Five-Repetition Sit-to-Stand Test Performance in Healthy Individuals: Reference Values and Predictors From 2 Prospective Cohorts

Objective: The 5-repetition-sit-to-stand (5R-STS) test is an objective test of functional impairment- commonly used in various diseases, including lumbar degenerative disc diseases. It is used to measure the severity of disease and to monitor recovery. We aimed to evaluate reference values for the test, as well as factors predicting 5R-STS performance in healthy adults.Methods: Healthy adults ( > 18 years of age) were recruited, and their 5R-STS time was measured. Their age, sex, weight, height, body mass index (BMI), smoking status, education level, work situation and EuroQOL-5D Healthy & Anxiety category were recorded. Linear regression analysis was employed to identify predictors of 5R-STS performance.Results: We included 172 individuals with mean age of 39.4 ± 14.1 years and mean BMI of 24.0 ± 4.0 kg/m². Females constituted 57%. Average 5R-STS time was 6.21 ± 1.92 seconds, with an upper limit of normal of 12.39 seconds. In a multivariable model, age (regression coefficient [RC], 0.07; 95% confidence interval [CI], 0.05/0.09; p < 0.001), male sex (RC, -0.87; 95% CI, -1.50 to -0.23; p = 0.008), BMI (RC, 0.40; 95% CI, 0.10–0.71; p = 0.010), height (RC, 0.13; 95% CI, 0.04–0.22; p = 0.006), and houseworker status (RC, -1.62; 95% CI, -2.93 to -0.32; p = 0.016) were significantly associated with 5R-STS time. Anxiety and depression did not influence performance significantly (RC, 0.82; 95% CI, -0.14 to 1.77; p = 0.097).Conclusion: The presented reference values can be applied as normative data for 5R-STS in healthy adults, and are necessary to judge what constitutes abnormal performance. We identified several significant factors associated with 5R-STS performance that may be used to calculate individualized expected test times.

CDKN2A Deletion Leading to Hematogenous Metastasis of Human Gastric Carcinoma

IntroductionSomatic copy number deletion (SCND) of CDKN2A gene is the most frequent event in cancer genomes. Whether CDKN2A SCND drives human cancer metastasis is far from clear. Hematogenous metastasis is the main reason of human gastric carcinoma (GC) death. Thus, prediction GC metastasis is eagerly awaited.MethodGC patients (n=408) enrolled in both a cross-sectional and a prospective cohorts were analysed. CDKN2A SCND was detected with a quantitative PCR assay (P16-Light). Association of CDKN2A SCND and GC metastasis was evaluated. Effect of CDKN2A SCND by CRISPR/Cas9 on biological behaviors of cancer cells was also studied.ResultsCDKN2A SCND was detected in 38.9% of GCs from patients (n=234) enrolled in the cross-sectional cohort. Association analysis showed that more CDKN2A SCND was recognized in GCs with hematogenous metastasis than those without (66.7% vs. 35.7%, p=0.014). CDKN2A SCND was detected in 36.8% of baseline pN0M0 GCs from patients (n=174) enrolled in the prospective study, the relationship between CDKN2A SCND and hematogenous metastasis throughout the follow-up period (62.7 months in median) was also significant (66.7% vs. 34.6%, p=0.016). Using CDKN2A SCND as a biomarker for predicting hematogenous metastasis of GCs, the prediction sensitivity and specificity were 66.7% and 65.4%. The results of functional experiments indicated that CDKN2A SCND could obviously downregulate P53 expression that consequently inhibited the apoptosis of MGC803 GC and HEK293T cells. This may account for hematogenous metastasis of GCs by CDKN2A SCND.ConclusionCDKN2A SCND may drive GC metastasis and could be used as a predictor for hematogenous metastasis of GCs.

Extent, pattern, and prognostic value of MGMT promotor methylation: does it differ between glioblastoma and IDH-wildtype/TERT-mutated astrocytoma?

Introduction The cIMPACT-NOW update 6 first introduced glioblastoma diagnosis based on the combination of IDH-wildtype (IDHwt) status and TERT promotor mutation (pTERTmut). In glioblastoma as defined by histopathology according to the WHO 2016 classification, MGMT promotor status is associated with outcome. Whether this is also true in glioblastoma defined by molecular markers is yet unclear. Methods We searched the institutional database for patients with: (1) glioblastoma defined by histopathology; and (2) IDHwt astrocytoma with pTERTmut. MGMT promotor methylation was analysed using methylation-specific PCR and Sanger sequencing of CpG sites within the MGMT promotor region. Results We identified 224 patients with glioblastoma diagnosed based on histopathology, and 54 patients with IDHwt astrocytoma with pTERTmut (19 astrocytomas WHO grade II and 38 astrocytomas WHO grade III). There was no difference in the number of MGMT methylated tumors between the two cohorts as determined per PCR, and also neither the number nor the pattern of methylated CpG sites differed as determined per Sanger sequencing. Progression-free (PFS) and overall survival (OS) was similar between the two cohorts when treated with radio- or chemotherapy. In both cohorts, higher numbers of methylated CpG sites were associated with favourable outcome. Conclusions Extent and pattern of methylated CpG sites are similar in glioblastoma and IDHwt astrocytoma with pTERTmut. In both tumor entities, higher numbers of methylated CpG sites appear associated with more favourable outcome. Evaluation in larger prospective cohorts is warranted.

Alterações no índice de massa corporal: Coorte em indivíduos em uso de dolutegravir

Goal: To assess body mass index (BMI) changes in people living with HIV (PLHIV) and using antiretroviral therapy (ART) with dolutegravir (DTG) and its associated factors. Methods: Retrospective and prospective cohorts of PLHIV who started ART with DTG or used DTG after changing the therapeutic regimen, from Belo Horizonte, between February/2017 and March/2020. Data were gathered from clinical records of the Drug Logistics and Laboratory Test Control Systems. BMI changes were analyzed in the following week intervals 1-24(t24), 25-48(t48), 49-72(t73), and 73-96(t96) using the Wilcoxon test and generalized estimation equation (GEE) model, at 5% significance level. Results: A total of 614 individuals were included and average was 38.4 years old. Most were men (85.5%) and 52.3% had started ART with DTG. These individuals, and the immunosuppressed ones, showed significant increases in BMI when compared to those who used DTG after switching therapeutics or the non-immunosuppressed ones (p-value <0.05). After 96 weeks, individuals starting ART with DTG had a mean increase in BMI of 1.02 Kg/m2, whereas those who used DTG after the therapeutic change had an increase of 0.56 Kg/m2 (p<0.05). DTG use length, ART type, immune status, baseline BMI, and age were associated (p<0.05) with BMI increases. Conclusions: We observed an increase in BMI both in individuals starting ART with DTG use and those using it after changing the therapeutic regimen.

Metabolic Biomarker Discovery for Risk of Peripheral Artery Disease Compared With Coronary Artery Disease: Lipoprotein and Metabolite Profiling of 31 657 Individuals From 5 Prospective Cohorts

Background Peripheral artery disease (PAD) and coronary artery disease (CAD) represent atherosclerosis in different vascular beds. We used detailed metabolic biomarker profiling to identify common and discordant biomarkers and clarify pathophysiological differences for these vascular diseases. Methods and Results We used 5 prospective cohorts from Finnish population (FINRISK 1997, 2002, 2007, and 2012, and Health 2000; n=31 657; median follow‐up time of 14 years) to estimate associations between >200 metabolic biomarkers and incident PAD and CAD. Metabolic biomarkers were measured with nuclear magnetic resonance, and disease events were obtained from nationwide hospital records. During the follow‐up, 498 incident PAD and 2073 incident CAD events occurred. In age‐ and sex‐adjusted Cox models, apolipoproteins and cholesterol measures were robustly associated with incident CAD (eg, hazard ratio [HR] per SD for higher apolipoprotein B/A‐1 ratio, 1.30; 95% CI, 1.25–1.36), but not with incident PAD (HR per SD for higher apolipoprotein B/A‐1 ratio, 1.04; 95% CI, 0.95–1.14; P heterogeneity <0.001). In contrast, triglyceride levels in low‐density lipoprotein and high‐density lipoprotein were associated with both end points ( P heterogeneity >0.05). Lower proportion of polyunsaturated fatty acids relative to total fatty acids, and higher concentrations of monounsaturated fatty acids, glycolysis‐related metabolites, and inflammatory protein markers were strongly associated with incident PAD, and many of these associations were stronger for PAD than for CAD ( P heterogeneity <0.001). Most differences in metabolic profiles for PAD and CAD remained when adjusting for traditional risk factors. Conclusions The metabolic biomarker profile for future PAD risk is distinct from that of CAD. This may represent pathophysiological differences.

Impact of empirical antibiotic regimens on mortality in neutropenic patients with bloodstream infection presenting with septic shock

Objectives: We analyzed risk factors for mortality in febrile neutropenic patients with bloodstream infections (BSI) presenting with septic shock and assessed the impact of empirical antibiotic regimens. Methods: Multicenter retrospective study (2010-2019) of two prospective cohorts comparing BSI episodes in patients with or without septic shock. Multivariate analysis was performed to identify independent risk factors for mortality in episodes with septic shock. Results: Of 1563 patients with BSI, 257 (16%) presented with septic shock. Those patients with septic shock had higher mortality than those without septic shock (55% vs 15%, p<0.001). Gram-negative bacilli caused 81% of episodes with septic shock; gram-positive cocci, 22%; and Candida species 5%. Inappropriate empirical antibiotic treatment (IEAT) was administered in 17.5% of septic shock episodes. Empirical β-lactam combined with other active antibiotics was associated with the lowest mortality observed. When amikacin was the only active antibiotic, mortality was 90%. Addition of empirical specific gram-positive coverage had no impact on mortality. Mortality was higher when IEAT was administered (76% vs 51%, p=0.002). Age >70 years (OR 2.3, 95% CI 1.2-4.7), IEAT for Candida spp. or gram-negative bacilli (OR 3.8, 1.3-11.1), acute kidney injury (OR 2.6, 1.4-4.9) and amikacin as the only active antibiotic (OR 15.2, 1.7-134.5) were independent risk factors for mortality, while combination of β-lactam and amikacin was protective (OR 0.32, 0.18-0.57). Conclusions: Septic shock in febrile neutropenic patients with BSI is associated with extremely high mortality, especially when IEAT is administered. Combination therapy including an active β-lactam and amikacin results in the best outcomes.