Barriers and Enablers for Physical Activity Engagement Among Individuals From India With Type 2 Diabetes Mellitus: A Mixed-Method Study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a complex, chronic condition that can cause multiple complications due to poor glycemic control. Self-management plays a crucial role in the management of T2DM. Lifestyle modifications, including physical activity (PA), are fundamental for self-management. This study explored the knowledge, perception, practice, enablers, and barriers of PA among individuals with T2DM. METHODS: A mixed-method study was conducted among individuals with T2DM in Udupi taluk, India. A cross-sectional survey (n = 467) followed by an in-depth interview (n = 35) was performed. The data were analyzed using descriptive statistics and thematic analysis, respectively. RESULTS: About half (48.8%) of the participants engaged in PA of which 28.3% had an adequate score in the practice of PA. Walking was the most preferred mode. Self-realization, Comprehension, perception, and source of information, PA training, Current PA practices, enablers and barriers for PA were 6 themes derived under knowledge, perception, and practice of PA. CONCLUSION: Despite knowing the importance of PA, compliance with PA was poor. The personal/internal, societal, and external factors constituted the trinity of barriers and enablers in compliance with PA. Behavioral changes, societal changes, policy initiatives, and PA training in health care settings may enhance PA practice among individuals with T2DM.

Luspatercept stimulates erythropoiesis, increases iron utilization, and redistributes body iron in transfusion-dependent thalassemia.

Luspatercept, a ligand-trapping fusion protein, binds select TGF-ß superfamily ligands implicated in thalassemic erythropoiesis, promoting late-stage erythroid maturation. Luspatercept reduced transfusion burden in the BELIEVE trial (NCT02604433) of 336 adults with transfusion-dependent thalassemia (TDT). Analysis of biomarkers in BELIEVE offers novel physiological and clinical insights into benefits offered by luspatercept. Transfusion iron loading rates decreased 20% by 1.4 g (~7 blood units; median iron loading rate difference: -0.05 ± 0.07 mg Fe/kg/day, p< .0001) and serum ferritin (s-ferritin) decreased 19.2% by 269.3 ± 963.7 µg/L (p < .0001), indicating reduced macrophage iron. However, liver iron content (LIC) did not decrease but showed statistically nonsignificant increases from 5.3 to 6.7 mg/g dw. Erythropoietin, growth differentiation factor 15, soluble transferrin receptor 1 (sTfR1), and reticulocytes rose by 93%, 59%, 66%, and 112%, respectively; accordingly, erythroferrone increased by 51% and hepcidin decreased by 53% (all p < .0001). Decreased transfusion with luspatercept in patients with TDT was associated with increased erythropoietic markers and decreasing hepcidin. Furthermore, s-ferritin reduction associated with increased erythroid iron incorporation (marked by sTfR1) allowed increased erythrocyte marrow output, consequently reducing transfusion needs and enhancing rerouting of hemolysis (heme) iron and non-transferrin-bound iron to the liver. LIC increased in patients with intact spleens, consistent with iron redistribution given the hepcidin reduction. Thus, erythropoietic and hepcidin changes with luspatercept in TDT lower transfusion dependency and may redistribute iron from macrophages to hepatocytes, necessitating the use of concomitant chelator cover for effective iron management.

Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial. METHODS: The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2-6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting). FINDINGS: Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69-80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8-37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) versus epoetin alfa (27 weeks [19-55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment). INTERPRETATION: In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups. FUNDING: Celgene and Acceleron Pharma.

Health-related quality of life in patients with ß-thalassemia: Data from the phase 3 BELIEVE trial of luspatercept.

BACKGROUND: Patients with transfusion-dependent (TD) ß-thalassemia require long-term red blood cell transfusions (RBCTs) that lead to iron overload, impacting health-related quality of life (HRQoL). METHODS: The impact of luspatercept, a first-in-class erythroid maturation agent, versus placebo on HRQoL of patients with TD ß-thalassemia was evaluated in the phase 3 BELIEVE trial. HRQoL was assessed at baseline and every 12 weeks using the 36-item Short Form Health Survey (SF-36) and Transfusion-dependent Quality of Life questionnaire (TranQol). Mean change in HRQoL was evaluated from baseline to week 48 for patients receiving luspatercept + best supportive care (BSC) and placebo + BSC and between luspatercept responders and non-responders. RESULTS: Through week 48, for both groups, mean scores on SF-36 and TranQol domains were stable over time and did not have a clinically meaningful change. At week 48, more patients who achieved clinical response (≥50% reduction in RBCT burden over 24 weeks) in the luspatercept + BSC group had improvement in SF-36 Physical Function compared with placebo + BSC (27.1% vs. 11.5%; p = .019). CONCLUSIONS: Luspatercept + BSC reduced transfusion burden while maintaining patients' HRQoL. HRQoL domain improvements from baseline through 48 weeks were also enhanced for luspatercept responders.

Psychometric evaluation of the NTDT-PRO questionnaire for assessing symptoms in patients with non-transfusion-dependent beta-thalassaemia.

OBJECTIVES: The non-transfusion-dependent beta-thalassaemia-patient-reported outcome (NTDT-PRO) questionnaire was developed for assessing anaemia-related tiredness/weakness (T/W) and shortness of breath (SoB) among patients with NTDT. Psychometric properties were evaluated using blinded data from the BEYOND trial (NCT03342404). DESIGN: Analysis of a phase 2, double-blind, randomised, placebo-controlled trial. SETTING: USA, Greece, Italy, Lebanon, Thailand and the UK. PARTICIPANTS: Adults (≥18 years) (N=145) with NTDT who had not received a red blood cell transfusion within 8 weeks prior to randomisation, with mean baseline haemoglobin level ≤100 g/L. MEASURES: NTDT-PRO daily scores from baseline until week 24, and scores at select time points for the 36-Item Short Form Health Survey version 2 (SF-36v2), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Patient Global Impression of Severity (PGI-S). RESULTS: Cronbach's alpha at weeks 13-24 was 0.95 and 0.84 for the T/W and SoB domains, respectively, indicating acceptable internal consistency reliability. Among participants self-reporting no change in thalassaemia symptoms via the PGI-S between baseline and week 1, intraclass correlation coefficients were 0.94 and 0.92 for the T/W and SoB domains, respectively, indicating excellent test-retest reliability. In a known-groups validity analysis, least-squares mean T/W and SoB scores at weeks 13-24 were worse in participants with worse scores for the FACIT-F Fatigue Subscale (FS), SF-36v2 vitality or PGI-S. Indicating responsiveness, changes in T/W and SoB domain scores were moderately correlated with changes in haemoglobin levels, and strongly correlated with changes in SF-36v2 vitality, FACIT-F FS, select FACIT-F items and the PGI-S. Improvements in least-squares mean T/W and SoB scores were higher in participants with greater improvements in scores on other PROs measuring similar constructs. CONCLUSIONS: The NTDT-PRO demonstrated adequate psychometric properties to assess anaemia-related symptoms in adults with NTDT and can be used to evaluate treatment efficacy in clinical trials.

Long-term safety and erythroid response with luspatercept treatment in patients with ß-thalassemia.

Background: ß-thalassemia is a hereditary blood disorder resulting in ineffective erythropoiesis and anemia. Management of anemia with regular blood transfusions is associated with complications including iron overload. Here, we report long-term safety and efficacy results of the first clinical study of luspatercept in ß-thalassemia, initiated in 2013, enrolling adults with both nontransfusion-dependent (NTD) and transfusion-dependent (TD) ß-thalassemia. Objectives: The objective was to report long-term safety data, for up to 5 years of treatment, for 64 patients with TD or NTD ß-thalassemia, and long-term efficacy data for a subset of 63 patients with ß-thalassemia who received high-dose luspatercept (0.6-1.25 mg/kg): 31 NTD and 32 TD patients. Design: The study was a phase 2, noncontrolled, open-label trial comprising a dose-finding base phase and a 5-year extension phase. Methods: Endpoints include safety; erythroid response over a continuous 12-week period [NTD: hemoglobin increase from baseline ⩾1.0 or ⩾1.5 g/dl; TD: red blood cell (RBC) transfusion burden reduction, ⩾20%, ⩾33%, or ⩾50%]; and changes in biomarkers of ineffective erythropoiesis, iron metabolism parameters, Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) scores, and 6-min walking distance. Results: Median duration of luspatercept exposure for NTD and TD patients was 910 days (range, 40-1850) and 433 days (range, 21-1790), respectively. Seventeen of 31 (54.8%) NTD patients achieved a mean hemoglobin increase of ⩾1.5 g/dl and 19 of 32 (59.4%) TD patients achieved ⩾50% reduction in RBC transfusion burden, during any continuous 12-week period. Median cumulative duration of response was 1126 days (range, 127-1790) for NTD patients and 909 days (range, 87-1734) for TD patients. The most common treatment-related adverse events of any grade were bone pain, headache, and myalgia. Conclusion: Long-term assessment of patients with ß-thalassemia showed luspatercept was associated with sustained increases in hemoglobin levels in NTD patients and sustained transfusion burden reductions in TD patients. Trial registration: (ClinicalTrials.gov Identifiers: NCT01749540 and NCT02268409). Plain Language Summary: Long-term safety and erythroid response with luspatercept treatment in patients with ß-thalassemia Background: ß-thalassemia is a genetic blood disorder caused by mutations in the ß-globin gene, which encodes one of the proteins that comprise hemoglobin, a key constituent of red blood cells. Patients with ß-thalassemia experience anemia, the main treatment for which is blood transfusions. Long-term repeated blood transfusions lower patients' quality of life, use hospital resources, and the resulting accumulation of excess iron can cause organ failure and decrease life expectancy. The severity of the anemia experienced by patients with ß-thalassemia varies; patients with transfusion-dependent ß-thalassemia require regular blood transfusions, compared with those with nontransfusion-dependent ß-thalassemia who require infrequent transfusions, or even none at all, to manage their symptoms. Luspatercept (Reblozyl®) is an agent that stimulates the production of red blood cells and is used to treat anemia caused by ß-thalassemia. However, the long-term effects of luspatercept treatment on patients with ß-thalassemia are not known.Objective: In this study, we report the long-term safety of luspatercept in 64 adult patients with either transfusion-dependent or nontransfusion-dependent ß-thalassemia, and the long-term efficacy of high-dose luspatercept (0.6-1.25 mg/kg) in a subset of 63 patients.Results: The average time period that patients were treated with luspatercept was 910 days for nontransfusion-dependent ß-thalassemia and 433 days for transfusion-dependent ß-thalassemia. We report that in patients with nontransfusion-dependent ß-thalassemia, luspatercept treatment was associated with sustained increases, just over 3 years, in hemoglobin levels. Likewise, in transfusion-dependent ß-thalassemia, luspatercept treatment was associated with a sustained reduction, 2.5 years, in the amount of blood transfusion required to manage their anemia. Long-term treatment with luspatercept was not associated with any new side effects compared with previous short-term treatment studies. The most common side effects were headache (27 patients), bone pain (20 patients), and muscle pain (14 patients) with more than 90% of these patients experiencing these side effects as mild severity.Conclusion: The results of this study show that in patients with either transfusion-dependent or nontransfusion-dependent ß-thalassemia, luspatercept provides lasting reduction in anemia with mostly mild and predictable side effects.

Receptor for Advanced Glycation End Product, Organ Crosstalk, and Pathomechanism Targets for Comprehensive Molecular Therapeutics in Diabetic Ischemic Stroke.

Diabetes mellitus, a well-established risk factor for stroke, is related to higher mortality and poorer outcomes following the stroke event. Advanced glycation end products(AGEs), their receptors RAGEs, other ligands, and several other processes contribute to the cerebrovascular pathomechanism interaction in the diabetes-ischemic stroke combination. Critical reappraisal of molecular targets and therapeutic agents to mitigate them is required to identify key elements for therapeutic interventions that may improve patient outcomes. This scoping review maps evidence on the key roles of AGEs, RAGEs, other ligands such as Leukotriene B4 (LTB4), High-mobility group box 1 (HMGB1) nuclear protein, brain-kidney-muscle crosstalk, alternate pathomechanisms in neurodegeneration, and cognitive decline related to diabetic ischemic stroke. RAGE, HMGB1, nitric oxide, and polyamine mechanisms are important therapeutic targets, inflicting common consequences of neuroinflammation and oxidative stress. Experimental findings on a number of existing-emerging therapeutic agents and natural compounds against key targets are promising. The lack of large clinical trials with adequate follow-up periods is a gap that requires addressing to validate the emerging therapeutic agents. Five therapeutic components, which include agents to mitigate the AGE-RAGE axis, improved biomarkers for risk stratification, better renal dysfunction management, adjunctive anti-inflammatory-antioxidant therapies, and innovative neuromuscular stimulation for rehabilitation, are identified. A comprehensive therapeutic strategy that features all the identified components is needed for outcome improvement in diabetic stroke patients.

Luspatercept for the treatment of anaemia in non-transfusion-dependent ß-thalassaemia (BEYOND): a phase 2, randomised, double-blind, multicentre, placebo-controlled trial.

BACKGROUND: In patients with non-transfusion-dependent ß-thalassaemia, haemoglobin concentrations lower than 10 g/dL are associated with a higher risk of morbidity, mortality, and impaired quality of life. No drugs are specifically approved for anaemia management in patients with non-transfusion-dependent ß-thalassaemia, other than transfusion therapy administered infrequently in accordance with patients' needs. We assessed the efficacy and safety of luspatercept versus placebo in patients with non-transfusion-dependent ß-thalassaemia. METHODS: We did a phase 2, randomised, double-blind, multicentre, placebo-controlled trial in 12 centres in six countries (Thailand [n=1], Lebanon [n=1], Greece [n=2], Italy [n=5], the UK [n=1], and the USA [n=2]). Eligible patients were aged 18 years or older, had confirmed diagnosis of ß-thalassaemia or haemoglobin E/ß-thalassaemia (concomitant α-globin deletion, mutation, or duplication were allowed), and a baseline haemoglobin concentration of 10·0 g/dL or lower. All patients were non-transfusion-dependent. Patients were randomly assigned (2:1) to luspatercept or placebo using an interactive response technology system and stratified by baseline haemoglobin concentration (≥8·5 g/dL vs <8·5 g/dL) and baseline Non-Transfusion-Dependent ß-thalassaemia-Patient-Reported Outcome Tiredness/Weakness domain score (≥3 vs <3). All patients, study site staff, and sponsor representatives (who reviewed the data), except for designated individuals, were masked to drug assignment until the time the study was unblinded. Luspatercept or placebo was given once subcutaneously every 3 weeks for 48 weeks in the double-blind treatment period. Luspatercept was started at 1·0 mg/kg with titration up to 1·25 mg/kg, or reduction in the event of toxicity or excessive haemoglobin concentration increase. The primary endpoint was achievement of an increase from baseline of 1·0 g/dL or higher in mean haemoglobin concentration over a continuous 12-week interval during weeks 13-24, in the absence of transfusions. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03342404, and is ongoing. FINDINGS: Between Feb 5, 2018, and Oct 14, 2019, 160 patients were screened for eligiblity, of whom 145 were randomly assigned to luspatercept (n=96) or placebo (n=49). 82 (57%) patients were female and 63 (43%) were male. 44 (30%) patients were Asian, 87 (60%) were White, and 14 (10%) identified as another race. The study met its primary endpoint: 74 (77%) of 96 patients in the luspatercept group and none in the placebo group had an increase of at least 1·0 g/dL in haemoglobin concentration (common risk difference 77·1 [95% CI 68·7-85·5]; p<0·0001). The proportion of patients with serious adverse events was lower in the luspatercept group than in the placebo group (11 [12%] vs 12 [25%]). Treatment-emergent adverse events most commonly reported with luspatercept were bone pain (35 [37%]), headache (29 [30%]), and arthralgia (28 [29%]). No thromboembolic events or deaths were reported during the study. INTERPRETATION: Luspatercept represents a potential treatment for adult patients with non-transfusion-dependent ß-thalassaemia, for whom effective approved treatment options are scarce. FUNDING: Celgene and Acceleron Pharma.

Long-Term Efficacy and Safety of Luspatercept for Anemia Treatment in Patients With Lower-Risk Myelodysplastic Syndromes: The Phase II PACE-MDS Study.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Luspatercept has high clinical activity in patients with transfusion-dependent lower-risk myelodysplastic syndromes (LR-MDS) and ring sideroblasts (RS) relapsed or refractory to erythropoietin. We report long-term luspatercept safety and efficacy in 108 patients with LR-MDS in the PACE-MDS study, including 44 non-RS and 34 non-transfusion-dependent or previously untreated patients. The primary end point was safety. Secondary end points included rates of hematologic improvement (HI) erythroid (HI-E), HI neutrophil, and HI platelet. Exploratory end points included erythropoiesis biomarker quantitation and mutation data. Median duration of luspatercept exposure was 315 days (range, 21-1,934 days). No new safety signals emerged. HI-E was observed in 53.7% of patients, including 36.4% of non-RS and 70.6% of non-transfusion-dependent patients. HI neutrophil and HI platelet were observed in 33.3% and 9.5% of patients, respectively. An almost three-fold increase in bone marrow late to early progenitor cell ratio accompanied HI-E response, irrespective of RS status. Lower baseline erythropoietin levels in non-RS patients (69.6 v 623.3 IU/L; P = .0077) and higher late to early erythroid progenitor cell ratio (10.44 v 4.48; P = .0106) in RS patients were associated with HI-E. This study highlights luspatercept's effects across LR-MDS subtypes, including untreated MDS-RS, serving as a platform for future trials.

Health-Related Quality of Life Outcomes in Patients with Myelodysplastic Syndromes with Ring Sideroblasts Treated with Luspatercept in the MEDALIST Phase 3 Trial.

Patients with myelodysplastic syndromes (MDS) often experience chronic anemia and long-term red blood cell transfusion dependence associated with significant burden on clinical and health-related quality of life (HRQoL) outcomes. In the MEDALIST trial (NCT02631070), luspatercept significantly reduced transfusion burden in patients with lower-risk MDS who had ring sideroblasts and were refractory to, intolerant to, or ineligible for prior treatment with erythropoiesis-stimulating agents. We evaluated the effect of luspatercept on HRQoL in patients enrolled in MEDALIST using the EORTC QLQ-C30 and the QOL-E questionnaire. Change in HRQoL was assessed every 6 weeks in patients receiving luspatercept with best supportive care (+ BSC) and placebo + BSC from baseline through week 25. No clinically meaningful within-group changes and between-group differences across all domains of the EORTC QLQ-C30 and QOL-E were observed. On one item of the QOL-E MDS-specific disturbances domain, patients treated with luspatercept reported marked improvements in their daily life owing to the reduced transfusion burden, relative to placebo. Taken together with previous reports of luspatercept + BSC reducing transfusion burden in patients from baseline through week 25 in MEDALIST, these results suggest luspatercept may offer a treatment option for patients that reduces transfusion burden while providing stability in HRQoL.

Population Pharmacokinetics and Exposure-Response Relationship of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With ß-Thalassemia.

ß-Thalassemia is an inherited blood disorder resulting from defects in hemoglobin production, leading to premature death of red blood cells (RBCs) or their precursors. Patients with transfusion-dependent ß-thalassemia often need lifelong regular RBC transfusions to maintain adequate hemoglobin levels. Frequent transfusions may lead to iron overload and organ damage. Thus, there is a large unmet need for alternative therapies. Luspatercept, a first-in-class erythroid maturation agent, is the first approved therapy in the United States for the treatment of anemia in adult patients with ß-thalassemia who require regular RBC transfusions. The population pharmacokinetics and exposure-response relationship of luspatercept were evaluated in 285 patients with ß-thalassemia. Luspatercept displayed linear and time-invariant pharmacokinetics when administered subcutaneously once every 3 weeks. Body weight was the only clinically relevant covariate of luspatercept clearance, favoring weight-based dosing. Magnitude and frequency of hemoglobin increase, if not influenced by RBC transfusions, was positively correlated with luspatercept area under the serum concentration-time curve (AUC), 0.2-1.25 mg/kg, whereas a significant reduction in RBC units transfused was observed in frequently transfused patients. The probability of achieving ≥33% or ≥50% reduction in RBC transfusion burden was similar across the time-averaged AUC (0.6-1.25 mg/kg), with the 1 mg/kg starting dose sufficient for most early responders (71%-80%). Increasing luspatercept AUC (0.2-1.25 mg/kg) did not increase incidence or severity of treatment-emergent adverse events. These results provide a positive benefit-risk profile for the recommended luspatercept doses (1-1.25 mg/kg) in treating adult patients with ß-thalassemia who require regular RBC transfusions.

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent ß-Thalassemia.

BACKGROUND: Patients with transfusion-dependent ß-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor ß superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent ß-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 µg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent ß-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).

Crestal Bone Loss around Dental Implants: Platform Switching vs Platform Matching-A Retrospective Study.

AIM: The objective of this study was to determine the vertical and horizontal marginal bone levels in platform-switched and platform-matched dental implants. MATERIALS AND METHODS: In the present study, 50 dental implants were placed in 50 patients over a 1-year period. Measurement was performed from the implant shoulder to the most apical and horizontal marginal defect by periapical radiographs to examine the changes of peri-implant alveolar bone before and 12 months after prosthodontic restoration delivery. RESULTS: These marginal bone measurements showed a bone gain of 0.53 ± 0.98 mm in the vertical gap and 0.52 ± 0.93 mm in the horizontal gap of the platform matching, while in the platform switching, a bone gain of 1.33 ± 1 mm in the vertical gap (p < 0.05) and 1.60 ± 0.56 mm in the horizontal gap was found. Statistically significant difference was found for bone regeneration in the vertical gap between the two groups (p < 0.05) using t-test with Statistical Package for the Social Sciences (SPSS) statistical test version 17. CONCLUSION: The crestal bone around the implants can be preserved with platform-switching concept and it can be applied in clinical condition. CLINICAL SIGNIFICANCE: The crestal bone around the implants can be preserved with platform-switching concept.

Bisalbuminemia in a Hypothyroid Patient with Diabetes: A Case Report.

Bisalbuminemia is a rarely encountered anomaly characterized by presence of bifid albumin bands or a single widened albumin band in electrophoretogram. Inherited bisalbuminemia is quite rare and inherited as an autosomal dominant form. The acquired form of bisalbuminemia is usually transient and may be observed during long term beta lactam antibiotic therapy, acute pancreatitis, myeloma and nephrotic syndrome. This is a case of bisalbuminemia in 61-year-old diabetic female with hypothyroidism came with acute exacerbation of bronchial asthma.

Phenotypic detection of inducible clindamycin resistance among Staphylococcus aureus isolates by using the lower limit of recommended inter-disk distance.

CONTEXT: Clindamycin is one of the important alternative antibiotics in the therapy of Staphylococcus aureus, particularly in methicillin-resistant S. aureus (MRSA) infections. Inducible clindamycin resistance (iMLS B--inducible Macrolide-Lincosamide-Streptogramin B resistance) is a critical factor in antimicrobial susceptibility testing. AIMS: To know the rate of inducible clindamycin resistance among clinical isolates of Staphylococcus aureus in our hospital by Disk approximation test (D-test) using the average recommended inter-disk distance and comparing the results with that of D-test using the lower limit of recommended inter-disk distance. MATERIALS AND METHODS: A total of 51 erythromycin-resistant and clindamycin-susceptible S. aureus isolates were subjected to disk approximation testing with 21 +/- 1 mm and 15 mm edge-to-edge distance between the clindamycin and erythromycin disks. STATISTICAL METHODS: Z-test levels. RESULTS: Among 51 erythromycin-resistant and clindamycin-susceptible S. aureus isolates, 25 (49%) were recorded as inducible clindamycin resistant by D-test with 21 +/- 1 mm edge-to-edge distance between the clindamycin and erythromycin disks. When we re-tested all the 51 strains by D-test with 15 mm inter-disk distance, we identified 14% more iMLS B strains previously reported as D-test negative. Z-test for MRSA indicates that 15 mm edge-to-edge distance has significant advantage. CONCLUSIONS: Since the incidence of inducible clindamycin resistance is high (63% in our study), accurate identification of inducible clindamycin resistance is important to prevent therapeutic failure in infections caused by these strains. We suggest the use of D-test with 15 mm edge-to-edge inter-disk distance for detecting iMLS B .

Relationship between free iron and glycated hemoglobin in uncontrolled type 2 diabetes patients associated with complications.

Free iron in serum has been found in several disease conditions including diabetes. In the present work, we studied the relationship between free iron, fasting blood glucose (FBG) and glycated haemoglobin (HbA(1c)). Study was carried out on 50 type 2 diabetes cases under poor glycemic control associated with complications, 53 type 2 diabetes cases under good glycemic control and 40 healthy controls. We estimated free iron, both ferrous (Fe(+2)) and ferric (Fe(+3)) form, protein thiols, lipid hydroperoxides, FBG, HbA1c and serum ferritin levels in serum. There was a significant increase in free iron in Fe(+3) state (p <0.01), HbA(1c) (p<0.01), serum ferritin (p<0.01), lipid hydroperoxides (p<0.01) and significant decrease in protein thiols (<0.01) in diabetes cases under poor glycemic control compared to diabetes cases under good glycemic control and healthy controls. Free iron correlated positively with HbA(1c) (p<0.01). Poor glycemic control and increase in glycation of haemoglobin is contributing to the increase in free iron pool which is known to increase oxidant generation.

Urinary protein thiols in different grades of proteinuria.

Total thiol status of plasma, especially thiol groups over protein contributes maximum to the plasma antioxidant status of the body. Serum protein thiols were found to be decreased in various disease conditions including chronic renal failure patients. Only few studies determined the levels of urinary protein thiols in disease conditions. The current study was designed to know the levels of urinary protein thiols in patients with different grades of proteinuria. The study was conducted on urine of 40 healthy controls and 61 cases with proteinuria. Based on proteinuria cases were further divided into two groups; group I - microproteinuria (150-300 mg protein/d), 32 cases, group II - frank proteinuria (>300 mg protein/d), 29 cases. Urinary thiol levels were determined by spectrophotometric method using dithionitrobenzoic acid. A significant decrease (p<0.01) in urinary thiol in group I and group II cases was observed in present study and this decrease was associated with proteinuria.