Nevin Manimala

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

Eur J Dent. 2024 Jul 16. doi: 10.1055/s-0044-1787820. Online ahead of print.

ABSTRACT

The objective of this review is to expose the main genetic changes and genetic polymorphisms that may or may not be associated with greater susceptibility to reduced survival of dental implants and, consequently, to their loss. Case-control studies that fully portrayed the specific types of genetic polymorphisms that may be associated with dental implant failure were included by searching in the PubMed, Scopus, and Web of Science databases from 2010 to 2023. The following descriptors and their combinations in English were used to search for articles: “dental implants,” “bone genes,” “genetics,” “polymorphism genetics,” “genetic risk factor,” and “interleukin.” The initial search resulted in 107 results (PubMed n = 47, Scopus n = 14, and Web of Science n = 46). After a manual search, reviewing each article’s title and abstract, and excluding duplicates, systematic reviews, and literature reviews, 30 articles were selected. After reading these 30 articles in full, 18 studies that did not describe the specific genetic polymorphism in relation to dental implant survival were excluded. Therefore, 12 articles were included in this review. The genetic polymorphisms of interleukin (IL)-1A, IL-1B, IL-4, IL-6, IL-10, IL-1 receptor antagonist, tumor necrosis factor-α, receptor activator of nuclear factor kappa B legend, and cluster of differentiation 14 were analyzed in the included studies. In seven of the studies, a statistically significant correlation between genetic polymorphisms and dental implant failure was observed. Of the polymorphisms studied, IL-1A (-899), IL-1B (+3954), and IL-4 (+33) showed a greater association with dental implant loss.

PMID:39013451 | DOI:10.1055/s-0044-1787820

Eur J Dent. 2024 Jul 16. doi: 10.1055/s-0044-1787105. Online ahead of print.

ABSTRACT

OBJECTIVES: Combining a three-dimensional scaffold with growth factors before implantation is one method used to increase scaffold bioactivity in bone tissue engineering. The mesenchymal stem cell (MSC)-conditioned medium (CM), called secretome, contains many proteins and growth factors required for tissue repair and growth. This study evaluated the bioactivity of a bovine bone scaffold combined with the secretome of human umbilical cord MSCs (hUC-MSCs) by analyzing MC3T3-E1 cell adhesion and viability on the scaffold.

MATERIALS AND METHODS: This in vitro laboratory study evaluated the effect of hUC-MSC secretome applied to bovine bone scaffolds processed using various techniques on MC3T3-E1 cell adhesion and viability. The three experimental groups included deproteinized bovine bone mineral-secretome (DBBM-CM), freeze-dried bovine bone-secretome (FDBB-CM), and decellularized FDBB-CM, whereas the control group was treated with DBBM alone. The cell adhesion test was performed using the centrifugation method after 6 and 24 hours, whereas the cell viability test was conducted using the trypan blue exclusion method after 24, 48, and 72 hours. Cell attachment was visualized after 4′,6-diamidino-2-phenylindole staining and viewed under inverted fluorescence microscopy.

STASTICAL ANALYSIS: Statistical analyses were performed using one-way analysis of variance, followed by a post hoc test in cases of significant differences.

RESULTS: Statistical analyses showed significantly greater adhesion of the preosteoblasts to the FDBB-CM scaffold at 6 hours (p = 0.002). The results of the adhesion test at 24 hours and the viability tests at all observation times showed no significant differences (p > 0.05). This study found that the average MC3T3-E1 cell adhesions and viabilities were highest for the FDBB-CM and DBBM-CM scaffolds. DBBM scaffolds with the secretome had better cell adhesion and viability than those without the secretome.

CONCLUSION: The addition of MSC secretome increased bovine bone scaffold bioactivity especially in DBBM and FDBB scaffolds.

PMID:39013448 | DOI:10.1055/s-0044-1787105