Category: Nevin Manimala

Alzheimers Dement. 2023 May 27. doi: 10.1002/alz.13159. Online ahead of print.

ABSTRACT

OBJECTIVE: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without β-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer’s Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses.

HIGHLIGHTS: Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants.

PMID:37243937 | DOI:10.1002/alz.13159

Clin Pharmacol Ther. 2023 May 27. doi: 10.1002/cpt.2960. Online ahead of print.

ABSTRACT

Pharmacogenomics studies how genes influence a person’s response to treatment. When complex phenotypes are influenced by multiple genetic variations with little effect, a single piece of genetic information is often insufficient to explain this variability. The application of machine learning (ML) in pharmacogenomics holds great potential; namely, it can be used to unravel complicated genetic relationships that could explain response to therapy. In this study, ML techniques were used to investigate the relationship between genetic variations affecting more than 60 candidate genes and carboplatin-, taxane-, and bevacizumab-induced toxicities in 171 patients with ovarian cancer enrolled in the MITO-16A/MaNGO-OV2A trial. Single nucleotide polymorphism (SNP) profiles were examined using ML to find and prioritise those associated with drug-induced toxicities, specifically hypertension, hematological toxicity, non-hematological toxicity, and proteinuria. The Boruta algorithm was used in cross-validation to determine the significance of SNPs in predicting toxicities. Important SNPs were then used to train eXtreme gradient boosting models. During cross-validation, the models achieved reliable performance with a Matthews correlation coefficient ranging from 0.375 to 0.410. A total of 43 SNPs critical for predicting toxicity were identified. For each toxicity, key SNPs were used to create a polygenic toxicity risk score that effectively divided individuals into high-risk and low-risk categories. In particular, compared with low-risk individuals, high-risk patients were 28- fold more likely to develop hypertension. The proposed method provided insightful data to improve precision medicine for ovarian cancer patients, which may be useful for reducing toxicities and improving toxicity management.

PMID:37243926 | DOI:10.1002/cpt.2960

Int J Comput Assist Radiol Surg. 2023 May 27. doi: 10.1007/s11548-023-02934-x. Online ahead of print.

ABSTRACT

PURPOSE: Intra-operative assessment of resection margins during oncological surgery is a field that needs improvement. Ultrasound (US) shows the potential to fulfill this need, but this imaging technique is highly operator-dependent. A 3D US image of the whole specimen may remedy the operator dependence. This study aims to compare and evaluate the image quality of 3D US between freehand acquisition (FA) and motorized acquisition (MA).

METHODS: Multiple 3D US volumes of a commercial phantom were acquired in motorized and freehand fashion. FA images were collected with electromagnetic navigation. An integrated algorithm reconstructed the FA images. MA images were stacked into a 3D volume. The image quality is evaluated following the metrics: contrast resolution, axial and elevation resolution, axial and elevation distance calibration, stability, inter-operator variability, and intra-operator variability. A linear mixed model determined statistical differences between FA and MA for these metrics.

RESULTS: The MA results in a statistically significant lower error of axial distance calibration (p < 0.0001) and higher stability (p < 0.0001) than FA. On the other hand, the FA has a better elevation resolution (p < 0.003) than the MA.

CONCLUSION: MA results in better image quality of 3D US than the FA method based on axial distance calibration, stability, and variability. This study suggests acquiring 3D US volumes for intra-operative ex vivo margin assessment in a motorized fashion.

PMID:37243918 | DOI:10.1007/s11548-023-02934-x

Pediatr Blood Cancer. 2023 May 27:e30421. doi: 10.1002/pbc.30421. Online ahead of print.

ABSTRACT

BACKGROUND: Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum.

METHODS: After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated.

RESULTS: After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth.

CONCLUSION: Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH.

PMID:37243889 | DOI:10.1002/pbc.30421

Cerebellum. 2023 May 27. doi: 10.1007/s12311-023-01561-1. Online ahead of print.

ABSTRACT

The Ataxia Global Initiative (AGI) aims to serve as a platform to facilitate clinical trial readiness for the hereditary ataxias. Clinical trials for these diseases have been hampered by the lack of objective measures to study disease onset, progression, and treatment efficacy. While these issues are not unique to the genetic ataxias, the relative rarity of these diseases makes the need for such measures even more pressing to achieve statistical power in clinical trials. In this report, we have described the efforts of the AGI fluid biomarker working group (WG) in developing uniform protocols for biomarker sampling and storage, both for human and preclinical studies in mice. By reducing collection variability, we anticipate reduced noise in downstream biomarker analysis that will improve statistical power and minimize the necessary sample size. The emphasis has been on defining and standardizing the sampling and pre-analytical work-up of minimal set of biological samples, specifically blood plasma and serum, keeping in mind the need for harmonization of collection and storage that can be achieved with relatively limited cost and resources. An optional package is detailed for those centers that have the resources and commitment for additional biofluids/sample processing and storage. Finally, we have delineated similar standardized protocols for mice that will be important for preclinical studies in the field.

PMID:37243885 | DOI:10.1007/s12311-023-01561-1

Diabetes Metab Res Rev. 2023 May 27:e3652. doi: 10.1002/dmrr.3652. Online ahead of print.

ABSTRACT

AIMS: Prevention of foot ulcers in persons with diabetes is important to help reduce the substantial burden on both individual and health resources. A comprehensive analysis of reported interventions is needed to better inform healthcare professionals about effective prevention. The aim of this systematic review and meta-analysis is to assess the effectiveness of interventions to prevent foot ulcers in persons with diabetes who are at risk thereof.

MATERIALS AND METHODS: We searched the available scientific literature in PubMed, EMBASE, CINAHL, Cochrane databases and trial registries for original research studies on preventative interventions. Both controlled and non-controlled studies were eligible for selection. Two independent reviewers assessed risk of bias of controlled studies and extracted data. A meta-analysis (using Mantel-Haenszel’s statistical method and random effect models) was done when >1 RCT was available that met our criteria. Evidence statements, including the certainty of evidence, were formulated according to GRADE.

RESULTS: From the 19,349 records screened, 40 controlled studies (of which 33 were Randomised Controlled Trials [RCTs]) and 103 non-controlled studies were included. We found moderate certainty evidence that temperature monitoring (5 RCTs; risk ratio [RR]: 0.51; 95% CI: 0.31-0.84) and pressure-optimised therapeutic footwear or insoles (2 RCTs; RR: 0.62; 95% CI: 0.26-1.47) likely reduce the risk of plantar foot ulcer recurrence in people with diabetes at high risk. Further, we found low certainty evidence that structured education (5 RCTs; RR: 0.66; 95% CI: 0.37-1.19), therapeutic footwear (3 RCTs; RR: 0.53; 95% CI: 0.24-1.17), flexor tenotomy (1 RCT, 7 non-controlled studies, no meta-analysis), and integrated care (3 RCTs; RR: 0.78; 95% CI: 0.58-1.06) may reduce the risk of foot ulceration in people with diabetes at risk for foot ulceration.

CONCLUSIONS: Various interventions for persons with diabetes at risk for foot ulceration with evidence of effectiveness are available, including temperature monitoring (pressure-optimised) therapeutic footwear, structured education, flexor tenotomy, and integrated foot care. With hardly any new intervention studies published in recent years, more effort to produce high-quality RCTs is urgently needed to further improve the evidence base. This is especially relevant for educational and psychological interventions, for integrated care approaches for persons at high risk of ulceration, and for interventions specifically targeting persons at low-to-moderate risk of ulceration.

PMID:37243880 | DOI:10.1002/dmrr.3652

J Pharmacokinet Pharmacodyn. 2023 May 27. doi: 10.1007/s10928-023-09864-w. Online ahead of print.

ABSTRACT

Population pharmacokinetics (popPK) of bempedoic acid and the popPK/pharmacodynamic (popPK/PD) relationship between bempedoic acid concentrations and serum low-density lipoprotein cholesterol (LDL-C) from baseline were characterized. A two-compartment disposition model with a transit absorption compartment and linear elimination best described bempedoic acid oral pharmacokinetics (PK). Multiple covariates, including renal function, sex, and weight, had statistically significant effects on the predicted steady-state area under the curve. Mild (estimated glomerular filtration rate (eGFR) 60 to < 90 mL/min vs. ≥ 90 mL/min) and moderate (eGFR 30 to < 60 mL/min vs. ≥ 90 mL/min) renal impairment, female sex, low (< 70 kg vs. 70-100 kg) and high (> 100 kg vs. 70-100 kg) body weight were predicted to have a 1.36-fold (90% confidence interval (CI) 1.32, 1.41), 1.85-fold (90% CI 1.74, 2.00), 1.39-fold (90% CI 1.34, 1.47), 1.35-fold (90% CI 1.30, 1.41), and 0.75-fold (90% CI 0.72, 0.79) exposure difference relative to their reference populations, respectively. An indirect response model described changes in serum LDL-C with a model-predicted 35% maximal reduction and bempedoic acid IC₅₀ of 3.17 µg/mL. A 28% reduction from LDL-C baseline was predicted for a steady-state average concentration of 12.5 µg/mL after bempedoic acid (180 mg/day) dosing, accounting for approximately 80% of the predicted maximal LDL-C reduction. Concurrent statin therapy, regardless of intensity, reduced the maximal effect of bempedoic acid but resulted in similar steady-state LDL-C levels. While multiple covariates had statistically significant effects on PK and LDL-C lowering, none were predicted to warrant bempedoic acid dose adjustment.

PMID:37243877 | DOI:10.1007/s10928-023-09864-w

EJNMMI Phys. 2023 May 27;10(1):33. doi: 10.1186/s40658-023-00554-7.

ABSTRACT

BACKGROUND: Total-body PET scanners with axial field of views (FOVs) longer than 1 m enable new applications to study multiple organs (e.g., the brain-gut-axis) simultaneously. As the spatial resolution and the associated partial volume effect (PVE) can vary significantly along the FOV, detailed knowledge of the contrast recovery coefficients (CRCs) is a prerequisite for image analysis and interpretation of quantitative results. The aim of this study was to determine the CRCs, as well as voxel noise, for multiple isotopes throughout the 1.06 m axial FOV of the Biograph Vision Quadra PET/CT system (Siemens Healthineers).

MATERIALS AND METHODS: Cylindrical phantoms equipped with three different sphere sizes (inner diameters 7.86 mm, 28 and 37 mm) were utilized for the PVE evaluation. The 7.86 mm sphere was filled with F-18 (8:1 and 4:1), Ga-68 (8:1) and Zr-89 (8:1). The 28 mm and 37 mm spheres were filled with F-18 (8:1). Background concentration in the respective phantoms was of ~ 3 kBq/ml. The phantoms were measured at multiple positions in the FOV (axial: 0, 10, 20, 30, 40 and 50 cm, transaxial: 0, 10, 20 cm). The data were reconstructed with the standard clinical protocol, including PSF correction and TOF information with up to 10 iterations for maximum ring differences (MRDs) of 85 and 322; CRCs, as well as voxel noise levels, were determined for each position.

RESULTS: F-18 CRCs (SBR 8:1 and 4:1) of the 7.86 mm sphere decreased up to 18% from the center FOV (cFOV) toward the transaxial edge and increased up to 17% toward the axial edge. Noise levels were below 15% for the default clinical reconstruction parameters. The larger spheres exhibited a similar pattern. Zr-89 revealed ~ 10% lower CRCs than F-18 but larger noise (9.1% (F-18), 19.1% (Zr-89); iteration 4, cFOV) for the default reconstruction. Zr-89 noise levels in the cFOV significantly decreased (~ 28%) when reconstructing the data with MRD322 compared with MRD85 along with a slight decrease in CRC values. Ga-68 exhibited the lowest CRCs for the three isotopes and noise characteristics comparable to those of F-18.

CONCLUSIONS: Distinct differences in the PVE within the FOV were detected for clinically relevant isotopes F-18, Ga-68 and Zr-89, as well as for different sphere sizes. Depending on the positions inside the FOV, the sphere-to-background ratios, count statistics and isotope used, this can result in an up to 50% difference between CRCs. Hence, these changes in PVE can significantly affect the quantitative analysis of patient data. MRD322 resulted in slightly lower CRC values, especially in the center FOV, whereas the voxel noise significantly decreased compared with MRD85.

PMID:37243869 | DOI:10.1186/s40658-023-00554-7

Prev Sci. 2023 May 27. doi: 10.1007/s11121-023-01513-5. Online ahead of print.

ABSTRACT

Evidence-based health interventions are frequently translated into real-world settings where practical needs drive changes to intervention protocols. Due to logistical and resource constraints, these naturally arising adaptations are rarely assessed for comparative effectiveness using a randomized trial. Nevertheless, when observational data are available, it is still possible to identify beneficial adaptations using statistical methods that adjust for differences among intervention groups. As implementation continues and more data are collected and assessed, we also require analysis methods that ensure low statistical error rates as multiple comparisons are made over time. This paper describes how to create a statistical analysis plan for evaluating adaptations to an intervention during ongoing implementation. This can be done by combining methods commonly used in platform clinical trials with methods used for real-world data. We also demonstrate how to use simulations based on previous data to decide the frequency with which to conduct statistical analyses. The illustration uses data from large-scale implementation of a school-based resilience and skill-building preventive intervention to which several adaptations were made. The proposed statistical analysis plan for evaluating the school-based intervention has potential to improve population-level outcomes as implementation scales up further and additional adaptations are anticipated.

PMID:37243867 | DOI:10.1007/s11121-023-01513-5

Ann Neurol. 2023 May 27. doi: 10.1002/ana.26712. Online ahead of print.

ABSTRACT

OBJECTIVE: The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them.

METHODS: Subitem-level correlation- and distribution-based analysis of 1637 SARA assessments in 884 patients with autosomal-recessive/early-onset ataxia (370 with 2-8 longitudinal assessments), complemented by linear mixed-effects modeling to estimate progression and sample sizes.

RESULTS: While SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA<25). Responsiveness was diminished by incomplete sub-scale use at intermediate or upper levels, non-transitions (“static periods”), and fluctuating decreases/increases. All subitems -except nose-finger- showed moderate-to-strong correlations to activities of daily living, indicating that metric properties -not content validity- limit SARA responsiveness. SARA captured mild-to-moderate progression in many genotypes, e.g., SYNE1-ataxia: 0.55 points/year, AOA2: 1.14, POLG-ataxia: 1.56; but no change in others (ARSACS, COQ8A-ataxia). While sensitivity to change was optimal in mild ataxia (SARA≤10), it substantially deteriorated in advanced ataxia (SARA>25; 2.7-fold sample size). Use of a novel rank-optimized SARA without subitems finger-chase and nose-finger reduces sample sizes by 20-25%.

INTERPRETATION: This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. This article is protected by copyright. All rights reserved.

PMID:37243847 | DOI:10.1002/ana.26712