Category: Nevin Manimala

JAMA Netw Open. 2023 Aug 1;6(8):e2328828. doi: 10.1001/jamanetworkopen.2023.28828.

ABSTRACT

IMPORTANCE: Ginkgo diterpene lactone meglumine (GDLM) has attracted much attention because of its potential neuroprotective properties in ischemic stroke. The efficacy of GDLM in patients with acute ischemic stroke (AIS) needs to be verified by well-designed randomized clinical trials.

OBJECTIVE: To assess the efficacy and safety of GDLM in patients with AIS.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial involved 3448 patients who had AIS, were aged 18 to 80 years, had a clinically diagnosed AIS symptom within 48 hours of onset, had a modified Rankin Scale (mRS) score of 0 or 1 prior to onset, and had a National Institutes of Health Stroke Scale score ranging from 4 to 24. The trial took place at 100 centers in China from February 1, 2016, to May 1, 2018. The mRS is a global stroke disability scale with scores ranging from 0 (no symptoms or completely recovered) to 6 (death). The National Institutes of Health Stroke Scale is a tool used by clinicians to quantify impairment caused by stroke (range, 0-42, with higher scores indicating greater severity). Data were analyzed from January 2019 to December 2022.

INTERVENTIONS: Patients were randomized to receive GDLM or placebo once daily via intravenous infusion in a 1:1 ratio. The treatment was dispensed within 48 hours after symptoms and continued for 14 days. Interventions of thrombolysis and thrombectomy were not permitted during the treatment.

MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients with an mRS of 0 or 1 on day 90 after randomization. Safety outcomes included adverse events and serious adverse events.

RESULTS: A total of 3448 patients were randomized, with 1725 patients assigned to the GDLM group and 1723 patients assigned to the placebo group. The median (IQR) age of the patients was 63 (55-71) years, and 1232 (35.7%) were women. The primary outcome on day 90 occurred in 877 patients (50.8%) in the GDLM group, and 759 patients (44.1%) in the placebo group (risk difference, 6.79%; 95% CI, 3.46%-10.10%; odds ratio, 1.31; 95% CI, 1.15-1.50; relative risk, 1.15; 95% CI, 1.08-1.24; P < .001). Adverse events occurred relatively equally between the 2 groups (303 [17.6%] vs 298 [17.3%]; risk difference, 0.27%; 95% CI, -2.26% to 2.80%; odds ratio, 1.02; 95% CI, 0.85-1.21; relative risk, 1.02; 95% CI, 0.88-1.17; P = .83).

CONCLUSIONS AND RELEVANCE: Among patients with AIS in this randomized clinical trial, GDLM improved the proportion of patients achieving favorable clinical outcomes at 90 days compared with placebo.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02526225.

PMID:37578791 | DOI:10.1001/jamanetworkopen.2023.28828

JAMA Neurol. 2023 Aug 14. doi: 10.1001/jamaneurol.2023.2560. Online ahead of print.

ABSTRACT

IMPORTANCE: An increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-β (Aβ) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear.

OBJECTIVE: To study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL+) in the absence of Aβ pathology (A-), and the association of this condition with the AD continuum.

DESIGN, SETTING, AND PARTICIPANTS: A multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aβ PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aβ PET and tau PET biomarker profiles (A+ TMTL-).

EXPOSURES: Tau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments.

MAIN OUTCOMES AND MEASURES: Cross-sectional and longitudinal measures for tau and Aβ PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aβ42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset).

RESULTS: Among the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A- individuals and 78% of A+ participants had increased tau PET signal in the entorhinal cortex (TMTL+) compared with healthy younger (aged <39 years) controls. Compared with A- TMTL-, A- TMTL+ participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A+ TMTL+ showed faster and more cortically widespread tau PET increases. In contrast to participants with A+ TMTL+, those with A- TMTL+ did not show any noticeable Aβ accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A- TMTL+ in the absence of increased Aβ accumulation. Participants with A- TMTL+ had accelerated MTL atrophy, whereas those with A+ TMTL+ showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A- individuals was associated with cognitive decline, but at a significantly slower rate compared with A+ TMTL+.

CONCLUSIONS AND RELEVANCE: In this study, individuals with A- TMTL+ exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aβ biomarkers. These data suggest that individuals with A- TMTL+ are not on a pathologic trajectory toward AD.

PMID:37578787 | DOI:10.1001/jamaneurol.2023.2560

Updates Surg. 2023 Aug 14. doi: 10.1007/s13304-023-01628-y. Online ahead of print.

ABSTRACT

Neoadjuvant therapy (NAT) + surgical resection for pancreatic cancer (PC) has gained consensus in recent years. Pathological response (PR) is generally assessed according to the College of American Pathologists grading system, ranging from 0 (complete response) to 3 (no response). The aim of our study is to evaluate the PR in a series of resections for PC after NAT and its prognostic implication. 112 patients undergone NAT and resection for PC between 2011 and 2020 were retrospectively evaluated. PR was 0/1, 2 and 3 in 18 (15%), 79 (61%) and 29 (24%) cases, respectively. Chemotherapy regimens different from FOLFIRINOX and gemcitabine + nab-paclitaxel (OR 11.61 (2.53-53.36), p = 0.002) and lymphovascular invasion (OR 11.28 (1.89-67.23), p = 0.008) were associated to PR-3. Median follow-up was 25.8 (3.6-130.5) months. For PR-0/1, PR-2 and PR-3, median DFS was 45.8, 11.5, 4.6 months (p < 0.0001), respectively, while median OS was not reached, 27.1 and 17.5 months (p = 0.0006), respectively. At univariate analysis, PR-0/1 was significantly associated to better DFS and OS (HR 0.33 (0.17-0.67), p = 0.002; HR 0.20 (0.07-0.54), p = 0.002, respectively). At multivariate analysis, pancreaticoduodenectomy (HR 0.50 (0.30-0.84), p = 0.009), LNR (HR 27.14 (1.21-608.9), p = 0.038) and lymphovascular invasion (HR 1.99 (1.06-3.76), p = 0.033) were independently associated to DFS; pre-treatment CA 19.9 value (HR 1.00 (1.00-1.00), p = 0.025), post-treatment resectability status (HR 0.51 (0.28-0.95), p = 0.035), pancreaticoduodenectomy (HR 0.56 (0.32-0.99), p = 0.050), severe morbidity (2.99 (1.22-7.55), p = 0.017), LNR (HR 56.8 (2.08-1548.3), p = 0.017), lymphovascular invasion (HR 2.18 (1.08-4.37), p = 0.029) were independently associated to OS. PR did not reach statistical significance at multivariate analysis. A favorable PR is observed only in a limited number of cases. The prognostic role of PR, despite being promising, remains unclear and further multicentric studies are needed.

PMID:37578734 | DOI:10.1007/s13304-023-01628-y

Breast Cancer Res Treat. 2023 Aug 14. doi: 10.1007/s10549-023-07011-0. Online ahead of print.

ABSTRACT

BACKGROUND: Neoadjuvant chemotherapy (NACT) is the mainstay of treatment of stages II and III triple-negative breast cancer (TNBC). This study aims to evaluate if the addition of carboplatin to NACT is associated with an increase in the pathological complete response (pCR) rates in TNBC.

METHODS: We conducted an open-label phase II randomized clinical trial in a single center in Brazil. Patients with stage II and III TNBC were randomized to receive standard NACT with or without carboplatin. All the patients received doxorubicin (60 mg/m²) plus cyclophosphamide (600 mg/m²) both intravenously (i.v.) q21 days for four cycles. Patients were then randomized for additional treatment with weekly (wk) paclitaxel (80 mg/m² i.v., for 12 cycles) plus wk carboplatin AUC 1.5 (experimental arm) or without wk carboplatin (control arm). Randomization was stratified according to gBRCA status, age, and AJCC 8th edition clinical stage (II vs. III). The primary endpoint was the pathologic complete response (pCR) rate. Secondary endpoints included recurrence-free survival and overall survival.

RESULTS: Between 2017 and 2021, 146 patients were randomized, 73 on each arm. The median age was 45 years. Most patients (66.4%) had locally advanced stage III disease, 67.1% had T3/T4 tumors, and 56.2% had clinically positive axillary lymph nodes. Germline BRCA status was available for all patients, and 19.9% had pathogenic BRCA1/2 variants. The pCR rate (ypT0ypN0) was numerically increased by 13.7%, being 43.8% (31 of 73 patients) in the experimental and 30.1% (22 of 73 patients) in the control arm, not meeting the prespecified goal of increasing the pCR in 15% (p-value = 0.08). Survival outcomes are immature.

CONCLUSION: The addition of carboplatin to standard NACT in stages II and III TNBC was associated with a non-statistically significant numerical increase in the pCR rate. Follow-up for survival outcomes and translational research initiatives are ongoing.

PMID:37578666 | DOI:10.1007/s10549-023-07011-0

Lasers Med Sci. 2023 Aug 14;38(1):184. doi: 10.1007/s10103-023-03835-w.

ABSTRACT

The aim of this study is to systematically summarize the available evidence regarding low-level laser therapy (LLLT) speed-up effect on dental alignment in comprehensive orthodontic treatment. An extensive electronic search was conducted in PubMed, ScienceDirect, Cochrane, Web of Science, and Scopus up to February 20, 2023. The Cochrane risk of bias tool and the Newcastle-Ottawa Quality Assessment Form were used by two authors independently to assess the risk of bias (RoB). Statistical analysis was performed by Review Manager 5.3. The eight eligible trials were reviewed and included in qualitative synthesis. Four studies reported the overall time of leveling and alignment (OLAT, days), enabling a synthesizing of the data. The meta-analysis results showed that LLLT significantly reduced the overall time of leveling and alignment compared to control group (MD=-30.36, 95% CI range -41.50 to -19.22, P<0.0001), with moderate heterogeneity (χ2=4.10, P=0.25, I²=27%). Based on the data available, statistically significant evidence with moderate risk of bias suggests that LLLT may have a positive effect on accelerating dental alignment. However, due to the differences in intervention strategy and evaluating method, the conclusions should be interpreted with caution.

PMID:37578665 | DOI:10.1007/s10103-023-03835-w

Urolithiasis. 2023 Aug 14;51(1):102. doi: 10.1007/s00240-023-01474-y.

ABSTRACT

Percutaneous nephrolithotomy (PNL) can be performed in a number of different positions. Our aim was to evaluate the convenience and advantages of the supine position following the transition from the prone to the supine position. 94 patients undergoing supine PNL (Group-1) and 93 patients undergoing prone PNL (Group-2) were retrospectively reviewed and included in the study. Patients who underwent mini-PNL (mPNL) were selected from Group-1 and Group-2 and divided into Group-1A supine mPNL patients (77) and Group-2A prone mPNL patients (53). Demographic characteristics, operative data and post-operative parameters were compared between these groups. The operation time was 74.4 ± 21.9 min in Group-1A and 79.2 ± 19.8 min in Group-2A (p = 0.076). The median value of fluoroscopy time was 30 s in Group-1A and 40 s in Group-2A (p = 0.003). In Group-1A, 59 patients had no intraoperative double-J stent (DJS) insertion and 18 patients had DJS insertion, while in Group-2A, 24 patients had no DJS insertion and 29 patients had DJS insertion (p < 0.001). MPNL was performed in 81.9% of patients in the supine position and 57% in the prone position. This difference was statistically significant (p < 0.001). No significant difference was found with regard to the success rate and the complications of mPNL. Fluoroscopy time is shorter in the supine position. Moreover, the insertion rates of DJS are low. With increasing experience, we have found that our standard PNL (sPNL) rate is gradually decreasing and more mPNL is being performed.

PMID:37578662 | DOI:10.1007/s00240-023-01474-y

Mol Ecol Resour. 2023 Aug 14. doi: 10.1111/1755-0998.13856. Online ahead of print.

ABSTRACT

Hardy-Weinberg proportions (HWP) are often explored to evaluate the assumption of random mating. However, in autopolyploids, organisms with more than two sets of homologous chromosomes, HWP and random mating are different hypotheses that require different statistical testing approaches. Currently, the only available methods to test for random mating in autopolyploids (i) heavily rely on asymptotic approximations and (ii) assume genotypes are known, ignoring genotype uncertainty. Furthermore, these approaches are all frequentist, and so do not carry the benefits of Bayesian analysis, including ease of interpretability, incorporation of prior information, and consistency under the null. Here, we present Bayesian approaches to test for random mating, bringing the benefits of Bayesian analysis to this problem. Our Bayesian methods also (i) do not rely on asymptotic approximations, being appropriate for small sample sizes, and (ii) optionally account for genotype uncertainty via genotype likelihoods. We validate our methods in simulations and demonstrate on two real datasets how testing for random mating is more useful for detecting genotyping errors than testing for HWP (in a natural population) and testing for Mendelian segregation (in an experimental S1 population). Our methods are implemented in Version 2.0.2 of the hwep R package on the Comprehensive R Archive Network https://cran.r-project.org/package=hwep.

PMID:37578636 | DOI:10.1111/1755-0998.13856

Handb Exp Pharmacol. 2023 Aug 15. doi: 10.1007/164_2023_676. Online ahead of print.

ABSTRACT

Adrenoceptors are class A G-protein-coupled receptors grouped into three families (α₁-, α₂-, and β-adrenoceptors), each one including three members. All nine corresponding adrenoceptor genes display genetic variation in their coding and adjacent non-coding genomic region. Coding variants, i.e., nucleotide exchanges within the transcribed and translated receptor sequence, may result in a difference in amino acid sequence thus altering receptor function and signaling. Such variants have been intensely studied in vitro in overexpression systems and addressed in candidate-gene studies for distinct clinical parameters. In recent years, large cohorts were analyzed in genome-wide association studies (GWAS), where variants are detected as significant in context with specific traits. These studies identified two of the in-depth characterized 18 coding variants in adrenoceptors as repeatedly statistically significant genetic risk factors – p.Arg389Gly in the β₁– and p.Thr164Ile in the β₂-adrenoceptor, along with 56 variants in the non-coding regions adjacent to the adrenoceptor gene loci, the functional role of which is largely unknown at present. This chapter summarizes current knowledge on the two coding variants in adrenoceptors that have been consistently validated in GWAS and provides a prospective overview on the numerous non-coding variants more recently attributed to adrenoceptor gene loci.

PMID:37578621 | DOI:10.1007/164_2023_676

Indian J Pediatr. 2023 Aug 14. doi: 10.1007/s12098-023-04756-w. Online ahead of print.

ABSTRACT

OBJECTIVES: To determine the effect of splint on the functional duration of peripheral intravenous cannula (PIVC) in neonates.

METHODS: The trial was prospectively registered with the Clinical Trial Registry of India (CTRI/2021/09/036337). One-hundred-fifty cannulations in 71 neonates were randomized to splint (n = 75) and no-splint (n = 75) groups, respectively. The median (interquartile range, IQR) functional duration of PIVC was calculated from the time of PIVC insertion till removal due to the development of signs of PIVC failure or treatment completion. Kaplan-Meier survival analysis was used to compute the time to complication of PIVC. Complications related to PIVC were noted and multivariate Cox-proportion hazard analysis was done to find the predictors associated with PIVC failure.

RESULTS: Median (IQR) functional duration of PIVC in the splint and the no-splint group was 28 (23-48) and 30 (25-48) h, respectively (p = 0.477). PIVC duration was higher in the splint group in term neonates and the no-splint group in preterm neonates; however, the differences were not statistically significant. No difference was observed in continuous vs. intermittent infusion subgroups. Time to complication development was also comparable between the groups.

CONCLUSIONS: Splint application did not affect functional PIVC duration and its related complications in neonates.

PMID:37578610 | DOI:10.1007/s12098-023-04756-w

Environ Sci Pollut Res Int. 2023 Aug 14. doi: 10.1007/s11356-023-29121-4. Online ahead of print.

ABSTRACT

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy. Metal exposure is an emerging factor affecting the risk of GDM. However, the effects of metal mixture on GDM and key metals within the mixture remain unclear. This study was aimed at investigating the association between metal mixture during early pregnancy and the risk of GDM using four statistical methods and further at identifying the key metals within the mixture associated with GDM. A nested case-control study including 128 GDM cases and 318 controls was conducted in Beijing, China. Urine samples were collected before 13 gestational weeks and the concentrations of 13 metals were measured. Single-metal analysis (unconditional logistic regression) and mixture analyses (Bayesian kernel machine regression (BKMR), quantile g-computation, and elastic-net regression (ENET) models) were applied to estimate the associations between exposure to multiple metals and GDM. Single-metal analysis showed that Ni was associated with lower risk of GDM, while positive associations of Sr and Sb with GDM were observed. Compared with the lowest quartile of Ni, the ORs of GDM in the highest quartiles were 0.49 (95% CI 0.24, 0.98). In mixture analyses, Ni and Mg showed negative associations with GDM, while Co and Sb were positively associated with GDM in BKMR and quantile g-computation models. No significant joint effect of metal mixture on GDM was observed. However, interestingly, Ni was identified as a key metal within the mixture associated with decreased risk of GDM by all three mixture methods. Our study emphasized that metal exposure during early pregnancy was associated with GDM, and Ni might have important association with decreased GDM risk.

PMID:37578585 | DOI:10.1007/s11356-023-29121-4