]. In other words, when margins are too large, a positive non-inferiority trial result may translate into a clinical detriment. In the DYNAMIC trial, testing the ctDNA approach in stage II colon cancer, the non-inferiority margin was 8.5 percentage points for the analysis of 2-year recurrence-free survival. This margin is large.
]. Large non-inferiority margins may guarantee the success of such trials without ensuring similar efficacy for patients.Solutions to our dilemma of molecular testing should balance a desire to use and embrace new technology with the need to appraise it rigorously in well-done studies.
A second strategy would be to limit de-escalation trials to settings where the current practice benefits have reach a widespread agreement. This would avoid the risk of testing non-inferiority against an ineffective therapy, which guarantees successes but provide no informative data. In the case of DYNAMIC, stage III colon cancer is a better target.
The third solution tackles the issue raised by non-inferiority margins. Test-based decision strategies should not be limited to de-escalation trials and be superiority trials instead. For instance, in stage III colon cancer, among those not receiving chemotherapy based on current management, does ctDNA detect a subgroup that may benefit from adjuvant chemotherapy?Simply because a molecular test is rational does not mean it can improve patient outcomes.
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Cardiovascular risk factors among people with drug-resistant tuberculosis in Uganda - BMC Cardiovascular DisordersBackground Tuberculosis (TB) and its risk factors are independently associated with cardiovascular disease (CVD). We determined the prevalence and associations of CVD risk factors among people with drug-resistant tuberculosis (DRTB) in Uganda. Methods In this cross-sectional study, we enrolled people with microbiologically confirmed DRTB at four treatment sites in Uganda between July to December 2021. The studied CVD risk factors were any history of cigarette smoking, diabetes mellitus (DM) hypertension, high body mass index (BMI), central obesity and dyslipidaemia. We used modified Poisson regression models with robust standard errors to determine factors independently associated with each of dyslipidaemia, hypertension, and central obesity. Results Among 212 participants, 118 (55.7%) had HIV. Overall, 196 (92.5%, 95% confidence interval (CI) 88.0-95.3) had ≥ 1 CVD risk factor. The prevalence; 95% CI of individual CVD risk factors was: dyslipidaemia (62.5%; 55.4–69.1), hypertension (40.6%; 33.8–47.9), central obesity (39.3%; 32.9–46.1), smoking (36.3%; 30.1–43.1), high BMI (8.0%; 5.0–12.8) and DM (6.5%; 3.7–11.1). Dyslipidaemia was associated with an increase in glycated haemoglobin (adjusted prevalence ratio (aPR) 1.14, 95%CI 1.06–1.22). Hypertension was associated with rural residence (aPR 1.89, 95% CI 1.14–3.14) and previous history of smoking (aPR 0.46, 95% CI 0.21–0.98). Central obesity was associated with increasing age (aPR 1.02, 95%CI 1.00–1.03), and elevated diastolic blood pressure (aPR 1.03 95%CI 1.00–1.06). Conclusion There is a high prevalence of CVD risk factors among people with DRTB in Uganda, of which dyslipidaemia is the commonest. We recommend integrated services for identification and management of CVD risk factors in DRTB.
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Postnatal deletion of Spns2 prevents neuroinflammation without compromising blood vascular functions - Cellular and Molecular Life SciencesProtein Spinster homolog 2 (Spns2) is a sphingosine-1-phosphate (S1P) transporter that releases S1P to regulate lymphocyte egress and trafficking. Global deletion of Spns2 (Spns2−/−) has been shown to reduce disease severity in several autoimmune disease models. To examine whether Spns2 could be exploited as a drug target, we generated and characterized the mice with postnatal knockout of Spns2 (Spns2-Mx1Cre). Our results showed that Spns2-Mx1Cre mice had significantly low number of lymphocytes in blood and lymphoid organs similar to Spns2−/− mice. Lymph but not plasma S1P levels were significantly reduced in both groups of knockout mice. Our lipidomic results also showed that Spns2 releases different S1P species into lymph. Interestingly, lymphatic vessels in the lymph nodes (LNs) of Spns2−/− and Spns2-Mx1Cre mice exhibited morphological defects. The structures of high endothelial venules (HEV) in the LNs of Spns2-Mx1Cre mice were disorganized. These results indicate that lack of Spns2 affects both S1P secretion and LN vasculatures. Nevertheless, blood vasculature of these Spns2 deficient mice was not different to controls under homeostasis and vascular insults. Importantly, Spns2-Mx1Cre mice were resistant to multiple sclerosis in experimental autoimmune encephalomyelitis (EAE) models with significant reduction of pathogenic Th17 cells in the central nervous system (CNS). This study suggests that pharmacological inhibition of Spns2 may be exploited for therapeutic applications in treatment of neuroinflammation.
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Breast cancer spread uncovered by new molecular microscopyNew technology can trace which populations of breast cancer cells are responsible for the spread of the disease, and for the first time highlights how the location of cancer cells could be as important as mutations in tumor growth.
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