Nationwide implementation of lenalidomide maintenance in multiple myeloma: A retrospective, real-world study.

Lenalidomide maintenance (LM) has shown benefit in progression-free survival (PFS) and overall survival (OS) in clinical trials. LM is the recommended standard of care in patients with newly diagnosed multiple myeloma (MM) after high-dose melphalan and autologous stem cell transplantation (HDM-ASCT). In Denmark, LM has been approved and publicly funded for all patients treated with HDM-ASCT since June 2019. Patients with newly diagnosed MM treated with their first HDM-ASCT between June 2019 and March 2022 were included and followed until data cut-off in June 2023. To compare outcomes, a historical pre-LM cohort from the Danish MM Registry, consisting of 364 MM patients treated with HDM-ASCT between June 2015 and June 2019, was used. Among 364 patients treated with HDM-ASCT after June 2019, 22.3% received consolidation therapy and 3.7% underwent tandem HDM-ASCT. During follow-up, 297 patients (81.6%) initiated maintenance therapy, with 277 (76.1%) receiving LM. Overall, 145 patients (52.3%) discontinued LM most commonly due to toxicity 75 (51.7%), with fatigue (30.7%), cytopenia (25.3%), and neuropathy (17.3%) being the main reasons. In a 6-month landmark analysis, early discontinuation did not negatively impact PFS or OS. The LM cohort had similar PFS, and OS compared to the pre-LM cohort. The 3-year PFS and OS rates in the LM cohort were 61% and 86%, respectively, while the pre-LM cohort had a 3-year PFS of 55% and a 3-year OS of 89%. In conclusion, the introduction of LM as a nationwide treatment option in Denmark did not lead to improved clinical outcomes.

Lower levels of small HDL particles associated with increased infectious disease morbidity and mortality: a population-based cohort study of 30 195 individuals.

AIMS: Low levels of HDL cholesterol have been associated with increased risk of infectious disease morbidity and mortality. Nuclear magnetic resonance (NMR) spectroscopy permits the measurement of HDL particle count and allows further subclassification according to particle size. We tested the hypothesis that low number of different HDL subfractions is associated with increased infectious disease morbidity and mortality. METHODS AND RESULTS: HDL particle counts were measured using NMR spectroscopy in 30 195 individuals aged 22-99 years from the Copenhagen General Population Study. Using multiple-event Cox regression and cause-specific hazard models, we assessed risk of hospitalizations due to infection and infectious disease-related death, from 2003 through 2018. During follow-up, 9303 individuals had one or more infectious disease events, and 1558 experienced infectious disease-related death. In multifactorial adjusted analyses, low number of small and medium HDL particles was associated with increased risk of any infection and infectious disease-related death, whereas low number of large and extra-large HDL particles was not. A very high number of small and medium HDL particles was also associated with increased risk of any infection, but not with infectious disease-related death. For small and medium HDL particles and compared to individuals in the 91-95th percentile, hazard ratios (HRs) in individuals in the lowest percentile were 2.31 (95% confidence interval: 1.75, 3.05) for any infection and 3.23 (2.08, 5.02) for infectious disease-related death. For the highest percentile, corresponding HRs were 1.36 (1.07, 1.74) and 1.06 (0.57, 1.98), respectively. Individuals in the lowest percentile had increased risk of pneumonia (HR: 1.86; 95% confidence interval: 1.30, 2.65), sepsis (2.17; 1.37, 3.35), urinary tract infection (1.76; 1.17, 2.63), skin infection (1.87; 1.24, 2.81), gastroenteritis (1.78; 1.01, 3.16), and other infections (2.57; 1.28, 5.16). CONCLUSION: Low number of the small HDL particles was associated with increased infectious disease morbidity and mortality.

Low High-Density Lipoprotein Cholesterol and High White Blood Cell Counts: A Mendelian Randomization Study.

OBJECTIVE: Animal studies suggest that HDL (high-density lipoprotein) regulates proliferation and differentiation of hematopoietic stem cells. Using a Mendelian randomization approach, we tested the hypothesis that low HDL cholesterol is associated with high white blood cell counts. Approach and Results: We included 107 952 individuals aged 20 to 100 years from the Copenhagen General Population Study with information on HDL cholesterol, white blood cell counts, and 9 genetic variants associated with HDL cholesterol. In multivariable-adjusted observational analyses, HDL cholesterol was inversely associated with white blood cell counts. On a continuous scale, a 1-mmol/L (39 mg/dL) lower HDL cholesterol was associated with 5.1% (95% CI, 4.7%-5.4%) higher leukocytes, 4.5% (95% CI, 4.0%-4.9%) higher neutrophils, 5.7% (95% CI, 5.3%-6.1%) higher lymphocytes, 5.7% (95% CI, 5.3%-6.2%) higher monocytes, 14.8% (95% CI, 13.9%-15.8%) higher eosinophils, and 3.9% (95% CI, 3.1%-4.7%) higher basophils. In age- and sex-adjusted genetic analyses using the inverse-variance weighted analysis, a 1-mmol/L (39 mg/dL) genetically determined lower HDL cholesterol was associated with 2.2% (95% CI, 0.3%-4.1%) higher leukocytes, 4.3% (95% CI, 1.6%-7.1%) higher lymphocytes, 4.3% (95% CI, 2.6%-6.1%) higher monocytes, and 4.8% (95% CI, 1.2%-8.5%) higher eosinophils. Overall, the genetic associations were robust across sensitivity analyses and replicated using summary statistics from the UK Biobank with up to 350 470 individuals. CONCLUSIONS: Genetic and hence lifelong low HDL cholesterol was associated with high peripheral blood leukocytes, including high lymphocytes, monocytes, and eosinophils. The concordance between observational and genetic estimates and independent replication suggest a potential causal relationship.

No evidence of increased risk of thyroid dysfunction in well treated people living with HIV.

OBJECTIVES: Possible effects of HIV on thyroid function in the modern combination antiretroviral therapy (cART) era are largely unknown. We aimed to investigate the prevalence and associated risk factors of thyroid dysfunction in well treated people living with HIV (PLWH) and matched uninfected controls and to examine whether HIV is independently associated with thyroid dysfunction. DESIGN AND METHODS: Thyroid-stimulating hormone (TSH), free thyroxine, total thyroxine, and free triiodothyronine were measured in 826 PLWH from the Copenhagen co-morbidity in HIV infection (COCOMO) Study and in 2503 matched uninfected controls, and medical treatment for hypothyroidism or hyperthyroidism was recorded. Multinomial logistic regression adjusting for known risk factor was used to examine the association between HIV and thyroid dysfunction and multivariate linear regression to study the association between HIV and serum TSH concentrations. RESULTS: The PLWH were generally well treated, with 95% having undetectable viral replication. Among PLWH and controls 31 (3.8%) and 114 (4.6%) had hypothyroidism, and 7 (0.8%) and 21 (0.8%) had hyperthyroidism, respectively. In adjusted analyses, we found no significant associations between HIV and hypothyroidism OR 0.8 [95% confidence interval (CI) 0.6-1.3], P = 0.40 or between HIV and hyperthyroidism OR 1.1 (95% CI 0.5-2.5), P = 0.91. Furthermore, serum TSH concentration was unrelated to HIV status (P = 0.6). CONCLUSION: There was no difference in the prevalence of hyperthyroidism or hypothyroidism in well treated PLWH compared with uninfected controls. HIV status was not associated with thyroid dysfunction or serum TSH concentration.

Fast neuronal labeling in live tissue using a biocytin conjugated fluorescent probe.

BACKGROUND: Biocytin has found numerous uses as a neuronal tracer, since it shows both antero- and retrograde transport in neuronal tracts. The main advantage of biocytin lies in the comprehensive intracellular distribution of the molecule, and in effective detection using avidin-based reactions. The main drawback is that biocytin cannot be visualized in live tissue. NEW METHOD: We demonstrate that TMR biocytin, a conjugate of biocytin and a rhodamine fluorophore, is an effective neuronal tracer in live tissue when applied by electroporation. RESULTS: The initial fiber transport velocity of TMR biocytin is high-5.4mm/h. TMR biocytin can be used in conjunction with AM calcium dyes to label neuronal somas from distances of several millimetres, and record calcium transients during the course of a few hours. Juxtacellular application of TMR biocytin leads to fast anterograde transport with labeling of local synapses within 10min. TMR biocytin is fixable, stable during methyl salicylate clearing, and can be visualized deep in nervous tissue. COMPARISON WITH EXISTING METHODS: Retrograde labeling with TMR biocytin enables long-range neuronal visualization and concurrent calcium imaging after only a few hours, which is substantially faster than other fluorescence-based tracers. The green emitting Atto 488 biotin is also taken up and transported retrogradely, but it is not compatible with standard green emitting calcium dyes. CONCLUSIONS: TMR biocytin is an attractive neuronal tracer. It labels neurons fast over long distances, and it can be used in conjunction with calcium dyes to report on neuronal activity in retrogradely labeled live neurons.