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In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients’ long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR 4.5 ; BCR-ABL ⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.

SummaryBoth sarcopenia and low bone mineral density (BMD) have become public health concerns. We found that presarcopenic and/or sarcopenic individuals were more likely to have lower BMD. And this relationship has race and sex-specific discrepancy.PurposeThe purpose of the study was to investigate the racial and gender differences in the relationship between sarcopenia and BMD among older adults.MethodsTotally, 5476 subjects (mean age = 65.7 ± 6.4) of non-Hispanic White (n = 3297), non-Hispanic Black (n = 1265), and non-Hispanic Asian (n = 914) were analyzed. Sarcopenia was defined according to the revised European consensus on definition and diagnosis of sarcopenia (EWGSOP2). General linear model and multivariable linear regression model were used to examine the relationship between sarcopenia and regional/whole body BMD stratified by race and sex. Adjustments were conducted for physiological, behavioral, and disease factors.ResultsComparing with normal older participants, presarcopenic and sarcopenic elderly were more likely to have lower BMD. Although the difference was not statistically significant in a few sub-groups, among the three racial groups, the strongest association between sarcopenia and BMD was found in non-Hispanic Black people, followed by non-Hispanic White people and non-Hispanic Asian people. In addition, significant differences of BMD across sarcopenia stages were found in more sub-groups in women than in men after adjusting for covariates.ConclusionsIn this older cohort, sarcopenia is significantly related to low regional/whole-body BMD, and these associations vary by race and sex. Consideration in race and sex is warranted when developing strategies to maintain or minimize BMD loss.

Summary The purpose of the study is to investigate the relationship between sarcopenia and body composition and osteoporosis in cohorts of three different races with a total of 17,891 subjects. Lean mass and grip strength were positively associated with bone mineral densities (BMDs). Subjects with sarcopenia were two times more likely to have osteoporosis compared with normal subjects. Introduction The relationship between sarcopenia and osteoporosis is not totally clear. First, the present study assessed this relationship by using two different definitions for sarcopenia. Second, we examined the associations of body composition (including muscle mass as a major and important component) and muscle strength on regional and whole-body BMDs. Methods In total, 17,891 subjects of African American, Caucasian, and Chinese ethnicities were analyzed. Sarcopenia was defined by relative appendicular skeletal muscle mass (RASM) cut points and also by the definition of the European Working Group on Sarcopenia in Older People (low RASM plus low muscle function). Multiple regression analyses were conducted to examine the association of fat mass, lean mass (including muscle mass), and grip strength with regional and whole-body BMDs. Multivariate logistic regression analysis was performed to explore the association between sarcopenia and osteopenia/osteoporosis. Results BMDs were positively associated with lean mass and negatively associated with fat mass, after controlling for potential confounders. Grip strength was significantly associated with higher BMDs. Each standard deviation (SD) increase in RASM resulted in a ~37 % reduction in risk of osteopenia/osteoporosis (odds ratio (OR) = 0.63; 95 % confidence interval (CI) = 0.59, 0.66). Subjects with sarcopenia defined by RASM were two times more likely to have osteopenia/osteoporosis compared with the normal subjects (OR = 2.04; 95 % CI = 1.61, 2.60). Similarly, subjects with sarcopenia (low muscle mass and low grip strength) were ~1.8 times more likely to have osteopenia/osteoporosis than normal subjects (OR = 1.87; 95 % CI = 1.09, 3.20). Conclusions High lean mass and muscle strength were positively associated with BMDs. Sarcopenia is associated with low BMD and osteoporosis.

Background Accurate and robust pathological image analysis for colorectal cancer (CRC) diagnosis is time-consuming and knowledge-intensive, but is essential for CRC patients’ treatment. The current heavy workload of pathologists in clinics/hospitals may easily lead to unconscious misdiagnosis of CRC based on daily image analyses. Methods Based on a state-of-the-art transfer-learned deep convolutional neural network in artificial intelligence (AI), we proposed a novel patch aggregation strategy for clinic CRC diagnosis using weakly labeled pathological whole-slide image (WSI) patches. This approach was trained and validated using an unprecedented and enormously large number of 170,099 patches, > 14,680 WSIs, from > 9631 subjects that covered diverse and representative clinical cases from multi-independent-sources across China, the USA, and Germany. Results Our innovative AI tool consistently and nearly perfectly agreed with (average Kappa statistic 0.896) and even often better than most of the experienced expert pathologists when tested in diagnosing CRC WSIs from multicenters. The average area under the receiver operating characteristics curve (AUC) of AI was greater than that of the pathologists (0.988 vs 0.970) and achieved the best performance among the application of other AI methods to CRC diagnosis. Our AI-generated heatmap highlights the image regions of cancer tissue/cells. Conclusions This first-ever generalizable AI system can handle large amounts of WSIs consistently and robustly without potential bias due to fatigue commonly experienced by clinical pathologists. It will drastically alleviate the heavy clinical burden of daily pathology diagnosis and improve the treatment for CRC patients. This tool is generalizable to other cancer diagnosis based on image recognition.

SummaryBy adopting the extension approaches of Mendelian randomization, we successfully detected and prioritized the potential causal risk factors for BMD traits, which might provide us novel insights for treatment and intervention into bone-related complex traits and diseases.IntroductionOsteoporosis (OP) is a common metabolic skeletal disease characterized by reduced bone mineral density (BMD). The identified SNPs for BMD can only explain approximately 10% of the variability, and very few causal factors have been identified so far.MethodsThe Mendelian randomization (MR) approach enables us to assess the potential causal effect of a risk factor on the outcome by using genetic IVs. By using extension methods of MR—multivariable MR (mvMR) and MR based on Bayesian model averaging (MR-BMA)—we intend to estimate the causal relationship between fifteen metabolic risk factors for BMD and try to prioritize the most potential causal risk factors for BMD.ResultsOur analysis identified three risk factors T2D, FG, and HCadjBMI for FN BMD; four risk factors FI, T2D, HCadjBMI, and WCadjBMI for FA BMD; and three risk factors FI, T2D, and HDL cholesterol for LS BMD, and all risk factors were causally associated with heel BMD except for triglycerides and WCadjBMI. Consistent with the mvMR results, MR-BMA confirmed those risk factors as top risk factors for each BMD trait individually.ConclusionsBy combining MR approaches, we identified the potential causal risk factors for FN, FA, LS, and heel BMD individually and we also prioritized and ranked the potential causal risk factors for BMD, which might provide us novel insights for treatment and intervention into bone-related complex traits and diseases.

The single-arm, phase 2 ENESTfreedom trial assessed the potential for treatment-free remission (TFR; i.e., the ability to maintain a molecular response after stopping therapy) following frontline nilotinib treatment. Patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with MR 4.5 ( BCR-ABL1 ⩽0.0032% on the International Scale ( BCR-ABL1 IS )) and ⩾2 years of frontline nilotinib therapy were enrolled. Patients with sustained deep molecular response during the 1-year nilotinib consolidation phase were eligible to stop treatment and enter the TFR phase. Patients with loss of major molecular response (MMR; BCR-ABL1 IS ⩽0.1%) during the TFR phase reinitiated nilotinib. In total, 215 patients entered the consolidation phase, of whom 190 entered the TFR phase. The median duration of nilotinib before stopping treatment was 43.5 months. At 48 weeks after stopping nilotinib, 98 patients (51.6%; 95% confidence interval, 44.2–58.9%) remained in MMR or better (primary end point). Of the 86 patients who restarted nilotinib in the treatment reinitiation phase after loss of MMR, 98.8% and 88.4%, respectively, regained MMR and MR 4.5 by the data cutoff date. Consistent with prior reports of imatinib-treated patients, musculoskeletal pain-related events were reported in 24.7% of patients in the TFR phase (consolidation phase, 16.3%).

SummaryLow bone mineral density (BMD) and osteoporosis have become a public health problem. We found that non-Hispanic white, black, and Asian adults with extremely low education and personal income are more likely to have lower BMD. This relationship is gender-specific. These findings are valuable to guide bone health interventions.IntroductionThe evidence is limited regarding the relationship between socioeconomic status (SES) and bone mineral density (BMD) for minority populations in the USA, as well as the relationship between SES and BMD for men. This study explored and examined the relationship between SES and BMD by race/ethnicity and gender.MethodsData (n = 6568) from the Louisiana Osteoporosis Study (LOS) was examined, including data for non-Hispanic whites (n = 4153), non-Hispanic blacks (n = 1907), and non-Hispanic Asians (n = 508). General linear models were used to estimate the relationship of SES and BMD (total hip and lumbar spine) stratified by race/ethnicity and gender. Adjustments were made for physiological and behavioral factors.ResultsAfter adjusting for covariates, men with education levels below high school graduate experienced relatively low hip BMD than their counterparts with college or graduate education (p < 0.05). In addition, women reporting a personal annual income under $20,000 had relatively low hip and spine BMD than their counterparts with higher income level(s) (p < 0.05).ConclusionsEstablishing a conclusive positive or negative association between BMD and SES proved to be difficult. However, individuals who are at an extreme SES disadvantage are the most vulnerable to have relatively low BMD in the study population. Efforts to promote bone health may benefit from focusing on men with low education levels and women with low individual income.

SummaryIn this study, label-free-based quantitative subcellular proteomics integrated with network analysis highlighted several candidate genes including P4HB, ITGB1, CD36, and ACTN1 that may be involved in osteoporosis. All of them are predicted as significant membrane proteins with high confidence and enriched in bone-related biological process. The results were further verified in transcriptomic and genomic levels.IntroductionOsteoporosis is a metabolic bone disease mainly characterized by low bone mineral density (BMD). As the precursors of osteoclasts, peripheral blood monocytes (PBMs) are supported to be important candidates for identifying genes related to osteoporosis. We performed subcellular proteomics study to identify significant membrane proteins that involved in osteoporosis.MethodsTo investigate the association between monocytes, membrane proteins, and osteoporosis, we performed label-free quantitative subcellular proteomics in 59 male subjects with discordant BMD levels, with 30 high vs. 29 low BMD subjects. Subsequently, we performed integrated gene enrichment analysis, functional annotation, and pathway and network analysis based on multiple bioinformatics tools.ResultsA total of 1070 membrane proteins were identified and quantified. By comparing the proteins’ expression level, we found 36 proteins that were differentially expressed between high and low BMD groups. Protein localization prediction supported the notion that the differentially expressed proteins, P4HB (p = 0.0021), CD36 (p = 0.0104), ACTN1 (p = 0.0381), and ITGB1 (p = 0.0385), are significant membrane proteins. Functional annotation and pathway and network analysis highlighted that P4HB, ITGB1, CD36, and ACTN1 are enriched in osteoporosis-related pathways and terms including “ECM-receptor interaction,” “calcium ion binding,” “leukocyte transendothelial migration,” and “reduction of cytosolic calcium levels.” Results from transcriptomic and genomic levels provided additional supporting evidences.ConclusionOur study strongly supports the significance of the genes P4HB, ITGB1, CD36, and ACTN1 to the etiology of osteoporosis risk.

SummaryThis study estimates causality of physical activity (PA) on bone mineral density (BMD) by conducting multivariable Mendelian randomization (MR). The findings suggest that habitual vigorous PA increases lumbar spine BMD, and higher overall acceleration average would improve forearm BMD. The results could promote PA intervention targeting individuals with optimized type.IntroductionEvidence from epidemiologic studies showed type, frequency, and duration of PA influenced BMD. However, these observational studies may be confounded by many factors, resulting in spurious associations. We aimed to conduct multivariable MR to estimate the causal effect of self-reported and device-measured PA on osteoporosis.MethodsThree self-reported and two device-measured PA-related traits were selected as exposures. Outcomes were BMD at different skeletal sites: femoral neck BMD (FN BMD), lumbar spine BMD (LS BMD), and forearm BMD (FA BMD). Exposure datasets were obtained from UK Biobank with total 377,234 subjects. Outcome datasets were obtained from GEFOS consortium with 53,236 subjects. Standard MR analysis and multivariable MR were conducted to assess the total and direct causal effect of PA on BMD.ResultsFor self-reported PA, inverse-normalized moderate-to-vigorous had a direct causal effect on FN BMD independently (β = − 1.116 (95% confidence interval, 95%CI: − 2.210, − 0.023), P = 0.045); vigorous PA showed a direct effect (β = 3.592 (95%CI: 0.310, 6.874), P = 0.032) on LS BMD independently. While overall acceleration average and fraction of accelerations both had a direct causal effect on FA BMD independently.ConclusionsHabitual vigorous PA could increase LS BMD. Individuals with higher overall acceleration average would have a higher FA BMD.

The effect and safety of Semaglutide and Liraglutide on weight loss in people with obesity or overweight were evaluated by a Network Meta-Analysis system to provide an evidence-based reference for clinical treatment. Computer searched PubMed, Embase, and Cochrane Library databases to collect Liraglutide and Semaglutide injection monotherapy RCTs until April 2022, using Stata 16 software for Network Meta-Analysis. Twenty-three RCTs study with 11,545 patients and 4 interventions (semaglutide 2.4mg, semaglutide 1.0mg, liraglutide 3.0mg and liraglutide 1.8 mg) were finally included. In terms of efficacy, semaglutide 2.4mg (-12.47 kg) had the best weight loss, followed by liraglutide 3.0mg (-5.24 kg), semaglutide 1.0mg (-3.74 kg) and liraglutide 1.8mg (-3.29 kg). In terms of decreased HbA1c, semaglutide 2.4mg (MD=-1.48%, 95% CI [-1.93, -1.04]), semaglutide 1.0mg (MD=-1.36%, 95% CI [-1.72, -1.01]), liraglutide 1.8mg (MD=-1.23%, 95%Cl [-1.66, -0.80]) more effective than placebo. In terms of safety, the total incidence of adverse events was semaglutide 2.4mg > liraglutide 3.0mg > liraglutide 1.8mg > semaglutide 1.0mg compare to placebo, the incidence of serious adverse events was liraglutide 3.0mg > liraglutide 1.8mg > semaglutide 2.4mg > semaglutide 1.0mg, the incidence of hypoglycemic events was semaglutide 2.4mg > liraglutide 3.0mg > semaglutide 1.0mg > liraglutide 1.8mg. This meta-analysis indicates that all GLP-1RAs were more efficacious than placebo in people with obesity or overweight on efficacy. Semaglutide 2.4mg has an absolute advantage in weight loss and decreased HbA1c, but the incidence of total adverse events is also the highest and can cause hypoglycemia. In addition, although liraglutide 3.0mg was less effective than semaglutide 2.4mg, serious adverse events were still the most elevated.