 patients receiving frontline fixed-duration bendamustine-rituximab (BR), a common chemoimmunotherapy for WM. At a median follow-up of 5.9 years, 5-year PFS and OS were 65% and 87%, respectively; 5-year PFS was similar between MYD88L265P (90%) and MYD88wild-type (WT) subcohorts (64% each; P = .4). Among 89 patients with known CXCR4 status, the subcohort with CXCR4mutation (28%) had shorter PFS (median 3.3 vs 8.8 years; hazard ratio [HR], 2.8; P = .0036) and OS (HR, 2.6; P = .036) compared with CXCR4WT. POD24 occurred in 11.5% of patients who demonstrated inferior subsequent OS (5-year OS, 71% vs 86%; HR, 3.1; P = .005) and higher mortality (standardized mortality ratio [SMR], 3.7), unlike the non-POD24 group, whose mortality was comparable to the matched general population (SMR, 1.1). In conclusion, BR is effective irrespective of the MYD88 status, but CXCR4 mutations and POD24 portend worse outcomes. Patients without POD24 represent a cohort with distinctly favorable outcome.

Abstract Purpose Recognizing the negative impact that antipsychotic-induced movement disorders have on the quality of life and treatment outcomes in bipolar disorder (BD), this study aimed to assess clinical correlates and antipsychotic use patterns of tardive dyskinesia (TD+) in BD. Materials and Methods Participants with and without TD were included. Clinical variables were compared using t-test and χ2 test. Antipsychotic use patterns in TD+, including number of trials, mean doses, and estimated cumulative exposure, were assessed in a case-only analysis. Results The prevalence rate of TD was 5.1%. In comparison to the TD− group (n = 1074), TD+ participants (n = 58) were older, more likely to be female and have type I bipolar illness. There were 60.3% of the TD+ group that continued using antipsychotics at study entry and had a mean cumulative exposure to antipsychotics of 18.2 ± 15.6 years. Average dose, in haloperidol equivalents, was 5.9 ± 3.5 mg and 77.7% of the trials were second-generation antipsychotics. Conclusions This study confirms previously identified TD risk factors, such as age, sex, and bipolar subtype in a large BD cohort. Limitations included a cross-sectional design and the lack of tardive illness severity assessment. As atypical antipsychotics continue to be primary mood stabilization treatment, attempting to harmonize large data sets to identify additional biomarkers of tardive risk will optimize individualized care for patients with BD.

SummaryPatients with asymptomatic/smouldering Waldenström macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow‐up of 9·5 [8·1–11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and β2‐microglobulin (β2M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time‐to‐progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88WT) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7–8·7) vs. 4·7 (2·4–7·7) years for the MYD88L265P cohort, n = 42; P = 0·11]. The presence of C‐X‐C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4WT vs. 5·6 years for CXCR4MUT, P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age‐, sex‐ and calendar year‐matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and β2M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre‐emptive intervention in this patient population.

AbstractAimsLong‐term lithium therapy (LTLT) has been associated with kidney insufficiency in bipolar disorder (BD). We aimed to investigate the risk factors of chronic kidney disease (CKD) development and progression among BD patients receiving LTLT.MethodsWe included adult patients with BD on LTLT (≥1 year) who were enrolled in the Mayo Clinic Bipolar Biobank, Rochester, Minnesota. We reviewed electronic medical records to extract information related to lithium therapy and kidney‐related data to assess changes in the estimated glomerular filtration rate (eGFR). CKD severity was assessed based on eGFR.ResultsAmong 154 patients who received LTLT, 41 patients (27%) developed CKD, of whom 20 (49%) patients continued lithium (continuers) and 19 (46%) discontinued it (discontinuers). The median time to stage 3 CKD development was 21.7 years from the start of Li treatment. Type‐2 diabetes mellitus and benzodiazepine use were independent predictors for CKD development in the survival analysis, after controlling for age. The subsequent CKD progression rate did not differ between continuers and discontinuers (mean GFR 48.6 vs. 44.1, p = 0.13) at the end of follow‐up duration (mean duration: 3.5 ± 4.4 years for continuers and 4.9 ± 5.3 years for discontinuers).ConclusionCKD was observed in one fourth of patients with BD receiving LTLT. There was no significant difference in the progression of CKD among Li continuers versus discontinuers, at the mean follow‐up duration of 4.2 years, after the CKD diagnosis. Progression of CKD could be influenced by existing comorbidities and may not necessarily be due to lithium alone.

Several antiepileptic drugs (AEDs) have US Food and Drug Administration (FDA) approval for use as mood stabilizers in bipolar disorder (BD), but not all BD patients respond to these AED mood stabilizers (AED‐MSs). To identify genetic polymorphisms that contribute to the variability in AED‐MS response, we performed a discovery genome‐wide association study (GWAS) of 199 BD patients from the Mayo Clinic Bipolar Disorder Biobank. Most of these patients had been treated with the AED‐MS valproate/divalproex and/or lamotrigine. AED‐MS response was assessed using the Alda scale, which quantifies clinical improvement while accounting for potential confounding factors. We identified two genome‐wide significant single‐nucleotide polymorphism (SNP) signals that mapped to the THSD7A (rs78835388, P = 7.1E‐09) and SLC35F3 (rs114872993, P = 3.2E‐08) genes. We also identified two genes with statistically significant gene‐level associations: ABCC1 (P = 6.7E‐07; top SNP rs875740, P = 2.0E‐6), and DISP1 (P = 8.9E‐07; top SNP rs34701716, P = 8.9E‐07). THSD7A SNPs were previously found to be associated with risk for several psychiatric disorders, including BD. Both THSD7A and SLC35F3 are expressed in excitatory/glutamatergic and inhibitory/γ‐aminobutyric acidergic (GABAergic) neurons, which are targets of AED‐MSs. ABCC1 is involved in the transport of valproate and lamotrigine metabolites, and the SNPs in ABCC1 and DISP1 with the strongest evidence of association in our GWAS are strong splicing quantitative trait loci in the human gut, suggesting a possible influence on drug absorption. In conclusion, our pharmacogenomic study identified novel genetic loci that appear to contribute to AED‐MS treatment response, and may facilitate precision medicine in BD.

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) is a common pre-malignant plasma cell disorder associated with a 1% per year risk of progression to multiple myeloma or related malignancy. Since the risk factors for MGUS are poorly defined, the goal of the present study was to determine if the risk of MGUS is increased in first degree relatives of patients with known multiple myeloma (MM) or MGUS. Methods: MGUS probands (index cases) were recruited from a population-based prevalence study of MGUS in Olmsted County, MN while MM probands were recruited through the Mayo Clinic practice. Consenting probands were asked to provide contact information on all first-degree relatives ages 40 years and older. Serum samples were then collected from first-degree relatives with informed consent and subjected to agaraose-gel electrophoresis and immunofixation. The prevalence of MGUS in first-degree relatives of MM and MGUS probands was compared to population-based rates from Olmsted County using risk ratios (RR). For comparisons to the reference population, only cases detected by protein electrophoresis and confirmed by immunofixation were included so that the diagnostic strategy was identical in the two groups being compared. Results: Serum samples were obtained from 911 relatives of 329 unique families, including 493 siblings, 324 children and 94 parents of patients with MGUS or MM. Using protein electrophoresis, monoclonal protein was detected in the serum of 55 (6%) while immunofixation identified 28 additional relatives (3%), for an age- and sex-adjusted prevalence rate of 8.1% (95%CI: 6.3, 9.8). The age-specific prevalence of MGUS in first-degree relatives increased with age (1.9%, 6.9%, 11.6%, 14.6%, and 21.0% for ages 40–49, 50–59, 60–69, 70–79 and ≥80, respectively; P<0.001). Based on similar MGUS detection methodology as the reference population, there was a significantly higher risk of MGUS in first-degree relatives (age-adjusted RR, 2.6, 95%CI: 1.9, 3.4) compared to the reference population. The increased risk (P<0.001) was seen both in relatives of MM probands (RR, 2.0, 95%CI: 1.4, 2.8), as well as MGUS probands (RR, 3.3, 95%CI: 2.1, 4.8). This association was similar across age of proband, age and gender of relative, and relationship of the first-degree relative. When examining whether the increased risk of MGUS in relatives was specific to probands with a large monoclonal protein concentration or specific monoclonal immunoglobulin isotype (i.e. high-risk MGUS phenotype), there was suggestion of a greater risk for relatives of probands with a high (3 1.5 g/dL) M-protein (RR, 2.8, 95%CI: 2.0,3.8) compared to lower M-protein levels (RR, 1.8, 95%CI: 1.1,2.8) although the difference did not reach statistical significance (P=0.12). The risk of MGUS in relatives did not differ by proband’s isotype (IgG vs. other). Conclusions: First-degree relatives of patients with MM or MGUS have a greater than two-fold risk of MGUS compared to the general population, implying underlying genetic predisposition for these diseases and providing rationale for identifying genetic determinants of MGUS. This study also provides important baseline rates of MGUS in first-degree relatives that impact the clinical care of these patients.

Abstract Background: Traditionally response to therapy in multiple myeloma (MM) is based on changes in the serum and urine monoclonal protein by immunoelectrophoresis. Immunofixation allows for detection of small amounts of monoclonal protein that cannot be quantitated on immunoelectrophoresis. Serum immunoglobulin free light chain (FLC) assay allows for detection of unbound kappa and lambda free light chain and has allowed disease measurement in patients with oligosecretory myelomas and can potentially allow detection of low levels of tumor burden, below the threshold of the standard tests. We examined this hypothesis in patients who had obtained a negative immunofixation in serum and urine following treatment of their MM. Methods: For the purposes of the study, we included selected patients with MM who had measurable monoclonal (M) protein levels at baseline (defined as >1 gm/dL in the serum or >200 mg/24 hour in the urine or involved free light chain > 10 mg/dL) on protein electrophoresis; patients with non-secretory and oligo-secretory myeloma were excluded. We then identified patients who since 1995 had a negative immunofixation in the serum and urine, all done at the same time (within 30 days of each other). Baseline demographics and clinical characteristics; date of diagnosis, last follow up, and follow up status; serum and urine M protein levels at diagnosis; and results of serum and urine immunofixation, and serum free light chain (FLC) ratio within 30 days of the immunofixation were all collected from the existing databases. Results: Eighty-four patients met the criteria for the study, all of whom had measurable disease at baseline and subsequently achieved negative immunofixation in serum and urine. Among these, 46 patients (55%) also had a normal FLC ratio (K/L ratio; 0.26–1.65). Th median time from diagnosis to the documented immunofixation was 7.5 months (range, 1–157). The median overall survival from diagnosis among those with a normal FLC ratio along with negative immunofixation was not reached compared to 76 months for those with abnormal FLC ratio, P = 0.02. The median overall survival from the documentation of negative immunofixation was not reached for the group with normal FLC ratio compared to 46.5 months for those with an abnormal FLC, P = 0.03. Conclusion: Attainment of a normal FLC ratio at the time of serum and urine immunofixation negative status identifies a group of patients with better outcome. The presence of an abnormal FLC ratio likely represents persistence of the clonal population that is secreting none or very small amounts of monoclonal protein. The data presented here supports the inclusion of FLC measurements as part of response criteria for MM as has been done for the definition of stringent CR in the IMWG response criteria. Figure: Overall survival from diagnosis in patients with or with out a normal FLC ratio at the time of serum and urine immunofixation. Figure:. Overall survival from diagnosis in patients with or with out a normal FLC ratio at the time of serum and urine immunofixation.

Abstract Background: Immunoglobulin free light chains (FLC) form the substrate for synthesis of amyloid fibrils in patients with AL amyloidosis. Development of FLC assay (Freelite) has allowed us to better assess the clonal cell burden in patients with AL amyloid. The relationship of the light chain types and their levels in serum to the clinical feature at presentation and the eventual outcome has not been systematically studied. Methods: We identified 730 patients with biopsy proven AL amyloidosis, who were seen at Mayo Clinic between January 1980 and July 2006, who were seen within 90 days of their diagnosis and in whom FLC levels were performed or had stored serum available for analysis. Cardiac biomarkers (cTnT, NT ProBNP) were also performed on stored serum for some of the patients as part of previous studies. Clinical data and follow up status are prospectively collected into the Dysproteinemia database, which was used for the study. Results: The median age of the study population was 63 years (range; 32–90) and 463 patients (63%) were male. The median estimated survival for the entire group was 37 months from diagnosis and the median follow up for the 263 patients (37%) alive at the time of the analysis was 27.8 months (range; 1–177 months). The plasma cell clone was lambda in 528 patients (72%) and kappa in 202 (28%) patients. The median absolute difference between the FLCs was 19.6 mg/dL for the entire group (range; 0.01–2478); for the kappa patients was 29.4 mg/dL (range; 0.01–1359) and for the lambda patients was 18.2 mg/dL (range; 0.03–2478). Kappa AL was associated with more involvement of the GI tract and liver as indicated by higher alkaline phosphatase (1.8 vs. 1.3 fold; P=0.03), higher total bilirubin (0.95 vs. 0.78 mg/dL, P = 0.04) and lower serum carotene (119 vs. 155 ug/dL; P = 0.0002). On the contrary, renal involvement was more in the lambda AL with the 24 hour urinary albumin higher in the lambda AL (2.4 gm vs. 1.4 gm; P = 0.0002) and lower serum albumin (2.77 vs. 2.97 mg/dL; P = 0.001). While there was no difference in the overall survival (OS) between the kappa and lambda AL, the median OS for those without a heavy chain was significantly shorter (12.6 months vs. 29.9 months; P= 0.01) compared to those with a heavy chain identified. There was also a correlation between high FLC difference and degree of organ involvement, especially cardiac. Among the 202 kappa AL patients, the median survival for those with a high FLC difference ( > 29.4 mg/dL) was 13 months vs. 48.8 months for those with low difference (P = 0.001). Similarly among the 528 patients with lambda AL, those with high difference (> 18.2 mg/dL) had a median OS of 9.3 months compared to 33 months for those with low difference (P < 0.0001) (Figure). The FLC difference was independent of the cTnT, NT Pro BNP, uric acid and fold-increase in alkaline phosphatase, all of which were significant in the multivariable analysis. Conclusions: The type of FLC impacts the spectrum of organ involvement, with gastrointestinal involvement observed more frequently with kappa, and renal involvement with lambda FLC. The FLC burden correlates with the degree of organ involvement, and is a significant predictor of overall survival in AL amyloidosis. Lambda FLC exerts similar effect as kappa FLCs, but at lower levels confirming the increased “amyloidogenicity” of lambda FLC. Finally, lack of a chaperone heavy chain is associated with a poorer outcome. Figure 1. Overall survival form diagnosis in patients with high vs. low FLC difference (using median values for cutoffs for kappa and lambda FLC) Figure 1. Overall survival form diagnosis in patients with high vs. low FLC difference (using median values for cutoffs for kappa and lambda FLC)

Abstract Background: In multiple myeloma (MM), a complete response (CR) is defined by the European Group for Blood and Bone Marrow Transplantation (EBMT) and the International Myeloma Working Group (IMWG) Uniform Response Criteria as absence of monoclonal protein in serum and urine by immunofixation (IFE), and a bone marrow (BM) aspirate/biopsy containing <5% plasma cells (PC). This definition of CR is widely adopted in clinical trials, but there is a high degree of non-compliance with the BM requirement. As a result, differences in CR rates across trials can occur not just as a result of treatment efficacy, but also on how rigorously the BM requirement for CR is implemented. Moreover, requiring BM examinations merely to confirm CR is cumbersome in clinical practice. The goal of this study was to determine the added value of BM examinations in patients who can otherwise be considered to be in CR by virtue of a negative IFE in the serum and urine. Methods: For the purpose of the study, we included only patients with MM who had measurable monoclonal (M) protein levels at baseline (defined as >1 gm/dL in the serum and/or >200 mg/24 hour in the urine) on protein electrophoresis; patients with non-secretory and oligo-secretory MM were excluded. We then identified patients who since 1995 had a negative IFE in the serum and urine and a BM aspirate/biopsy, all done at the same time (within 30 days of each other). Baseline demographics and clinical characteristics; date of diagnosis, last follow up, and follow up status; serum and urine M protein levels at diagnosis; and results of serum and urine IFE, serum free light chain (FLC) ratio and BM aspirate/biopsy within 30 days of complete response were all collected from the existing databases. Results: Ninety-five patients met the criteria for the study, all of whom had measurable disease at baseline and subsequently achieved negative IFE in serum and urine (‘IF- CR’). Of these, only 83 patients (87%) met criteria for CR by the EBMT/IMWG criteria with less than 5% PC in the BM; 13% of patients had 5% or more PC despite the apparent IF-CR on serum and urine IFE. In fact, the BM showed 10% or more PC in 5% of IF-CR patients. We then assessed whether a normal serum FLC ratio in addition to negative serum and urine IFE would eliminate the need for a BM biopsy. The additional requirement of the serum FLC ratio to negative IFE was not fully adequate in eliminating false positive CR’s. Among 34 patients who had IF- CR plus a normal serum FLC ratio, only 88% of patients met CR definition with <5% BM PC; 12% had 5% or more PC, and one patient (3%) had 10% or more PC. We studied the survival (from time of diagnosis) of patients who had true CR’s (negative IFE and <5% PC) versus patients who had IF- CR’s but BM had 5% or more PC. Overall survival from diagnosis between the two groups was 10.7 years versus 5.6 years, respectively, P=0.001 (see Figure 1). Conclusions: BM examination is essential to accurately estimate CR. Up to 13% of patients with negative IFE in serum and urine fail to meet the BM requirement. The addition of a normal serum FLC ratio to negative IFE did not significantly reduce the proportion of patients who fail to meet the BM requirement. Based on this study, we recommend that the CR definition in the EBMT and IMWG criteria should not be revised to eliminate the need for BM examination. Moreover, the consistent collection of BM samples is essential for future strategies to evaluate immunophenotypic CR and molecular CR in MM. Figure 1: Kaplan-Meier curve showing survival benefit (in years) of patients in complete response with less than 5% bone marrow plasma cells. Figure 1:. Kaplan-Meier curve showing survival benefit (in years) of patients in complete response with less than 5% bone marrow plasma cells.