A systematic review and dose-response meta-analysis on the efficacy of dapagliflozin in patients with type 1 diabetes mellitus.

Formulation of insulin analogs and its delivery are developed in over recent years but glycemic control in most patients with type-1 diabetes mellitus (DM) is not adequate yet. The aim of this meta-analysis is to evaluate the efficacy of dapagliflozin in patients with type-1 DM. The MEDLINE/PubMed, Scopus, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases were searched up to Aug 2020 to identify the potential literature. Random-effects model (DerSimonian and Laird method) was used to estimate the pooled effect size as weighted mean difference (WMD) with 95 % confidence interval (CI). Five randomized placebo-controlled trials with 11 arms were included in the quantitative analysis. The pooled results suggested a significant reduction in glycated hemoglobin A1C (HbA1C; WMD: -0.36 %, 95 % CI: -0.55, -0.18), body weight (WMD: -4.02 kg, 95 % CI: -4.78, -3.25), and total daily insulin dose (TDID; WMD: -10.36 %, 95 % CI: -13.42, -7.29), as well as an increase in 24-h urinary glucose excretion (24-h UGE; WMD: 90.02 g/24-h, 95 % CI: 72.96, 107.09) in dapagliflozin group compared to control group. Dose of dapagliflozin had a significant effect on body weight reduction (Coef = -3.7, p = 0.01) and 24-h UGE (coef = 0.85, p = 0.005). Pooled results of this meta-analysis identified a significant reduction in HbA1c levels, body weight, and TDID, and a substantial increase in 24-h UGE in patients who received dapagliflozin versus placebo.

Clonal Hematopoiesis and Cardiovascular Disease in Patients With Multiple Myeloma Undergoing Hematopoietic Cell Transplant.

Importance: There is a paucity of information on the association between clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular disease (CVD) in patients with cancer, including those with multiple myeloma (MM) undergoing hematopoietic cell transplant (HCT), a population at high risk of developing CVD after HCT. Objective: To examine the association between CHIP and CVD in patients with MM and to describe modifiers of CVD risk among those with CHIP. Design, Setting, and Participants: This was a retrospective cohort study of patients with MM who underwent HCT between 2010 and 2016 at City of Hope Comprehensive Cancer Center in Duarte, California, and had pre-HCT mobilized peripheral blood stem cell (PBSC) products cryopreserved and accessible for CHIP analyses. The study team performed targeted panel DNA sequencing to detect the presence of CHIP (variant allele frequency 2% or more). Main Outcomes and Measures: The primary end point was the 5-year cumulative incidence and risk for developing de novo CVD (heart failure, coronary artery disease, or stroke) after HCT. Results: Of 1036 consecutive patients with MM (580 male [56%]; median age, 60.0 years) who underwent a first autologous HCT, 201 patients had at least 1 CHIP variant (19.4%) and 35 patients had 2 or more variants (3.4%). The 5-year incidence of CVD was significantly higher in patients with CHIP (21.1% vs 8.4%; P < .001) compared with those without CHIP; the 5-year incidence among those with 2 or more variants was 25.6%. In the multivariable model, CHIP was associated with increased risk of CVD (hazard ratio [HR], 2.72; 95% CI, 1.70-4.39), as well as of individual outcomes of interest, including heart failure (HR, 4.02; 95% CI, 2.32-6.98), coronary artery disease (HR, 2.22; 95% CI, 1.06-4.63), and stroke (HR, 3.02; 95% CI, 1.07-8.52). Patients who had both CHIP and preexisting hypertension or dyslipidemia were at nearly 7-fold and 4-fold increased risk of CVD, respectively (reference: no CHIP, no hypertension, or dyslipidemia). Conclusion and Relevance: CHIP was significantly and independently associated with risk of CVD in patients with MM undergoing HCT and may serve as a novel biologically plausible biomarker for CVD in this cohort. Patients with MM and both CHIP and cardiovascular risk factors had an exceptionally high risk of CVD. Additional studies are warranted to determine if cardiovascular preventive measures can reduce CHIP-associated CVD risk.

Monoclonal gammopathies of clinical significance (MGCS): In pursuit of optimal treatment.

Monoclonal gammopathy of clinical significance (MGCS) represents a new clinical entity referring to a myriad of pathological conditions associated with the monoclonal gammopathy of undetermined significance (MGUS). The establishment of MGCS expands our current understanding of the pathophysiology of a range of diseases, in which the M protein is often found. Aside from the kidney, the three main organ systems most affected by monoclonal gammopathy include the peripheral nervous system, skin, and eye. The optimal management of these MGUS-related conditions is not known yet due to the paucity of clinical data, the rarity of some syndromes, and limited awareness among healthcare professionals. Currently, two main treatment approaches exist. The first one resembles the now-established therapeutic strategy for monoclonal gammopathy of renal significance (MGRS), in which chemotherapy with anti-myeloma agents is used to target clonal lesion that is thought to be the culprit of the complex clinical presentation. The second approach includes various systemic immunomodulatory or immunosuppressive options, including intravenous immunoglobulins, corticosteroids, or biological agents. Although some conditions of the MGCS spectrum can be effectively managed with therapies aiming at the etiology or pathogenesis of the disease, evidence regarding other pathologies is severely limited to individual patient data from case reports or series. Future research should pursue filling the gap in knowledge and finding the optimal treatment for this novel clinical category.

Looking beyond VEXAS: Coexistence of undifferentiated systemic autoinflammatory disease and myelodysplastic syndrome.

It has been established that individuals with myelodysplastic syndromes (MDS) have a higher frequency of systemic inflammatory disorders. On the other hand, patients with autoimmune diseases are at increased risk of MDS development. Both diseases can be associated with various genetic lesions and share diverse pathogenetic mechanisms. Recently identified VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, associated with somatic mutations in UBA1, encompasses a range of inflammatory conditions involving multiple organs along with hematological pathologies, including MDS, as well as characteristic bone marrow vacuolization of myeloid and erythroid precursors. This novel syndrome drove further attention to complex associations between MDS and adult-onset inflammatory conditions. The present narrative literature review discusses the clinical presentation, pathophysiology, management of concurrent MDS and systemic inflammatory diseases in parallel to the clinical picture of VEXAS syndrome.

Systemic Inflammation (C-Reactive Protein) in Older Chinese Adults Is Associated with Long-Term Exposure to Ambient Air Pollution.

There is an established association between air pollution and cardiovascular disease (CVD), which is likely to be mediated by systemic inflammation. The present study evaluated links between long-term exposure to ambient air pollution and high-sensitivity C reactive protein (hs-CRP) in an older Chinese adult cohort (n = 7915) enrolled in the World Health Organization (WHO) study on global aging and adult health (SAGE) China Wave 1 in 2008-2010. Multilevel linear and logistic regression models were used to assess the associations of particulate matter (PM) and nitrogen dioxide (NO2) on log-transformed hs-CRP levels and odds ratios of CVD risk derived from CRP levels adjusted for confounders. A satellite-based spatial statistical model was applied to estimate the average community exposure to outdoor air pollutants (PM with an aerodynamic diameter of 10 µm or less (PM10), 2.5 µm or less (PM2.5), and 1 µm or less (PM1) and NO2) for each participant of the study. hs-CRP levels were drawn from dried blood spots of each participant. Each 10 µg/m3 increment in PM10, PM2.5, PM1, and NO2 was associated with 12.8% (95% confidence interval; (CI): 9.1, 16.6), 15.7% (95% CI: 10.9, 20.8), 10.2% (95% CI: 7.3, 13.2), and 11.8% (95% CI: 7.9, 15.8) higher serum levels of hs-CRP, respectively. Our findings suggest that air pollution may be an important factor in increasing systemic inflammation in older Chinese adults.

Managing multiple myeloma in a resource-limited region: Diagnosis and treatment in Armenia.

Multiple myeloma (MM) is the second most common blood cancer in adults leading to 117,000 deaths every year. Major breakthroughs in clinical research of the past decades transformed the diagnosis and treatment of MM improving the survival rates and overall quality of life of patients. Unfortunately, scientific advancements are not distributed equally around the globe leading to disparities in the treatment outcomes between different regions of the world. Management of MM in low- and middle-income countries represents a big challenge for healthcare providers considering the economic, technological, and infrastructural restraints in comparison to developed countries. Many standards of practice, including diagnostic tools and therapeutic regimens, are not available in developing regions of the world. As an example of an upper-middle-income country, Armenia has been witnessing considerable progress in the diagnosis and treatment of MM, including but not limited to the establishment of autologous stem cell transplant (ASCT), accessibility to modern anti-myeloma medications, and improved diagnostic and monitoring workup. Despite significant improvements, there is still a need for refinement in the management of MM. The aim of this review article is to discuss the latest developments and the current diagnosis and treatment of MM in Armenia as an example of a resource-limited region.

USAID Associated with Myeloid Neoplasm and VEXAS Syndrome: Two Differential Diagnoses of Suspected Adult Onset Still's Disease in Elderly Patients.

BACKGROUND: Patients with solid cancers and hematopoietic malignancy can experience systemic symptoms compatible with adult-onset Still's disease (AOSD). The newly described VEXAS, associated with somatic UBA1 mutations, exhibits an overlap of clinical and/or biological pictures with auto inflammatory signs and myelodysplastic syndrome (MDS). OBJECTIVES: To describe a cohort of patients with signs of undifferentiated systemic autoinflammatory disorder (USAID) concordant with AOSD and MDS/chronic myelomonocytic leukemia (CMML) and the prevalence of VEXAS proposed management and outcome. METHODS: A French multicenter retrospective study from the MINHEMON study group also used for other published works with the support of multidisciplinary and complementary networks of physicians and a control group of 104 MDS/CMML. RESULTS: Twenty-six patients were included with a median age at first signs of USAID of 70.5 years with male predominance (4:1). Five patients met the criteria for confirmed AOSD. The most frequent subtypes were MDS with a blast excess (31%) and MDS with multilineage dysplasia (18%). Seven patients presented with acute myeloid leukemia and twelve died during a median follow-up of 2.5 years. Six out of 18 tested patients displayed a somatic UBA1 mutation concordant with VEXAS, including one woman. High-dose corticosteroids led to a response in 13/16 cases and targeted biological therapy alone or in association in 10/12 patients (anakinra, tocilizumab, and infliximab). Azacytidine resulted in complete or partial response in systemic symptoms for 10/12 (83%) patients including 3 VEXAS. CONCLUSIONS: Systemic form of VEXAS syndrome can mimic AOSD. The suspicion of USAID or AOSD in older males with atypia should prompt an evaluation of underlying MDS and assessment of somatic UBA1 mutation.

Ambient air pollution, lung function and COPD: cross-sectional analysis from the WHO Study of AGEing and adult health wave 1.

BACKGROUND: Long-term exposure to ambient air pollution leads to respiratory morbidity and mortality; however, the evidence of the effect on lung function and chronic obstructive pulmonary disease (COPD) in older adult populations is inconsistent. OBJECTIVE: To address this knowledge gap, we investigated the associations between particulate matter (PM), nitrogen dioxide (NO2) exposure and lung function, as well as COPD prevalence, in older Chinese adults. METHODS: We used data from the WHO Study on global AGEing and adult health (SAGE) China Wave 1, which includes 111 693 participants from 64 townships in China. A cross-sectional analysis explored the association between satellite-based air pollution exposure estimates (PM with an aerodynamic diameter of ≤10 µm [PM10], ≤2.5 µm [PM2.5] and NO2) and forced expiratory volume in one second (FEV1), forced vital capacity (FVC), the FEV1/FVC ratio and COPD (defined as post-bronchodilator FEV1/FVC <70%). Data on lung function changes were further stratified by COPD status. RESULTS: Higher exposure to each pollutant was associated with lower lung function. An IQR (26.1 µg/m3) increase in PM2.5 was associated with lower FEV1 (-71.88 mL, 95% CI -92.13 to -51.64) and FEV1/FVC (-2.81 mL, 95% CI -3.37 to -2.25). For NO2, an IQR increment of 26.8 µg/m3 was associated with decreases in FEV1 (-60.12 mL, 95% CI -84.00 to -36.23) and FVC (-32.33 mL, 95% CI -56.35 to -8.32). A 31.2 µg/m3 IQR increase in PM10 was linked to reduced FEV1 (-8.86 mL, 95% CI -5.40 to 23.11) and FEV1/FVC (-1.85 mL, 95% CI -2.24 to -1.46). These associations were stronger for participants with COPD. Also, COPD prevalence was linked to higher levels of PM2.5 (POR 1.35, 95% CI 1.26 to 1.43), PM10 (POR 1.24, 95% CI 1.18 to 1.29) and NO2 (POR 1.04, 95% CI 0.98 to 1.11). CONCLUSION: Ambient air pollution was associated with lower lung function, especially in individuals with COPD, and increased COPD prevalence in older Chinese adults.