Nevin Manimala

CPT Pharmacometrics Syst Pharmacol. 2022 Mar 14. doi: 10.1002/psp4.12784. Online ahead of print.

ABSTRACT

The relationship between SARS-CoV-2 viral load reduction and disease symptom resolution remains largely undefined for COVID-19. While vaccine-derived immunity takes time to develop, neutralizing monoclonal antibodies offer immediate, passive immunity to patients with COVID-19. Bamlanivimab and etesevimab are two potent neutralizing monoclonal antibodies directed to the receptor binding domain (RBD) of the spike (S) protein of SARS-CoV-2. This study aims to describe the relationship between viral load and resolution of 8 common COVID-19-related symptoms in patients following treatment with neutralizing monoclonal antibodies (bamlanivimab alone or bamlanivimab and etesevimab together), in a Phase 2 clinical trial. Corresponding pharmacokinetics (PK), viral load and COVID-19-related symptom data were modelled using Nonlinear Mixed Effects Modeling (NONMEM) to describe the time-course of 8 COVID-19-related symptoms in an ordered categorical manner (none, mild, moderate, severe), following administration of bamlanivimab or bamlanivimab and etesevimab together to participants with COVID-19. The PK/PD models characterized the exposure-viral load-symptom time course of the 8 pre-selected COVID-19-related symptoms. Baseline viral load (BVL), change in viral load from baseline (ΔVL) and time since the onset of symptoms, demonstrated statistically significant effects on symptom score probabilities. Higher BVL generally indicated an increased probability of symptom severity. The severity of symptoms decreased over time, partially driven by the decrease in viral load. The effect of increasing time resulting in decreased severity of symptoms was over and above the effect of decreasing viral load. Administration of bamlanivimab alone or together with etesevimab results in a faster time to resolution of COVID-19-related symptoms compared to placebo.

PMID:35289125 | DOI:10.1002/psp4.12784

J Pathol Clin Res. 2022 Mar 14. doi: 10.1002/cjp2.266. Online ahead of print.

ABSTRACT

The tumor microenvironment (TME) is a critical regulator of the development of malignant lymphoma. Therapeutics targeting the TME, especially immune checkpoint molecules, are changing the treatment strategy for lymphoma. However, the overall response to these therapeutics for diffuse large B-cell lymphoma (DLBCL) is modest and new targets of immunotherapy are needed. To find critical immune checkpoint molecules for DLBCL, we explored the prognostic impact of immune checkpoint molecules and their ligands using publicly available datasets of gene expression profiles. In silico analysis of three independent datasets (GSE117556, GSE10846, and GSE181063) revealed that DLBCL expressing CD24 had a poor prognosis and had a high frequency of MYC aberrations. Moreover, gene set enrichment analysis showed that the ‘MYC-targets-hallmark’ (false discovery rate [FDR] = 0.024) and ‘inflammatory-response-hallmark’ (FDR = 0.001) were enriched in CD24-high and CD24-low DLBCL, respectively. In addition, the expression of cell-specific markers of various immune cells was higher in CD24-low DLBCL than in CD24-high DLBCL. CIBERSORT analysis of the datasets showed fewer macrophages in CD24-high DLBCL than in CD24-low DLBCL. Additionally, immunohistochemical analysis of 335 cases of DLBCL showed that few TME cells were found in CD24-high DLBCL, although statistical differences were not observed. These data indicate that CD24 expression suppresses immune cell components of the TME in DLBCL, suggesting that CD24 may be a target for cancer immunotherapy in aggressive large B-cell lymphoma.

PMID:35289116 | DOI:10.1002/cjp2.266

Thorac Cancer. 2022 Mar 15. doi: 10.1111/1759-7714.14384. Online ahead of print.

ABSTRACT

PURPOSE: A previous study demonstrated that intracranial tumor volume had some correlation with gastrointestinal cancer patients’ outcome. The aim of this study was to analyze patients with esophageal carcinoma (EC) and brain metastases to investigate if intracranial tumor volume would be a predictor of these patients’ survival.

METHODS: A total of 52 patients with brain metastases from esophageal squamous cell carcinoma or esophageal adenocarcinoma were retrospectively reviewed. Patients without images of brain metastases in the hospital information system were eliminated.

RESULTS: The median follow-up time duration was 8.4 months (interquartile range 4.0-15.2). The median overall survival (OS) from time of brain metastases diagnosis was 8.0 months for all cases. Median OS of patients with small and large cumulative intracranial tumor volume (CITV) (<6.65 cm³ , ≥6.65 cm³ ) was 11.23 and 7.4 months, respectively. Median OS of patients with large and small largest intracranial tumor volume (LITV) (≥7.75 cm³ , <7.75 cm³ ) was 6.4 and 10.6 months, respectively. Univariate analysis demonstrated that CITV (hazard ratio [HR] 1.255, 95% confidence interval [CI] 0.673-2.342, p = 0.475) or LITV (HR 1.037, 95% CI 0.570-1.887, p = 0.904) was not significantly associated with improved OS. Multivariate analysis demonstrated that CITV and LITV were not significantly associated with improved OS.

CONCLUSION: EC patients with small intracranial tumor volume may have longer OS than those with large intracranial tumor volume, but this difference did not reach statistical difference. Future studies with a larger sample size may validate the correlation of intracranial tumor volume and patient survival.

PMID:35289101 | DOI:10.1111/1759-7714.14384

J Biophotonics. 2022 Mar 14:e202100330. doi: 10.1002/jbio.202100330. Online ahead of print.

ABSTRACT

Functional 2-photon microscopy is a key technology for imaging neuronal activity. The recorded image sequences, however, can contain non-rigid movement artifacts which requires high-accuracy movement correction. Variational optical flow (OF) estimation is a group of methods for motion analysis with established performance in many computer vision areas. However, it has yet to be adapted to the statistics of 2-photon neuroimaging data. In this work, we present the motion compensation method Flow-Registration that outperforms previous alignment tools and allows to align and reconstruct even low signal-to-noise ratio 2-photon imaging data and is able to compensate high-divergence displacements during local drug injections. The method is based on statistics of such data and integrates previous advances in variational OF estimation. Our method is available as an easy-to-use ImageJ / FIJI plugin as well as a MATLAB toolbox with modular, object oriented file IO, native multi-channel support and compatibility with existing 2-photon imaging suites. This article is protected by copyright. All rights reserved.

PMID:35289100 | DOI:10.1002/jbio.202100330

Clin Otolaryngol. 2022 Mar 15. doi: 10.1111/coa.13929. Online ahead of print.

ABSTRACT

OBJECTIVES: To identify paediatric intracapsular Coblation tonsillectomy procedures from routine administrative data in England, and determine their safety.

DESIGN: Retrospective observational cohort study of four ENT centres using routine data from Hospital Episode Statistics (HES).

SETTING: Acute NHS trusts in England conducting exclusively intracapsular Coblation tonsillectomy PARTICIPANTS: Children (≤16 years old) undergoing bilateral intracapsular Coblation tonsillectomy MAIN OUTCOME MEASURES: Number of procedures, readmissions for pain, readmissions for bleeding and requirement for additional surgery for regrowth.

RESULTS: 5525 procedures were identified. The median patient age was 4 (IQR 2-5). In-hospital complications occurred in 1%, with 0.1% returning to theatre for arrest of primary tonsil bleeding. Almost half of the procedures were conducted as a day-case (44%), with only a small proportion staying in hospital more than one night (7%). Within 28 days, 1.2% of patients were readmitted with bleeding, 0.7% with infection and 0.3% with pain. 0.2% of patients required return to theatre for control of secondary haemorrhage. Longitudinal follow-up has found that revision tonsil surgery is 0.3% at 1 year (n=4498), 1.1% at 2 years (n=2938), 1.7% at 3 years (n=1781), 1.9% at 4 years (n=905), 2.2% at 5 years (n=305) CONCLUSIONS: Intracapsular coblation tonsillectomy safety outcomes in this study show primary and secondary bleed rates and emergency return to theatre rates are lower than all tonsillectomy techniques reported in the National Prospective Tonsillectomy Audit and also lower than previously published Hospital Episode Statistics analysis of tonsillectomy procedures.

PMID:35289094 | DOI:10.1111/coa.13929

Asia Pac J Clin Oncol. 2022 Mar 14. doi: 10.1111/ajco.13687. Online ahead of print.

ABSTRACT

AIMS: To investigate the implications of soluble programmed cell death-ligand 1 (sPD-L1) in hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE) and to evaluate the potential value of sPD-L1 to guide selection of the optimal time to begin combination therapy with TACE and immune checkpoint inhibitors (ICIs).

MATERIALS AND METHODS: Thirty-one HCC patients suitable for TACE and 55 healthy volunteers were enrolled in this study. Three milliliters of peripheral venous blood of patients were collected on 1 day before TACE and 3, 7, and 30 days after TACE respectively for assay of sPD-L1 using enzyme-linked immunosorbent assay. The associations of the sPD-L1 level with the clinical features, outcomes, and the fluctuation of sPD-L1 during the treatment were analyzed.

RESULTS: The initial sPD-L1 level of patients was significantly higher than that of the control group. And it was significantly associated with BCLC stage, portal venous invasion, tumor size, and number of foci. The sPD-L1 levels of 3 and 7 days after TACE were both significantly higher than the initial level. And that of 30 days after TACE was lower than the initial level, but the difference was not statistically significant. There was no significant difference of sPD-L1 level after embolization with embolic beads of different size. The level of sPD-L1 of CR patients was lower than that of PR, SD patients, but the differences were not significant.

CONCLUSION: The level of sPD-L1 was associated with tumor aggressiveness and outcomes, suggesting its role as a possible predictive biomarker. The increases in sPD-L1 after TACE suggests that combined treatment with TACE and ICIs may be a promising therapeutic strategy in HCC. One week after TACE might be a suitable time to begin the administration of immunotherapy.

PMID:35289092 | DOI:10.1111/ajco.13687

J Thromb Haemost. 2022 Mar 15. doi: 10.1111/jth.15699. Online ahead of print.

ABSTRACT

INTRODUCTION: Symptomatic venous thromboembolism (VTE) is diagnosed in 3-14% of patients during pediatric acute lymphoblastic leukemia (ALL) therapy. There are well-known risk factors, but the role of others as inherited thrombophilia is still controversial. Prophylaxis with low molecular weight heparin (LMWH) has been described, but its use is not globally accepted.

METHODS: A retrospective multicentric study in ALL patients 1-18 years old following SEHOP-PETHEMA-2013 treatment guideline was performed to evaluate VTE rate, anticoagulant treatment, outcome, risk factors, and safety and usefulness of LMWH administration as primary thromboprophylaxis in children with inherited thrombophilia.

RESULTS: A total of 652 patients were included in the study. VTE incidence was 8.7%. Most of the cases occurred during induction therapy, associated to central venous catheter. Univariant analysis showed that family history of thrombosis, presence of mediastinal mass, high-risk treatment group and inherited thrombophilia were statistically significant risk factors. LMWH administration seemed to decrease VTE rate in patients with inherited thrombophilia and those with T-ALL phenotype.

CONCLUSION: Most of VTE cases occurred in patients without inherited thrombophilia, but when it is present, VTE risk is higher. LMWH administration was useful to decrease VTE in these patients.

PMID:35289066 | DOI:10.1111/jth.15699

BJOG. 2022 Mar 14. doi: 10.1111/1471-0528.17138. Online ahead of print.

ABSTRACT

OBJECTIVE: To quantify parents’ experiences of respectful care around stillbirth globally.

DESIGN: Multi-country, online, cross-sectional survey.

SETTING AND POPULATION: Self-identified bereaved parents (n=3769) of stillborn babies from 44 high- and middle-income countries.

METHODS: Parents’ perspectives of 7 aspects of care quality, factors associated with respectful care, and 7 bereavement care practices were compared across geographical regions using descriptive statistics. Respectful care was compared between country income groups using multivariable logistic regression.

MAIN OUTCOME MEASURES: Self-reported experience of care around the time of stillbirth RESULTS: A quarter (25.4%) of 3769 respondents reported disrespectful care after stillbirth and 23.5% reported disrespectful care of their baby. Gestation <30 weeks, and primiparity were associated with disrespect. Reported respectful care was lower in middle-income countries (MICs) than in high-income countries (HICs) (aOR=0.35, 95%CI (0.29-0.42), p <0.01). In many countries, aspects of care quality need improvement, such as ensuring families have enough time with providers. Participating respondents from Latin America and Southern Europe reported lower satisfaction across all aspects of care quality compared to Northern Europe. Unmet need for memory-making activities in MICs is high.

CONCLUSIONS: Many parents experience disrespectful care around stillbirth. Provider training, and system-level support to address practical barriers are urgently needed. However, some practices (which are important to parents) can be readily implemented such as memory-making activities and referring to the baby by name.

PMID:35289061 | DOI:10.1111/1471-0528.17138

Dyslexia. 2022 Mar 14. doi: 10.1002/dys.1711. Online ahead of print.

ABSTRACT

The assumption that statistical learning is affected in dyslexia has generally been evaluated in children and adults with diagnosed dyslexia, not in pre-literate children with a family risk (FR) of dyslexia. In this study, four-to-five-year-old FR children (n = 25) and No-FR children (n = 33) completed tasks of emerging literacy (phoneme awareness and RAN). They also performed an online non-adjacent dependency learning (NADL) task, based on the Serial Reaction Time (SRT) task paradigm. Children’s accuracy (hits), signal sensitivity (d’) and reaction times were measured. The FR group performed marginally more poorly on phoneme awareness and significantly more poorly on RAN than the No-FR group. Regarding NADL outcomes, the results were less straightforward: the data suggested successful statistical learning for both groups, as indicated by the hit and reaction time curves found. However, the FR group was less accurate and slower on the task than the No-FR group. Furthermore, unlike the No-FR group, performance in the FR group varied as a function of the specific stimulus presented. Taken together, these findings fail to show a robust difference in statistical learning between children with and without an FR of dyslexia at preschool age, in line with earlier work on older children and adults with dyslexia.

PMID:35289019 | DOI:10.1002/dys.1711

J Magn Reson Imaging. 2022 Mar 15. doi: 10.1002/jmri.28150. Online ahead of print.

ABSTRACT

BACKGROUND: Diffusion kurtosis imaging (DKI) is used to differentiate between benign and malignant breast lesions. DKI fits are performed either on voxel-by-voxel basis or using volume-averaged signal.

PURPOSE: Investigate and compare DKI parameters’ diagnostic performance using voxel-by-voxel and volume-averaged signal fit approach.

STUDY TYPE: Retrospective.

STUDY POPULATION: A total of 104 patients, aged 24.1-86.4 years.

FIELD STRENGTH/SEQUENCE: A 3 T Spin-echo planar diffusion-weighted sequence with b-values: 50 s/mm² , 750 s/mm² , and 1500 s/mm² . Dynamic contrast enhanced (DCE) sequence.

ASSESSMENT: Lesions were manually segmented by M.P. under supervision of S.O. (2 and 5 years of experience in breast MRI). DKI fits were performed on voxel-by-voxel basis and with volume-averaged signal. Diagnostic performance of DKI parameters DK (kurtosis corrected diffusion coefficient) and kurtosis K was compared between both approaches.

STATISTICAL TESTS: Receiver operating characteristics analysis and area under the curve (AUC) values were computed. Wilcoxon rank sum and Students t-test tested DKI parameters for significant (P <0.05) difference between benign and malignant lesions. DeLong test was used to test the DKI parameter performance for significant fit approach dependency. Correlation between parameters of the two approaches was determined by Pearson correlation coefficient.

RESULTS: DKI parameters were significantly different between benign and malignant lesions for both fit approaches. Median benign vs. malignant values for voxel-by-voxel and volume-averaged approach were 2.00 vs. 1.28 ( DK in μm² /msec), 2.03 vs. 1.26 ( DK in μm² /msec), 0.54 vs. 0.90 ( K ), 0.55 vs. 0.99 ( K ). AUC for voxel-by-voxel and volume-averaged fit were 0.9494 and 0.9508 ( DK ); 0.9175 and 0.9298 ( K ). For both, AUC did not differ significantly (P = 0.20). Correlation of values between the two approaches was very high (r = 0.99 for DK and r = 0.97 for K ).

DATA CONCLUSION: Voxel-by-voxel and volume-averaged signal fit approach are equally well suited for differentiating between benign and malignant breast lesions in DKI.

EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

PMID:35289015 | DOI:10.1002/jmri.28150