Since the World Health Organization (WHO) issued guidelines for developing a non-sputum test for active tuberculosis (TB) diagnosis that exhibits similar performance characteristics to sputum-based diagnosis, salivary diagnostic techniques have gained prominence as potential screening tools or adjuncts to existing diagnostics. We searched online databases for studies that looked at salivary diagnostic techniques. Afterwards, duplicates were removed, titles and abstracts were screened, and full-text studies were assessed for eligibility based on inclusion and exclusion criteria. The studies chosen for final analysis underwent a rigorous quality assessment following a QUADAS-2 template, and data were extracted. The primary outcome assessed the difference in mean levels of interleukins between TB+ patients and TB-controls (Hedges’ g). We then conducted two subgroup analyses: the first segregated the control group into healthy patients, and those with other respiratory diseases (ORD), and the second addressed three different interleukins separately (IL-6, IL-5, IL-17). The secondary outcome involved comparing salivary molecular diagnostic assays to WHO guidelines. This study is registered with PROSPERO, CRD42024536884. A total of 17 studies, out of an initial 1010, were chosen for the final analysis, but one was then excluded for being of poor quality. Our meta-analyses for the primary outcome revealed minimal diagnostic potential for interleukins. Our first subgroup analysis showed that interleukins were incapable of differentiating active TB patients from both healthy controls and ORD patients. Our second subgroup analysis showed that IL-17 was reduced in active TB patients. Assessment of the secondary outcome revealed that most studies relied on a GeneXpert MTB/RIF assay on saliva, but none fulfilled WHO guidelines for a non-sputum test. Individual biomarkers currently lack sufficient discriminatory power to definitively distinguish active tuberculosis from healthy individuals or those with other respiratory diseases (ORD), reinforcing the need for multi-biomarker panels. Interleukins may be alternatively used as markers for prognosis, severity, or treatment response. Our findings also suggest that assays are unable to meet WHO guidelines.

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.

Objectives To estimate thresholds for defining meaningful within-patient improvement from baseline to weeks 13–24 and interpreting meaningfulness of between-group difference for the non-transfusion-dependent beta-thalassaemia patient-reported outcome (NTDT-PRO) tiredness/weakness (T/W) and shortness of breath (SoB) scores. A secondary objective was to determine the symptom severity threshold for the NTDT-PRO T/W domain to identify patients with symptomatic T/W.Design Pooled blinded data from the phase 2, double-blind, placebo-controlled, randomised BEYOND trial in NTDT (NCT03342404) were used. Anchor-based analyses supplemented with distribution-based analyses and empirical cumulative distribution function (eCDF) curves were applied. Distribution-based analyses and receiver operating characteristic curves were used to estimate between-group difference and symptomatic thresholds, respectively.Setting Greece, Italy, Lebanon, Thailand, the UK and the USA.Participants Adults (N=145; mean age 39.9 years) with NTDT who were transfusion-free ≥8 weeks before randomisation.Measures Score changes from baseline to weeks 13–24 in PROs used as anchors (correlation coefficient ≥0.3): NTDT-PRO T/W and SoB scores, Patient Global Impression of Severity, Functional Assessment of Chronic Illness Therapy–Fatigue (Fatigue Subscale, item HI12 and item An2) and Short Form Health Survey version 2.Results The eCDF curves support the use of estimates from the improvement by one level group for all anchors to determine the threshold(s) for meaningful within-patient improvement. Mean (median) changes from these groups and estimates from distribution-based analyses suggest that a ≥1-point reduction in the NTDT-PRO T/W or SoB domains represents a clinically meaningful improvement. Meaningful between-group difference threshold ranges were 0.53–1.10 for the T/W domain and 0.65–1.15 for the SoB domain. The optimal symptomatic threshold for the T/W domain (by maximum Youden’s index) was ≥3 points.Conclusions The thresholds proposed may support the use of NTDT-PRO in assessing and interpreting treatment effects in clinical studies and identifying patients with NTDT in need of symptom relief.

Diabetes mellitus has a global impact affecting 422 million individuals and leading to significant health complications. This makes it a pressing global health concern. Present treatments prioritize alleviating symptoms; however, it is imperative to adopt a multitarget strategy. Herbal medicines, which have been historically employed in traditional medicine, have undergone animal experiments to assess their efficacy in reducing or preventing the disease. Known data shows that the phytochemicals found in medicinal plants have anti-hypoglycemic properties. Hence, we review the therapeutic properties of Withania somnifera, Trigonella foenum-graecum, Moringa oliefera, Memmordica charantia and Allium sativa.

Introduction: ESAs are an established treatment (tx) for pts with TD LR-MDS and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L; however, eligible pts often do not respond, or the response duration is limited. Luspatercept is approved in the US and EU to treat anemia due to LR-MDS after ESA failure. The preplanned interim analysis of the phase 3 COMMANDS trial (NCT03682536), comparing luspatercept with epoetin alfa in ESA-naive TD pts with anemia due to LR-MDS (with or without ring sideroblasts [RS]) showed for the first time the superiority of another therapy over ESAs in improving red blood cell transfusion independence (RBC-TI) rates (Platzbecker U, et al. Lancet 2023. doi:10.1016/S0140-6736[23]00874-7). Here we report the full efficacy and safety analysis of the COMMANDS trial. Methods: Eligible pts were ≥ 18 y of age, had Revised International Prognostic Scoring System-defined LR-MDS with < 5% bone marrow blasts, sEPO < 500 U/L, and were TD (received 2-6 RBC U/8 wk for ≥ 8 wk before randomization). Pts were randomized 1:1 to luspatercept (1.0-1.75 mg/kg) subcutaneously (SC) Q3W, or epoetin alfa (450-1050 IU/kg) SC Q1W for ≥ 24 wk and stratified by baseline RBC transfusion burden (< 4 vs ≥ 4 RBC U/8 wk), RS status (RS+ vs RS−), and sEPO (≤ 200 vs > 200 U/L). The primary endpoint was the achievement of RBC-TI ≥ 12 wk with a concurrent mean hemoglobin (Hb) increase ≥ 1.5 g/dL (wk 1-24). Key secondary endpoints (wk 1-24) included achievement of RBC-TI ≥ 12 and for 24 wk and hematologic improvement-erythroid (HI-E) ≥ 8 wk. Other endpoints included duration of RBC-TI ≥ 12 wk, progression to acute myeloid leukemia (AML), and safety. Results: As of Mar 31, 2023, 182 pts were randomized to luspatercept and 181 to epoetin alfa, with a median (range) tx duration of 51.3 (3-196) and 37.0 (1-202) wk and median (range) follow-up of 17.2 (1-46) and 16.9 (0-46) months, respectively. The primary endpoint was achieved by110 (60.4%) pts in the luspatercept arm versus 63 (34.8%) in the epoetin alfa arm ( P < 0.0001). Subgroup analysis of the primary endpoint response showed that response rates achieved with luspatercept versus epoetin alfa, respectively, were greater for SF3B1-mutated and non-mutated pts (Table), greater for pts with baseline sEPO ≤ 200 U/L and with baseline sEPO > 200 to < 500 U/L (Table), and greater for RS+ pts (Table). The response rates were comparable between tx arms for RS− pts (Table). RBC-TI ≥ 12 wk was achieved by 124 (68.1%) and 88 (48.6%) pts in the luspatercept and epoetin alfa arms, respectively, RBC-TI for 24 wk by 87 (47.8%) and 56 (30.9%) pts, and HI-E ≥ 8 wk by 135 (74.2%) and 96 (53.0%) pts. The median (95% CI) duration of RBC-TI ≥ 12 wk was longer with luspatercept versus epoetin alfa (128.1 wk [108.3-not estimable (NE)] versus 89.7 wk [5.9-157.3]; HR, 0.534; Figure), and longer for clinically relevant subgroups, including RS+ and RS−. The median duration of tx was longer in the luspatercept arm compared with the epoetin alfa arm (51.3 versus 37.0 wk). Five (2.7%) and 6 (3.3%) pts in the luspatercept and epoetin alfa arms, respectively, progressed to AML. Overall, 178 (97.8%) and 165 (92.2%) pts receiving luspatercept and epoetin alfa reported tx-emergent adverse events (TEAEs) of any grade; 107 (58.8%) and 88 (49.2%) pts reported grade 3/4 TEAEs, respectively. The most common any-grade TEAEs in either arm (≥ 10% of pts) were diarrhea (17.6% luspatercept vs 14.0% epoetin alfa), COVID-19 (14.8% vs 15.6%), asthenia (13.7% vs 16.2%), and anemia (12.1% vs 10.6%). TEAEs of interest were reported by 105 (57.7%) and 81 (45.3%) pts receiving luspatercept and epoetin alfa, respectively, with asthenia including fatigue, malaise, and lethargy (30.8% vs 24.6%), hypertension (15.9% vs 9.5%), malignancies and premalignant disorders (14.3% vs 12.8%), kidney toxicity (8.8% vs 6.7%), and injection site reactions (6.6% vs 2.2%), occurring in > 5% pts. In both tx arms, rates of on-tx deaths (8.2% for luspatercept and 7.2% for epoetin alfa) and post-tx deaths (13.2% and 13.4%) were similar. Conclusions: Results of this full analysis confirm the findings from the interim analysis; RBC-TI duration and erythroid responses achieved with luspatercept are superior compared with epoetin alfa. Luspatercept safety results were consistent with previous MDS studies. These data show that luspatercept could represent a new standard of care for pts with TD LR-MDS.

Patients with transfusion‐dependent (TD) β‐thalassemia require long‐term red blood cell transfusions (RBCTs) that lead to iron overload, impacting health‐related quality of life (HRQoL).

Background Anaemia is a major health problem worldwide. Global estimates of anaemia burden are crucial for developing appropriate interventions to meet current international targets for disease mitigation. We describe the prevalence, years lived with disability, and trends of anaemia and its underlying causes in 204 countries and territories. Methods We estimated population-level distributions of haemoglobin concentration by age and sex for each location from 1990 to 2021. We then calculated anaemia burden by severity and associated years lived with disability (YLDs). With data on prevalence of the causes of anaemia and associated cause-specific shifts in haemoglobin concentrations, we modelled the proportion of anaemia attributed to 37 underlying causes for all locations, years, and demographics in the Global Burden of Disease Study 2021. Findings In 2021, the global prevalence of anaemia across all ages was 24 center dot 3% (95% uncertainty interval [UI] 23 center dot 9-24 center dot 7), corresponding to 1 center dot 92 billion (1 center dot 89-1 center dot 95) prevalent cases, compared with a prevalence of 28 center dot 2% (27 center dot 8-28 center dot 5) and 1 center dot 50 billion (1 center dot 48-1 center dot 52) prevalent cases in 1990. Large variations were observed in anaemia burden by age, sex, and geography, with children younger than 5 years, women, and countries in sub-Saharan Africa and south Asia being particularly affected. Anaemia caused 52 center dot 0 million (35 center dot 1-75 center dot 1) YLDs in 2021, and the YLD rate due to anaemia declined with increasing Socio-demographic Index. The most common causes of anaemia YLDs in 2021 were dietary iron deficiency (cause-specific anaemia YLD rate per 100 000 population: 422 center dot 4 [95% UI 286 center dot 1-612 center dot 9]), haemoglobinopathies and haemolytic anaemias (89 center dot 0 [58 center dot 2-123 center dot 7]), and other neglected tropical diseases (36 center dot 3 [24 center dot 4-52 center dot 8]), collectively accounting for 84 center dot 7% (84 center dot 1-85 center dot 2) of anaemia YLDs. Interpretation Anaemia remains a substantial global health challenge, with persistent disparities according to age, sex, and geography. Estimates of cause-specific anaemia burden can be used to design locally relevant health interventions aimed at improving anaemia management and prevention. Funding Bill & Melinda Gates Foundation. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

This systematic analysis assesses the total and risk-attributable burden of lip and oral cavity cancer and other pharyngeal cancer for 204 countries and territories and by Socio-demographic Index using 2019 Global Burden of Diseases, Injuries, and Risk Factors Study estimates.

Importance:Lip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning. Objective:To analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates. Evidence Review:The incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019. Findings:In 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia. Conclusions and Relevance:In this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.

Background: Pts with NTDT can develop serious clinical complications due to untreated anemia. While there are no approved treatments (txs) for NTDT-associated anemia, luspatercept tx was shown to decrease transfusion burden and durably increase hemoglobin (Hb) levels in transfusion-dependent β-thalassemia (Cappellini MD, et al. N Engl J Med 2020;382:1219–1231; Taher AT, et al. HemaSphere 2021;5[suppl 2]. Abstract S101). Aims: To report long-term efficacy data from pts with NTDT receiving luspatercept in the BEYOND trial (NCT03342404). Methods: Eligible pts (N=145) had NTDT or HbE/β-thalassemia (defined as 0–5 RBC units transfused in the 24 wk prior to randomization) and Hb levels ≤10 g/dL. Pts were randomized to receive luspatercept (1.0–1.25 mg/kg) or placebo subcutaneously for ≥48 wk. Pt assignment at randomization determined assessment groups: pts randomized to luspatercept were assessed on tx, while pts receiving placebo were assessed up to discontinuation or crossover to luspatercept. Mean change in Hb from baseline was assessed for continuous 12-wk intervals up to wk 144. Erythroid response was defined as mean change in Hb from baseline of ≥1 g/dL, assessed over rolling 12-wk intervals. The incidence of RBC transfusion events and units transfused was assessed. Results: As of Sep 22, 2021, 83 (86.5%) and 16 (32.7%) pts in the luspatercept and placebo arms completed ≥96 wk of tx, respectively; 72 (75.0%) pts in the luspatercept arm completed ≥120 wk of tx. In the luspatercept and placebo arms, the median (range) duration of tx was 150.1 (15.0–185.4) wk and 61.1 (3.0–138.0) wk, respectively. A median (range) of 42.0 (3.0–61.0) and 20.0 (1.0–46.0) doses were received per pt in the luspatercept and placebo arms, respectively. In the luspatercept arm, mean (standard error) Hb change from baseline was 1.28 (0.069) g/dL during wk 1–12 and 1.48 (0.078) g/dL during wk 13–24; the increase was maintained in pts remaining on study across all time points. Hb level improvements from baseline were nominally significant versus placebo at 12-wk intervals assessed up to wk 96 (Figure). The mean (standard deviation [SD]) change from baseline in liver iron content at wk 48 was −0.24 (1.51) mg/g dry weight with luspatercept (n=85). The proportion of pts who had an erythroid response during any 12-wk interval increased from 91.7% (88/96 pts) at the primary data cutoff date (Sep 14, 2020) to 93.8% (90/96 pts) at the current data cutoff date. The proportion of luspatercept arm responders with ≥1 12-wk rolling response increased from 35.2% (31/88 pts) to 61.1% (55/90 pts) between the primary and current data cutoff dates; the mean (SD) total duration of erythroid response in pts with ≥1 12-wk rolling response also increased, from 611.1 (243.3) to 873.1 (363.4) days. A smaller proportion of pts in the luspatercept than the placebo arm (10.4% [10/96 pts] vs 32.7% [16/49 pts]) received ≥2 RBC transfusions during wk 1–96. The mean number of RBC units transfused (0.7 vs 2.2) and transfusion events (0.4 vs 1.3) per pt was lower in the luspatercept than the placebo arm over the same period. The mean number of transfusion units and events per pt remained stable in the luspatercept arm (0.2 units and 0.2 events) during wk 97–144. Summary/Conclusion: Hb levels were sustained and significantly improved in pts with NTDT receiving long-term luspatercept tx. Erythroid response duration was improved with an additional year of luspatercept tx. Few pts required RBC transfusions, with the cumulative incidence of transfusions remaining low and relatively stable through 144 wk.Keywords: Hemoglobin, Clinical trial, Erythroid, beta thalassemia

ABSTRACT Background The study aimed to estimate the attributable burden to kidney dysfunction as a metabolic risk factor in the North Africa and Middle East (NAME) region and its 21 countries in 1990–2019. Methods The data used in this study were obtained from the Global Burden of Diseases (GBD) 2019 study, which provided estimated measures of deaths, disability-adjusted life years (DALYs), and other epidemiological indicators of burden. To provide a better insight into the differences in the level of social, cultural, and economic factors, the Socio-Demographic Index (SDI) was used. Results In the NAME region in 2019, the number of deaths attributed to kidney dysfunction was 296 632 (95% uncertainty interval: 249 965–343 962), which was about 2.5 times higher than in the year 1990. Afghanistan, Egypt, and Saudi Arabia had the highest, and Kuwait, Turkey, and Iran (Islamic Republic of) had the lowest age-standardized rate of DALYs attributed to kidney dysfunction in the region in 2019. Kidney dysfunction was accounted as a risk factor for ischemic heart disease, chronic kidney disease, stroke, and peripheral artery disease with 150 471, 111 812, 34 068, and 281 attributable deaths, respectively, in 2019 in the region. In 2019, both low-SDI and high-SDI countries in the region experienced higher burdens associated with kidney dysfunction compared to other countries. Conclusions Kidney dysfunction increases the risk of cardiovascular diseases burden and accounted for more deaths attributable to cardiovascular diseases than chronic kidney disease in the region in 2019. Hence, policymakers in the NAME region should prioritize kidney disease prevention and control, recognizing that neglecting its impact on other diseases is a key limitation in its management.

Introduction: Kodagu district in India had catastrophic landslides in 2018, the rarest occurrence known to people until 2018. It has become an annual affair radiated to other districts of the Western Ghats range. Aim: To explore landslide survivors' experiences, conventional knowledge, and responses during the emergency relief response. Methods: In the emergency relief response phase, a qualitative study was conducted using the purposive sampling technique of landslide survivors in the Kodagu District. Ninety-nine participants were interviewed in 10 Focus Group Discussions (FGD). The FGDs were audio-recorded, transcribed verbatim and thematically analysed. Results: In this study, 35 males and 64 females participated. All have endured horrifying experiences, and fear of life and social triggers have played an essential role in self-evacuation. The effective group work among the survivors was perceptible. The issues include improper communication of situational information, disruption of road and cellular connectivity, physical and mental health problems, direct and indirect losses, and other cross-cutting themes. Themes have been recognised as Experiencing the Darkness in Life; Disputed Communication; community-managed Immediate Disaster Response; Health Concerns of the Landslide Survivors; and Cross-Cutting Themes. Conclusion: The study concludes that community-driven community-managed evacuation minimised the causalities. The response from the government in the immediate disaster response phase was satisfactory; fear of life and social trigger played a vital role in the self-evacuation, subsequently reducing the casualties. With community participation, disaster planning at the village/ward level would be the way forward for the well-coordinated emergency relief response.

Background Low back pain is highly prevalent and the main cause of years lived with disability (YLDs). We present the most up-to-date global, regional, and national data on prevalence and YLDs for low back pain from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021. Methods Population-based studies from 1980 to 2019 identified in a systematic review, international surveys, US medical claims data, and dataset contributions by collaborators were used to estimate the prevalence and YLDs for low back pain from 1990 to 2020, for 204 countries and territories. Low back pain was defined as pain between the 12th ribs and the gluteal folds that lasted a day or more; input data using alternative definitions were adjusted in a network meta-regression analysis. Nested Bayesian meta-regression models were used to estimate prevalence and YLDs by age, sex, year, and location. Prevalence was projected to 2050 by running a regression on prevalence rates using Socio-demographic Index as a predictor, then multiplying them by projected population estimates. Findings In 2020, low back pain affected 619 million (95% uncertainty interval 554-694) people globally, with a projection of 843 million (759-933) prevalent cases by 2050. In 2020, the global age-standardised rate of YLDs was 832 per 100 000 (578-1070). Between 1990 and 2020, age-standardised rates of prevalence and YLDs decreased by 10 center dot 4% (10 center dot 9-10 center dot 0) and 10 center dot 5% (11 center dot 1-10 center dot 0), respectively. A total of 38 center dot 8% (28 center dot 7-47 center dot 0) of YLDs were attributed to occupational factors, smoking, and high BMI. Interpretation Low back pain remains the leading cause of YLDs globally, and in 2020, there were more than half a billion prevalent cases of low back pain worldwide. While age-standardised rates have decreased modestly over the past three decades, it is projected that globally in 2050, more than 800 million people will have low back pain. Challenges persist in obtaining primary country-level data on low back pain, and there is an urgent need for more high-quality, primary, country-level data on both prevalence and severity distributions to improve accuracy and monitor change. Funding Bill and Melinda Gates Foundation. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Topic: 27. Thalassemias Background: Osteoporosis and osteopenia are common in patients (pts) with β-thalassemia due to bone marrow expansion, chronic anemia, ineffective erythropoiesis, and hormone dysregulation. Reduced bone mineral density (BMD) results in an increased risk of bone fractures. It is therefore crucial that treatments for pts with β-thalassemia do not further worsen BMD. Correction of anemia by transfusion limits bone marrow expansion and may maintain or improve BMD in pts with thalassemia. Luspatercept is an erythroid maturation agent approved in the EU and USA to treat anemia in adult pts with β-thalassemia who require red blood cell (RBC) transfusions. Results from the phase 3, double-blind, randomized, placebo-controlled, multicenter BELIEVE trial (NCT02604433) showed that luspatercept significantly reduced RBC transfusion burden in the first 48 wk of treatment (Cappellini MD, N Engl J Med 2020;382;1219–31), and subsequent analysis has demonstrated durable efficacy (Cappellini MD, HemaSphere 2022;6 [Suppl 3]. Abstract 270). However, the impact of luspatercept on BMD has yet to be assessed. Aims: To evaluate the effect of long-term luspatercept treatment on BMD in pts enrolled in the BELIEVE trial. Methods: Enrolled pts were adults with β-thalassemia or hemoglobin E/β-thalassemia who required RBC transfusions (6–20 RBC units/24 wk prior to randomization, no transfusion-free period >35 days). Pts were randomized 2:1 to receive luspatercept (1.0–1.25 mg/kg) or placebo subcutaneously every 3 wk. BMD of total hip and lumbar spine were assessed using dual-energy X-ray absorptiometry (DXA) and T-scores calculated at baseline and every 48 wk. Data for placebo pts are presented at baseline and wk 48 as most pts had discontinued placebo treatment by wk 96. After study unblinding, data were assessed only for pts who were randomized to luspatercept. Change from baseline was calculated using an ANCOVA model with the geographical region at randomization and baseline measurements as covariates. Results: The BELIEVE trial followed 336 pts from May 2016 to January 2021; 224 pts were randomized to receive luspatercept and 112 to placebo. BMD in the luspatercept arm up to wk 96 remained similar to baseline for hip (mean [standard deviation (SD)] change +0.02 [0.064] g/cm2) and spine (mean [SD] change +0.01 [0.065] g/cm2). BMD for hip and spine were comparable between luspatercept and placebo arms at wk 48 (Figure). Hip T-scores in the luspatercept arm were slightly improved from baseline to wk 96 (mean [SD] change +0.15 [0.437]), whereas spine T-scores remained similar to baseline (Figure). The mean changes from baseline were not significantly different between luspatercept and placebo for any measure at wk 48 (hip BMD least squares mean of difference [95% CI] 0.00 [−0.01 to 0.01], P=0.9201; hip T-score −0.02 [−0.12 to 0.08], P=0.6912; spine BMD −0.01 [−0.02 to 0.01], P=0.4620; spine T-score −0.10 [−0.25 to 0.04]; P=0.1475). BMD remained similar to baseline up to wk 192 of luspatercept treatment (hip mean [SD] change +0.01 [0.080] g/cm2; spine mean [SD] change −0.00 [0.053] g/cm2), as did T-scores (hip mean [SD] change +0.09 [0.537]; spine mean [SD] change +0.19 [0.714]). Summary/Conclusion: After 48 wk of treatment, BMD and T-scores of the hip and lumbar spine were similar to baseline and similar between the luspatercept and placebo arms in pts with β-thalassemia from the BELIEVE trial. With longer-term luspatercept treatment up to wk 192, BMD remained near baseline levels, indicating that patient bone health remained stable with luspatercept treatment. Importantly, BMD did not significantly worsen despite reduced transfusion burden.Keywords: Clinical trial, Thalassemia, Bone mineral density

Background The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to 2019.Methods We collected detailed information on six major causes of IMIDs, including asthma, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, psoriasis, and atopic dermatitis, between 1990 and 2019, derived from the Global Burden of Disease study in 2019. The average annual percent change (AAPC) in number of incidents and age standardized incidence rate (ASR) on IMIDs, by sex, age, region, and causes, were calculated to quantify the temporal trends.Findings In 2019, rheumatoid arthritis, atopic dermatitis, asthma, multiple sclerosis, psoriasis, inflammatory bowel disease accounted 1.59%, 36.17%, 54.71%, 0.09%, 6.84%, 0.60% of overall new IMIDs cases, respectively. The ASR of IMIDs showed substantial regional and global variation with the highest in High SDI region, High-income North America, and United States of America. Throughout human lifespan, the age distribution of incident cases from six IMIDs was quite different. Globally, incident cases of IMIDs increased with an AAPC of 0.68 and the ASR decreased with an AAPC of -0.34 from 1990 to 2019. The incident cases increased across six IMIDs, the ASR of rheumatoid arthritis increased (0.21, 95% CI 0.18, 0.25), while the ASR of asthma (AAPC = -0.41), inflammatory bowel disease (AAPC = -0.72), multiple sclerosis (AAPC = -0.26), psoriasis (AAPC = -0.77), and atopic dermatitis (AAPC = -0.15) decreased. The ASR of overall and six individual IMID increased with SDI at regional and global level. Countries with higher ASR in 1990 experienced a more rapid decrease in ASR.Interpretation The incidence patterns of IMIDs varied considerably across the world. Innovative prevention and integrative management strategy are urgently needed to mitigate the increasing ASR of rheumatoid arthritis and upsurging new cases of other five IMIDs, respectively.Copyright (c) 2023 The Author(s). Published by Elsevier Ltd.

Alpha ( α )-thalassemia hemoglobin H (HbH) disease is a blood disorder in which 3 of the 4 genes encoding α -globin are defective, leading to ineffective erythropoiesis and chronic anemia. Patients (pts) with non-deletional mutations have higher red blood cell (RBC) transfusion and iron chelation therapy (ICT) requirements, and some may become transfusion dependent (TD). Regular RBC transfusions are associated with increased risk of morbidity and mortality, emphasizing the need for effective treatments for anemia

Luspatercept, a ligand-trapping fusion protein, binds select TGF-β 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.

Topic: 10. Myelodysplastic syndromes - Clinical Background: LR-MDS pts who require RBC transfusions experience chronic anemia, increased morbidity, iron overload, and poor overall survival. The current standard tx, erythropoiesis-stimulating agents (ESAs), is suboptimal as many pts are ineligible or have limited and/or transient responses. There is an unmet need for effective tx of anemia due to LR-MDS. Luspatercept is approved in the US and EU to treat anemia in LR-MDS following ESA failure and until now has not been directly compared with ESAs in ESA-naive pts. Aims: To report interim efficacy and safety data from the phase 3, open-label, randomized COMMANDS trial (NCT03682536) comparing luspatercept with epoetin alfa in ESA-naive LR-MDS pts. Methods: Eligible pts were ≥18 y old, had serum erythropoietin (sEPO) <500 U/L, and required RBC transfusions. Pts received subcutaneous luspatercept (1.0–1.75 mg/kg; once every 3 wk) or epoetin alfa (450–1050 IU/kg; weekly) for ≥24 wk. Pts were stratified by baseline (BL) RBC transfusion burden (<4 vs ≥4 RBC U/8 wk), BL sEPO (≤200 vs >200 U/L), and RS status (RS+, RS−). The primary endpoint was the proportion of pts who were RBC transfusion independent (RBC-TI) ≥12 wk with a concurrent mean hemoglobin increase ≥1.5 g/dL during wk 1–24. Secondary endpoints included hematologic improvement-erythroid (HI-E) ≥8 wk, RBC TI 24 wk, and ≥12 wk in wk 1–24, as well as subgroup analyses, impact of MDS-associated gene mutations on response, and safety. Results: 178 pts were randomized to luspatercept and 178 to epoetin alfa (31Aug2022); median tx durations were 41.6 and 27.0 wk, respectively. BL characteristics were balanced between arms. The primary endpoint was achieved by 86/147 (58.5%) luspatercept and 48/154 (31.2%) epoetin alfa pts (P<0.0001; Fig. A); primary endpoint achievement favored luspatercept or was similar to epoetin alfa for all subgroups (Fig. B). Luspatercept tx also favored achievement of HI-E ≥8 wk, RBC-TI 24 wk, and RBC-TI ≥12 wk in wk 1–24 (Fig. A). Median duration of RBC-TI ≥12 wk (wk 1 to end of tx) was longer with luspatercept vs epoetin alfa tx overall (126.6 and 77.0 weeks, respectively), and for clinically relevant subgroups, including RS+ and RS−. Pts with SF3B1, SF3B1α, ASXL1, TET2, DNMT3A, EZH2, IDH2, and U2AF1 mutations also demonstrated favorable luspatercept response vs epoetin alfa (Fig. C). Luspatercept pts had a higher probability of achieving clinical benefit, regardless of overall mutational burden. 164 (92.1%) luspatercept and 150 (85.2%) epoetin alfa pts reported tx-emergent adverse events (TEAEs) of any grade; 8 (4.5%) and 4 (2.3%) pts discontinued tx due to TEAEs. The most common TEAEs (any grade) with luspatercept were fatigue (14.6%), diarrhea (14.6%), and hypertension (12.9%), and with epoetin alfa were asthenia (14.2%), diarrhea (11.4%), and anemia (9.7%). The most common TEAEs in luspatercept pts were mild to moderate, non-serious, and generally did not lead to discontinuation. 4 (2.2%) luspatercept and 5 (2.8%) epoetin alfa pts progressed to AML; overall death rates were similar between arms (32 [18.0%] vs 32 [18.2%], respectively). Summary/Conclusion: Luspatercept demonstrated superiority over epoetin alfa with clinically meaningful improvements in RBC-TI and HI-E rates in ESA-naive LR-MDS pts who require transfusions. Luspatercept showed more favorable outcomes compared to epoetin alfa across a spectrum of known MDS mutations. Luspatercept safety profile was comparable with previous reports; no new safety events were identified. Luspatercept may transform the current landscape by establishing a new standard of tx for ESA-naive pts with transfusion dependent LR-MDS.Keywords: Mutation analysis, Myelodysplastic syndrome, Erythropoieisis, Clinical trial

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.