Tag: nevin manimala

Contemp Clin Trials. 2024 Jul 14:107633. doi: 10.1016/j.cct.2024.107633. Online ahead of print.

ABSTRACT

BACKGROUND: Early preterm birth (ePTB) – born before 34 weeks of gestation – poses a significant public health challenge. Two randomized trials indicated an ePTB reduction among pregnant women receiving high-dose docosahexaenoic acid (DHA) supplementation. One of them is Assessment of DHA on Reducing Early Preterm Birth (ADORE). A survey employed in its secondary analysis identified women with low DHA levels, revealing that they derived greater benefits from high-dose DHA supplementation. This survey’s inclusion in future trials can provide critical insights for informing clinical practices.

OBJECTIVE: To optimize a Phase III trial design, ADORE Precision, aiming at assessing DHA supplement (200 vs. 1000 mg/day) on reducing ePTB among pregnant women with a low baseline DHA.

METHODS: We propose a Bayesian Hybrid Response Adaptive Randomization (RAR) Design utilizing a finite mixture model to characterize gestational age at birth. Subsequently, a dichotomized ePTB outcome is used to inform trial design using RAR. Simulation studies were conducted to compare a Fixed Design, an Adaptive Design with early stopping, an ADORE-like Adaptive RAR Design, and two new Hybrid Designs with different hyperpriors.

DISCUSSION: Simulation reveals several advantages of the RAR designs, such as higher allocation to the more promising dose and a trial duration reduction. The proposed Hybrid RAR Designs addresses the statistical power drop observed in Adaptive RAR. The new design model shows robustness to hyperprior choices. We recommend Hybrid RAR Design 1 for ADORE Precision, anticipating that it will yield precise determinations, which is crucial for advancing our understanding in this field.

PMID:39013543 | DOI:10.1016/j.cct.2024.107633

Mitochondrion. 2024 Jul 14:101938. doi: 10.1016/j.mito.2024.101938. Online ahead of print.

ABSTRACT

Protein function is dependent on charge interactions and charge biased regions, which are involved in a wide range of cellular and biochemical processes. We report the development of a new algorithm implemented in Python and its use to identify charge clusters CC (NegativeCC: NCC, PositiveCC: PCC and MixedCC: MCC) and compare their presence in mitochondrial proteins of plant groups. To characterize the resulting CC, statistical, structural and functional analyses were conducted. The screening of 105,399 protein sequences showed that 2.6 %, 0.48 % and 0.03 % of the proteins contain NCC, PCC and MCC, respectively. Mitochondrial proteins encoded by the nuclear genome of green algae have the biggest proportion of both PCC (1.6 %) and MCC (0.4 %) and mitochondrial proteins coded by the nuclear genome of other plants group have the highest portion of NCC (7.5 %). The mapping of the identified CC showed that that they are mainly located in the terminal regions of the protein. Annotation showed that proteins with CC are classified as binding proteins, are included in the transmembrane transport processes, and are mainly located in the membrane. The CC scanning revealed the presence of 2373 and 784 sites and 192 and 149 motif profiles within NCC and PCC, respectively. The investigation of CC within pentatricopeptide repeat-containing proteins revealed that they are involved in correct and specific RNA editing. CC were proven to play a key role in providing insightful structural and functional information of complex protein assemblies which could be useful in biotechnological applications.

PMID:39013535 | DOI:10.1016/j.mito.2024.101938

Radiother Oncol. 2024 Jul 14:110437. doi: 10.1016/j.radonc.2024.110437. Online ahead of print.

ABSTRACT

PURPOSE: Re-irradiation (reRT) is an effective treatment modality for patients with recurrent glioma. Data on dose escalation, the use of simulated integrated boost and concomitant therapy to reRT are still scarce. In this monocentric cohort of n = 223 patients we investigated the influence of reRT dose escalation as well as the concomitant use of bevacizumab (BEV) with regard to post-recurrence survival (PRS) and risk of radionecrosis (RN).

PATIENTS AND METHODS: Patients with recurrent glioma treated between July 2008 and August 2022 with reRT with BEV, reRT with temozolomide (TMZ) and reRT without concomitant systemic therapy were retrospectively analyzed. PRS and RN-free survival (RNFS) were calculated for all patients using the Kaplan-Meier estimator. Univariable and multivariable cox regression was performed for PRS and for RNFS. The reRT Risk Score (RRRS) was calculated for all patients.

RESULTS: Good, intermediate and poor risk of the RRRS translated into 11 months, 9 months and 7 months of median PRS (univariable: p = 0.008, multivariable: p = 0.013). ReRT was applied with a dose of ≤36 Gy (n = 140) or >36 Gy (n = 83). Concomitant bevacizumab (BEV) therapy was performed in n = 122 and concomitant temozolomide (TMZ) therapy in n = 32 patients. Median PRS was 10 months in patients treated with >36 Gy and 8 months in patients treated with ≤36 Gy (univariable: p = 0.032, multivariable: p = 0.576). Regarding concomitant TMZ therapy, median PRS was 14 months vs. 9 months for patients treated with or without TMZ (univariable: p = 0.041, multivariable: p = 0.019). No statistically significant influence on PRS was seen for concomitant BEV therapy in this series. RN was less frequent for reRT with concomitant BEV, (17/122; 13.9 %) than for reRT without BEV (30/101; 29.7 %). Regarding RNFS, the hazard ratio for reRT with BEV was 0.436 (univariable; p = 0.006) and 0.479 (multivariable; p = 0.023), respectively. ReRT dose did not show statistical significance in regards to RN (univariable: p = 0.073, multivariable: p = 0.404). RNFS was longer for patients receiving concomitant BEV to reRT than for patients treated with reRT only (mean 31.7 vs. 30.9 months, p = 0.004).

CONCLUSION: In this cohort, in patients treated with concomitant BEV therapy RN was less frequently detected and in patients treated with concomitant TMZ longer PRS was observed. Based on these results, the best concomitant therapy and the optimal dose should be decided on a patient-by-patient basis.

PMID:39013502 | DOI:10.1016/j.radonc.2024.110437

World Neurosurg. 2024 Jul 14:S1878-8750(24)01222-1. doi: 10.1016/j.wneu.2024.07.083. Online ahead of print.

ABSTRACT

BACKGROUND: The prior trials investigating triple-H therapy for preventing delayed cerebral ischemia (DCI) enrolled patients with aneurysmal subarachnoid hemorrhage (aSAH) who underwent early aneurysm therapy within three days. However, surgical clipping might be performed during 4-7 days that high incidence cerebral vasospasm is likely. We examined effects of hypervolemia-augmented blood pressure (HV-ABP) protocol on DCI prevention when clipping was delayed.

METHODS: The study enrolled aSAH patients hospitalized during 2013-2019 who underwent clipping 4-7 days after rupture in a university hospital in Thailand. DCI and secondary outcomes were compared among patients, who achieved the HV-ABP protocol (3-5L/day fluid intake and 140-180mmHg SBP maintained for 72 hours postoperatively) and those who did not. The intervention-outcome associations were estimated using logistic regression for the whole group and a patient sub-group with similar propensity scores (PS) for protocol achievement.

RESULTS: 177 aSAH patients were clipped 4-7 days after rupture, 97 patients (54.8%) achieved the HV-ABP protocol, while 80 patients (45.2%) did not. 122 patients with one-to-one PS matching reduced the originally unequal patient characteristics. The observed DCI was lower in patients with protocol-achieved (8.3%) than in their non-achieved counterparts (22.5%). This resulted in an association with the HV-ABP intervention with adjusted odds ratios of 0.201 (95% confidence interval, 0.066-0.613) in the whole sample and 0.228 (0.065-0.794) in the PS-matched sub-sample. No statistically significant differences in the secondary outcomes were found.

CONCLUSIONS: Achieving the targets recommended in the HV-ABP protocol was associated with reducing the DCI incidence in patients with aSAH who underwent delayed clipping.

PMID:39013498 | DOI:10.1016/j.wneu.2024.07.083

Pharm Stat. 2024 Jul 16. doi: 10.1002/pst.2416. Online ahead of print.

ABSTRACT

The ICH E9(R1) Addendum (International Council for Harmonization 2019) suggests treatment-policy as one of several strategies for addressing intercurrent events such as treatment withdrawal when defining an estimand. This strategy requires the monitoring of patients and collection of primary outcome data following termination of randomised treatment. However, when patients withdraw from a study early before completion this creates true missing data complicating the analysis. One possible way forward uses multiple imputation to replace the missing data based on a model for outcome on- and off-treatment prior to study withdrawal, often referred to as retrieved dropout multiple imputation. This article introduces a novel approach to parameterising this imputation model so that those parameters which may be difficult to estimate have mildly informative Bayesian priors applied during the imputation stage. A core reference-based model is combined with a retrieved dropout compliance model, using both on- and off-treatment data, to form an extended model for the purposes of imputation. This alleviates the problem of specifying a complex set of analysis rules to accommodate situations where parameters which influence the estimated value are not estimable, or are poorly estimated leading to unrealistically large standard errors in the resulting analysis. We refer to this new approach as retrieved dropout reference-base centred multiple imputation.

PMID:39013479 | DOI:10.1002/pst.2416

Benef Microbes. 2024 Jul 17:1-19. doi: 10.1163/18762891-bja00019. Online ahead of print.

ABSTRACT

Childhood obesity is a crucial public health concern worldwide. Dietary intervention is the most common intervention for the treatment of obesity. Therefore, we tested an improved diet-based nutritional interventions to improve the childhood obesity and its gut microbiota. Thirty obese children received a 12-week intervention with the adjust-energy-restricted dietary pattern (A-CRD). Body composition was measured by bioelectrical impedance (Inbody S10) and faecal microbes were profiled by sequencing 16S rRNA. Compared to the NTB group (at 0 week), the NTA group (at 12 weeks) had a significantly greater decrease in body weight, body mass index (BMI) and percent body fat (PBF) ( P < 0.001, respectively), whereas skeletal muscle mass (SMM) and fat free mass (FFM) were not statistically significantly different ( P > 0.05). The gut microbiota was found significantly different between the NTB and NTA groups based on alpha and beta diversity. Bifidobacterium, Blautia, and Streptococcus was significantly increased, whereas Bacteroides and Megamonas was significantly decreased in the NTA group ( P < 0.05, respectively). Meanwhile, NTA group significantly increased the ability to produce short-chain fatty acids (SCFAs; e.g. acetic acid/total dietary energy) and changed he predictive metabolic functional features of the microbiota communities ( P < 0.05, respectively) than the NTB group. In conclusion, A-CRD can significantly improve childhood obesity, and the underlying mechanism may be its effect on gut microbiota and metabolism. Therefore, the diet-based nutrition intervention targeting gut microbiota will be more effective management of body weight and prevention of obesity. Chinese Clinical Trial Register: ChiCTR2300074571.

PMID:39013478 | DOI:10.1163/18762891-bja00019

J Oral Maxillofac Surg. 2024 Jun 29:S0278-2391(24)00586-X. doi: 10.1016/j.joms.2024.06.176. Online ahead of print.

ABSTRACT

BACKGROUND: In the therapy of medication-related osteonecrosis of the jaw (MRONJ), the healing rate, effectiveness of operative therapy, and factors associated with healing remain unclear.

PURPOSE: This study aimed to estimate MRONJ therapy healing rates and identify associated prognostic factors.

STUDY DESIGN, SETTING, SAMPLE: A 25-center prospective cohort study was conducted on 291 patients with MRONJ treated with a common therapeutic protocol during 2013-2016. Patients unable to continue examinations or treatment were excluded.

PREDICTOR VARIABLE: The primary predictor variable was MRONJ therapy grouped into two categories: operative and nonoperative. Secondarily, the prognostic factors categorized as demographic, medical, clinical, and perioperative were evaluated.

MAIN OUTCOME VARIABLES: The primary outcome variable was treatment duration, defined as the time (in months) between the initiation of therapy and when the site was healed or the date of the final visit or loss to follow-up.

COVARIATES: Not applicable.

ANALYSES: Descriptive statistics and 3-year cumulative healing rates were calculated. The association between clinical factors and time to healing was analyzed using bivariate and multivariate analyses and propensity score analysis. P < .05 was considered significant.

RESULTS: We analyzed data from 291 subjects with 76 (26.1%) and 215 (73.9%) subjects in the operative and nonoperative therapy groups, respectively. The healing rates for operative and nonoperative therapies were 95.8 and 70.7%, respectively (hazard ratio [HR] = 1.6, 95% confidence interval [CI] = 1.1-2.2, P value [P] < .01). The healing rates in patients for whom anti-resorptive agent (ARA) treatment was discontinued and continued were 87.2 and 37.4%, respectively (HR = 1.8, 95% CI = 1.1-3.0, P = .02). In a multiple regression analysis using ARA indication, the therapy method showed a significant association in the MRONJ malignancy group (HR = 2.75, 95% CI = 1.46-5.17, P < .01).

CONCLUSION AND RELEVANCE: Operative therapy and ARA discontinuation were associated with better healing rates in MRONJ therapy. However, the choice of therapy for MRONJ should be based on a comprehensive consideration of the patient’s condition. ARA discontinuation should be considered an adjunctive measure because of the possibility of adverse events such as fragility fractures and skeletal related events.

PMID:39013476 | DOI:10.1016/j.joms.2024.06.176

Neuron. 2024 Jul 10:S0896-6273(24)00446-X. doi: 10.1016/j.neuron.2024.06.011. Online ahead of print.

ABSTRACT

Every day, hundreds of thousands of people undergo general anesthesia. One hypothesis is that anesthesia disrupts dynamic stability-the ability of the brain to balance excitability with the need to be stable and controllable. To test this hypothesis, we developed a method for quantifying changes in population-level dynamic stability in complex systems: delayed linear analysis for stability estimation (DeLASE). Propofol was used to transition animals between the awake state and anesthetized unconsciousness. DeLASE was applied to macaque cortex local field potentials (LFPs). We found that neural dynamics were more unstable in unconsciousness compared with the awake state. Cortical trajectories mirrored predictions from destabilized linear systems. We mimicked the effect of propofol in simulated neural networks by increasing inhibitory tone. This in turn destabilized the networks, as observed in the neural data. Our results suggest that anesthesia disrupts dynamical stability that is required for consciousness.

PMID:39013467 | DOI:10.1016/j.neuron.2024.06.011

Immunity. 2024 Jul 6:S1074-7613(24)00319-4. doi: 10.1016/j.immuni.2024.06.013. Online ahead of print.

ABSTRACT

Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host, Mastomys rodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of the Lassa virus’s glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we used pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affected cell entry and antibody neutralization. Our experiments defined functional constraints throughout GPC. We quantified how GPC mutations affected neutralization with a panel of monoclonal antibodies. All antibodies tested were escaped by mutations that existed among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid the design of therapeutics and vaccines.

PMID:39013466 | DOI:10.1016/j.immuni.2024.06.013

Pharm Stat. 2024 Jul 16. doi: 10.1002/pst.2423. Online ahead of print.

ABSTRACT

Finding an adequate dose of the drug by revealing the dose-response relationship is very crucial and a challenging problem in the clinical development. The main concerns in dose-finding study are to identify a minimum effective dose (MED) in anesthesia studies and maximum tolerated dose (MTD) in oncology clinical trials. For the estimation of MED and MTD, we propose two modifications of Firth’s logistic regression using reparametrization, called reparametrized Firth’s logistic regression (rFLR) and ridge-penalized reparametrized Firth’s logistic regression (RrFLR). The proposed methods are designed by directly reducing the small-sample bias of the maximum likelihood estimate for the parameter of interest. In addition, we develop a method on how to construct confidence intervals for rFLR and RrFLR using profile penalized likelihood. In the up-and-down biased-coin design, numerical studies confirm the superior performance of the proposed methods in terms of the mean squared error, bias, and coverage accuracy of confidence intervals.

PMID:39013454 | DOI:10.1002/pst.2423