Nevin Manimala

Lifetime Data Anal. 2022 Jun 28. doi: 10.1007/s10985-022-09565-5. Online ahead of print.

ABSTRACT

Conventional semiparametric hazards regression models rely on the specification of particular model formulations, such as proportional-hazards feature and single-index structures. Instead of checking these modeling assumptions one-by-one, we proposed a class of dimension-reduced generalized Cox models, and then a consistent model selection procedure among this class to select covariates with proportional-hazards feature and a proper model formulation for non-proportional-hazards covariates. In this class, the non-proportional-hazards covariates are treated in a nonparametric manner, and a partial sufficient dimension reduction is introduced to reduce the curse of dimensionality. A semiparametric efficient estimation is proposed to estimate these models. Based on the proposed estimation, we further constructed a cross-validation type criterion to consistently select the correct model among this class. Most importantly, this class of hazards regression models contains the fully nonparametric hazards regression model as the most saturated submodel, and hence no further model diagnosis is required. Overall speaking, this model selection approach is more effective than performing a sequence of conventional model checking. The proposed method is illustrated by simulation studies and a data example.

PMID:35763127 | DOI:10.1007/s10985-022-09565-5

Bull Math Biol. 2022 Jun 28;84(8):78. doi: 10.1007/s11538-022-01028-0.

ABSTRACT

A compartmental epidemiological model with distributed recovery and death rates is proposed. In some particular cases, the model can be reduced to the conventional SIR model. However, in general, the dynamics of epidemic progression in this model is different. Distributed recovery and death rates are evaluated from COVID-19 data. The model is validated by the epidemiological data for different countries, and it shows better agreement with the data than the SIR model. The time-dependent disease transmission rate is estimated.

PMID:35763126 | DOI:10.1007/s11538-022-01028-0

Transgenic Res. 2022 Jun 28. doi: 10.1007/s11248-022-00312-y. Online ahead of print.

ABSTRACT

Two conserved Glycine max (soybean) mitogen activated protein kinase 3 (MAPK3) paralogs function in defense to the parasitic soybean cyst nematode Heterodera glycines. Gene Ontology analyses of RNA seq data obtained from MAPK3-1-overexpressing (OE) and MAPK3-2-OE roots compared to their control, as well as MAPK3-1-RNA interference (RNAi) and MAPK3-2-RNAi compared to their control, hierarchically orders the induced and suppressed genes, strengthening the hypothesis that their heterologous expression in Gossypium hirsutum (upland cotton) would impair parasitism by the root knot nematode (RKN) Meloidogyne incognita. MAPK3-1 expression (E) in G. hirsutum suppresses the production of M. incognita root galls, egg masses, and second stage juveniles (J2s) by 80.32%, 82.37%, and 88.21%, respectfully. Unexpectedly, egg number increases by 28.99% but J2s are inviable. MAPK3-2-E effects are identical, statistically. MAPK3-1-E and MAPK3-2-E decreases root mass 1.49-fold and 1.55-fold, respectively, as compared to the pRAP15-ccdB-E control. The reproductive factor (RF) of M. incognita for G. hirsutum roots expressing MAPK3-1-E or MAPK3-2-E decreases 60.39% and 50.46%, respectively, compared to controls. The results are consistent with upstream pathogen activated molecular pattern (PAMP) triggered immunity (PTI) and effector triggered immunity (ETI) functioning in defense to H. glycines. The experiments showcase the feasibility of employing MAPK3, through heterologous expression, to combat M. incognita parasitism, possibly overcoming impediments otherwise making G. hirsutum’s defense platform deficient. MAPK homologs are identified in other important crop species for future functional analyses.

PMID:35763120 | DOI:10.1007/s11248-022-00312-y

J Neurol. 2022 Jun 28. doi: 10.1007/s00415-022-11231-7. Online ahead of print.

ABSTRACT

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disease where a deficient amount of SMN protein leads to progressive lower motor neuron degeneration. SMN-enhancing therapies are now available. Yet, fatigue and signs of impaired neuromuscular junction (NMJ) transmission could contribute to SMA phenotype. Amifampridine prolongs presynaptic NMJ terminal depolarization, enhancing neuromuscular transmission.

METHODS: SMA-001 was a phase 2, 1:1 randomized, double-blind, placebo-controlled crossover study. Ambulatory (walking unaided at least 30 m) SMA Type 3 patients, untreated with SMN-enhancing medications, entered a run-in phase where amifampridine was titrated up to an optimized stable dose. Patients achieving at least three points improvement in Hammersmith Functional Motor Score Expanded (HFMSE) were randomized to amifampridine or placebo, alternatively, in the 28-day double-blind crossover phase. Safety was evaluated by adverse events (AE) collection. Primary efficacy measure was the HFMSE change from randomization. Secondary outcomes included timed tests and quality of life assessment. Descriptive analyses and a mixed effects linear model were used for statistics.

RESULTS: From 14 January 2019, 13 patients, mean age 34.5 years (range 18-53), with 5/13 (38.5%) females, were included. No serious AE were reported. Transient paresthesia (33.3%) was the only amifampridine-related AE. Six patients for each treatment sequence were randomized. Amifampridine treatment led to a statistically significant improvement in HFMSE (mean difference 0.792; 95% CI from 0.22 to 1.37; p = 0.0083), compared to placebo, but not in secondary outcomes.

DISCUSSION: SMA-001 study provided Class II evidence that amifampridine was safe and effective in treating ambulatory SMA type 3 patients.

CLINICAL TRIAL REGISTRATION: NCT03781479; EUDRACT 2017-004,600-22.

PMID:35763114 | DOI:10.1007/s00415-022-11231-7

Eur Radiol. 2022 Jun 28. doi: 10.1007/s00330-022-08941-x. Online ahead of print.

ABSTRACT

OBJECTIVES: To assess whether radiomic features could improve the accuracy of survival predictions of IDH-wildtype (IDHwt) histological lower-grade gliomas (LGGs) over clinicopathological features.

METHODS: Preoperative MRI data of 61 patients with IDHwt histological LGGs were included as the institutional training set. The test set consisted of 32 patients from The Cancer Genome Atlas. Radiomic features (n = 186) were extracted using conventional MRIs. The radiomics risk score (RRS) for overall survival (OS) was derived from the elastic net. Multivariable Cox regression analyses with clinicopathological features (including epidermal growth factor receptor [EGFR] amplification and telomerase reverse transcriptase promoter [TERTp] mutation status) and the RRS were performed. The integrated area under the receiver operating curves (iAUCs) from the models with and without the RRS were compared. The net reclassification index (NRI) for 1-year OS was also calculated. The prognostic value of the RRS was evaluated using the external validation set.

RESULTS: The RRS independently predicted OS (hazard ratio = 48.08; p = 0.001). Compared with the clinicopathological model alone, adding the RRS had a better OS prediction performance (iAUCs 0.775 vs. 0.910), which was internally validated (iAUCs 0.726 vs. 0.884, 1-year OS NRI = 0.497), and a similar trend was found on external validation (iAUCs 0.683 vs. 0.705, 1-year OS NRI = 0.733). The prognostic significance of the RRS was confirmed in the external validation set (p = 0.001).

CONCLUSIONS: Integrating radiomics with clinicopathological features (including EGFR amplification and TERTp mutation status) can improve survival prediction in patients with IDHwt LGGs.

KEY POINTS: • Radiomics risk score has the potential to improve survival prediction when added to clinicopathological features (iAUCs increased from 0.775 to 0.910). • NRIs for 1-year OS showed that the radiomics risk score had incremental value over the clinicopathological model. • The prognostic significance of the radiomics risk score was confirmed in the external validation set (p = 0.001).

PMID:35763095 | DOI:10.1007/s00330-022-08941-x

Oncologist. 2022 Jun 28:oyac117. doi: 10.1093/oncolo/oyac117. Online ahead of print.

ABSTRACT

BACKGROUND: Patient-reported adverse events may be a useful adjunct for assessing a drug’s tolerability in dose-finding oncology trials (DFOT). We conducted surveys of international stakeholders and the National Cancer Research Institute (NCRI) Consumer Forum to understand attitudes about patient-reported outcome (PRO) use in DFOT.

METHODS: A 35-question survey of clinicians, trial managers, statisticians, funders, and regulators of DFOT was distributed via professional bodies examining experience using PROs, benefits/barriers, and their potential role in defining tolerable doses. An 8-question survey of the NCRI Consumer Forum explored similar themes.

RESULTS: International survey: 112 responses from 15 September-30 November 2020; 103 trialists [48 clinicians (42.9%), 38 statisticians (34.0%), 17 trial managers (15.2%)], 7 regulators (6.3%), 2 funders (1.8%)]. Most trialists had no experience designing (73, 70.9%), conducting (52, 50.5%), or reporting (88, 85.4%) PROs in DFOT. Most agreed that PROs could identify new toxicities (75, 67.0%) and provide data on the frequency (86, 76.8%) and duration (81, 72.3%) of toxicities. The top 3 barriers were lack of guidance regarding PRO selection (73/103, 70.9%), missing PRO data (71/103, 68.9%), and overburdening staff (68/103, 66.0%). NCRI survey: 57 responses on 21 March 2021. A total of 28 (49.1%) were willing to spend <15 min/day completing PROs. Most (55, 96.5%) preferred to complete PROs online. 61 (54.5%) trialists and 57 (100%) consumers agreed that patient-reported adverse events should be used to inform dose-escalation decisions.

CONCLUSION: Stakeholders reported minimal experience using PROs in DFOT but broadly supported their use. Guidelines are needed to standardize PRO selection, analysis, and reporting in DFOT.

PMID:35762393 | DOI:10.1093/oncolo/oyac117

Oral Health Prev Dent. 2022 Jun 28;20(1):279-294. doi: 10.3290/j.ohpd.b3170043.

ABSTRACT

PURPOSE: To summarise the available data on the effects of chlorhexidine (CHX) mouthwash in treating gingivitis during treatment with fixed orthodontic appliances.

MATERIALS AND METHODS: Multiple electronic databases were searched up to December 7th, 2021. Only randomised controlled trials (RCTs) were eligible for inclusion. The quality of the included RCTs was assessed with the Cochrane risk of bias tool for randomised trials (RoB 2.0). After data extraction and risk of bias assessment, differences were recorded in several oral hygiene indices in time and mean percentage change in those indices using different antimicrobial solutions.

RESULTS: Fourteen studies were deemed eligible for inclusion, reporting on a total of 602 patients with an age range of 11-35 years. The experimental solution was a 0.06%, 0.12%, or 0.2% CHX mouthwash with the control either a placebo mouthwash or a selection from a variety of mouthwashes. Treatment duration varied from 1 day to almost 5 months and the follow-up period varied from 1 min to 5 months. Chlorhexidine mouthrinses led to reduced plaque accumulation and gingival inflammation during orthodontic treatment, while at the same time, some of the control group mouthrinses were deemed equally effective. No statistically significant difference was detected in the meta-analysis between CHX and mouthwashes with propolis/probiotics/herbs in terms of the gingival index at 3 to 4 weeks (mean difference 0.07, 95% CI: -0.18, 0.31, p = 0.59).

CONCLUSION: Chlorhexidine mouthwash in orthodontic patients successfully controls gingival inflammation and bleeding when compared to untreated controls, but is equally effective as other mouthrinses where various oral health indices are concerned.

PMID:35762364 | DOI:10.3290/j.ohpd.b3170043

Oral Health Prev Dent. 2022 Jun 28;20(1):271-278. doi: 10.3290/j.ohpd.b3170031.

ABSTRACT

PURPOSE: Conservative restorations of endodontically treated premolars have yielded mixed results. The present study aimed to compare fracture resistance of endodontically treated premolars with Class II mesial-occlusal cavity preparations, restored with either Smart Dentin Replacement (SDR; Dentsply Sirona) material, Biodentine (Septodont) or ceramic inlays.

MATERIALS AND METHODS: Thirty-two extracted premolars were randomly divided into four equal groups (n = 8): Group 1 served as a control group with teeth left intact; teeth in the remaining three groups received root canal treatment followed by a mesio-occlusal cavity preparation. These crowns were restored with: Biodentine in group 2, SDR in group 3 and ceramic inlays in group 4. A computer-controlled Instron universal testing machine subjected all specimens to compressive load until failure. Force at failure and fracture mode (above or below the cementoenamel junction) were recorded. The data were analysed using Fisher’s exact test and one-way ANOVA followed by the post-hoc Tukey’s test. Statistical significance was set at p < 0.05.

RESULTS: The lowest mean load at failure was recorded for the inlay group. Loads at failure were statistically significantly higher for teeth restored with Biodentine than with SDR (p = 0.012) and ceramic inlays (p = 0.007). There were no statistically significant differences between the groups in terms of fracture mode (p = 0.440).

CONCLUSION: Endodontically treated premolars with mesial-occlusal cavity preparation restored with Biodentine were more resistant to fracture than those restored with either SDR or ceramic inlays. Biodentine may prove a promising material to restore endodontically treated teeth with one missing proximal wall.

PMID:35762363 | DOI:10.3290/j.ohpd.b3170031

Biotechnol J. 2022 Jun 28:e2200134. doi: 10.1002/biot.202200134. Online ahead of print.

ABSTRACT

Plant-based production systems are inexpensive and easy to handle, allowing them to complement existing platforms for the production of protein-based vaccines, therapeutics and diagnostic reagents. However, screening product candidates in whole plants requires a large facility footprint and is challenging due to natural variations in recombinant protein accumulation. In contrast, plant cell packs (PCPs) allow more than 1000 samples to be screened per day in microtiter plates. PCPs enable rapid development cycles based on transient expression in as little as 3 days, and yield milligram quantities of product for initial quality assessment and functional testing. However, this requires high-level expression in BY-2 cells and consistent cell quality across batches. We therefore used a statistical design of experiments (DoE) approach to systematically assess factors that contribute to consistent high yields of recombinant proteins in PCPs. Specifically, we tested the osmolality, pH, carbon source, light source and additives during cell cultivation, as well as cell and PCP harvest times. The careful adjustment of these factors increased overall productivity by approximately fourfold. Remarkably all cultivation conditions leading to high productivities during transient expression in PCPs were associated with limited water uptake into the central vacuole. The universal presence of a vacuole in plant cells indicates that our results should be transferrable to other cells lines. Our findings therefore support the broad application of PCPs for screening and product analysis during the development of protein-based pharmaceuticals and reagents in plants. This article is protected by copyright. All rights reserved.

PMID:35762355 | DOI:10.1002/biot.202200134

Proc Inst Mech Eng H. 2022 Jun 28:9544119221102814. doi: 10.1177/09544119221102814. Online ahead of print.

ABSTRACT

The purpose of this study is to investigate the effect of different application methods on the adaptation to dentin and porosity properties of calcium silicate based materials. This study included 72 maxillary canine teeth that had been extracted for various reasons. Following the root canal treatment, root, end resections were performed on the specimens. After the apicectomy, 3 mm deep cavities were created. All materials were mixed according to the manufacturer’s instructions. Retrograde cavities were filled with RetroMTA [Group 1a-1c], Biodentine [Group 2a-2c] and BioAggregate [Group 3a-3c]. Placement techniques were applied for each material by using incremental, bulk technique and ultrasonic activation, respectively. The samples were scanned with the SkyScan 1272 μCT system. Porosity values were higher in bulk fill and incremental placement techniques than ultrasonic technique when using MTA and BioAggregate (p < 0.05), but Biodentine showed no statistically significant difference (p > 0.05) on using different placement techniques. The ultrasonic activation technique is beneficial to improve the condensation quality of MTA and BioAggregate. Biodentine showed better results regardless of different application techniques.

PMID:35762350 | DOI:10.1177/09544119221102814