Tag: nevin manimala

Inflammopharmacology. 2022 Dec 31. doi: 10.1007/s10787-022-01123-7. Online ahead of print.

ABSTRACT

OBJECTIVE AND DESIGN: Prostatic inflammation is the driving force in benign prostatic hyperplasia (BPH). This work investigated the potential modulatory effect of COX-2 inhibition on ADAM-17/EGFR/ERK1/2 axis.

MATERIALS OR SUBJECTS: Adult male Wistar rats were used.

TREATMENT: Celecoxib (10 and 20 mg/kg; i.p.) was injected i.p. daily for three weeks. Testosterone (TST) (3 mg/kg; s.c.) was used to induce BPH.

METHODS: Prostatic inflammation and hyperplasia were assessed by organ weight and histopathology. Inflammatory mediators were measured using ELISA technique. Protein analysis was performed using western blotting and immunohistochemistry. Gene expression analysis was performed using qRT-PCR. Statistical analyses included one-way ANOVA and Tukey’s multiple comparison test.

RESULTS: Testosterone-treated rats had a marked increase in COX-2, prostate weight, and index. Moreover, TST-induced COX-2 was inferred from cytoskeletal changes and was attributable to the overexpression of PGE2, NF-κB (p65), and IL-6. COX-2-derived PGE2 increased the activity of ADAM-17, TGF-α, and TNF-α. Consequently, EGFR-ERK1/2 pathway was over-activated, disrupting anti-apoptotic Bcl-2, cyclin D1, and pro-apoptotic Bax. Celecoxib reversed these effects.

CONCLUSION: COX-2 stimulates the ERK1/2 pathway via PGE2-ADAM-17-catalyzed shedding of TGF-α in testosterone-induced BPH. The results indicate a functional correlation between inflammation and hyperplasia in BPH.

PMID:36586043 | DOI:10.1007/s10787-022-01123-7

Eur Phys J E Soft Matter. 2022 Dec 31;45(12):102. doi: 10.1140/epje/s10189-022-00258-3.

ABSTRACT

The problem of classifying turbulent environments from partial observation is key for some theoretical and applied fields, from engineering to earth observation and astrophysics, e.g., to precondition searching of optimal control policies in different turbulent backgrounds, to predict the probability of rare events and/or to infer physical parameters labeling different turbulent setups. To achieve such goal one can use different tools depending on the system’s knowledge and on the quality and quantity of the accessible data. In this context, we assume to work in a model-free setup completely blind to all dynamical laws, but with a large quantity of (good quality) data for training. As a prototype of complex flows with different attractors, and different multi-scale statistical properties we selected 10 turbulent ‘ensembles’ by changing the rotation frequency of the frame of reference of the 3d domain and we suppose to have access to a set of partial observations limited to the instantaneous kinetic energy distribution in a 2d plane, as it is often the case in geophysics and astrophysics. We compare results obtained by a machine learning (ML) approach consisting of a state-of-the-art deep convolutional neural network (DCNN) against Bayesian inference which exploits the information on velocity and entropy moments. First, we discuss the supremacy of the ML approach, presenting also results at changing the number of training data and of the hyper-parameters. Second, we present an ablation study on the input data aimed to perform a ranking on the importance of the flow features used by the DCNN, helping to identify the main physical contents used by the classifier. Finally, we discuss the main limitations of such data-driven methods and potential interesting applications.

PMID:36586035 | DOI:10.1140/epje/s10189-022-00258-3

Ann Nucl Med. 2022 Dec 31. doi: 10.1007/s12149-022-01815-8. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the efficiency of a novel lymph node radiotracer ^99mTc-rituximab in sentinel lymph node (SLN) lymphoscintigraphy and SLN biopsy (SLNB), and the influence of SLNB results on the prognosis of cutaneous malignant melanoma (CMM) patients.

METHODS: A retrospective study was performed on 533 patients with CMM who underwent lymphoscintigraphy and SLNB. All patients received a preoperative peritumoral injection of 11.1-18.5 MBq of ^99mTc-rituximab 0.5 to 1 h before lymphoscintigraphy and SLNB.

RESULTS: The detection rate of lymphoscintigraphy and SLNB was both 99.81% (532/533), and the average number of detected SLNs was 2.1 (range 1 to 8) and 2.7 (range 1 to 11) per patient, respectively. 12.1% SLNs and 22.2% patients were found metastatic, with an average of 1.5 (range 1 to 5) metastatic SLNs per patient. The SLN metastatic rates were different in patients with different Breslow thickness, Clark levels, ulceration, mitotic counts, and HMB45 expression (p < 0.05). Ninety patients were proceeded with the regional lymph node dissection (RLND) after SLNB, and the sensitivity, specificity and accuracy of SLNB in metastatic diagnosis is 97.4, 100 and 96.7%, respectively. And SLNs with metastases was an independent prognostic factor for OS and PFS by multivariate prognostic analyses (HR was 5.9 and 4.3, p < 0.001). For patients with metastatic SLNs, the non-SLNs with metastasis and non-SLNs without metastasis in RLND, and observation groups showed different mean PFS as 14.9, 24.8 and 25.5 months (p = 0.018), but no statistically significant difference existed in the OS.

CONCLUSION: The novel radiotracer ^99mTc-rituximab could identify SLNs specifically in SLN lymphoscintigraphy and SLNB in CMM patients, and the pathology obtained from SLNB rather than from RLND better indicated the staging and long-term prognosis.

PMID:36586034 | DOI:10.1007/s12149-022-01815-8

Environ Sci Pollut Res Int. 2022 Dec 31. doi: 10.1007/s11356-022-24958-7. Online ahead of print.

ABSTRACT

Telomere length (TL) is considered a marker of biological aging and lifetime health, and some epidemiological studies report that the environmental exposures may influence TL at birth. We aimed to investigate the associations between prenatal rare earth elements (REE) exposure and newborn TL. A total of 587 mother-newborn pairs were recruited during 2013 to 2015 in Wuhan, China. Maternal urinary concentrations of REE collected during three trimesters were measured by inductively coupled plasma mass spectrometry. Quantitative real-time polymerase chain reaction was used to measure relative cord blood TL. The trimester-specific associations between prenatal REE exposure and cord blood TL were evaluated using multiple informant models. Weighted quantile sum regression was used to estimate the mixture effect of urinary REE on cord blood TL. After adjustment for potential confounders, per doubling of urinary REE (Dy, Yb, Pr, Nd, and Tm) concentrations (μg/g creatinine) during the second trimester was respectively associated with 1.94% (95% CI 0.19%, 3.72%), 2.10% (95% CI 0.31%, 3.92%), 2.11% (95% CI 0.35%, 3.89%), 2.08% (95% CI 0.01%, 4.20%), and 1.38% (95% CI 0.09%, 2.70%) increase in cord blood TL. Furthermore, exposure to the mixture of REE during the second trimester was also significantly associated with increased cord blood TL (percent change 1.20%, 95% CI 0.30%, 2.11%). However, these associations were not statistically significant in the first and third trimesters. This study provides new evidence on the potential effect of prenatal REE exposure on the initial (newborn) setting of offspring’s telomere biology. Further epidemiological studies are warranted to confirm our findings.

PMID:36586020 | DOI:10.1007/s11356-022-24958-7

Eur Arch Otorhinolaryngol. 2022 Dec 31. doi: 10.1007/s00405-022-07797-7. Online ahead of print.

ABSTRACT

BACKGROUND: The optimal treatments for adult benign laryngotracheal stenosis presently remains controversial. The majority of the disadvantages of endoscopic interventions with high recurrence rate and open surgical therapy accompanied by sophisticated techniques, complication and mortality, highlights the dilemma of option for treatments.

PURPOSE: To compare endoscopic treatments with open surgical interventions in adult patients with benign laryngotracheal stenosis, analyze their clinical outcomes, recurrence, complication and mortality.

METHODS: In the meta-analysis, the databases including PubMed, Embase, Ovid and Web of Science were searched for studies reporting adult benign laryngotracheal stenosis, and clinical outcomes were compared. The duplicate publications, reviews, comments or letters, conference abstracts, case reports were excluded. The random effect model was used for calculating the pooled effect estimates.

RESULTS: Eight studies (1627 cases) referring to six retrospective and two prospective researches were ultimately included in the meta-analysis. The decreased risk estimates of recurrence rate in patients receiving open surgical interventions were detected, comparing with endoscopic interventions (P < 0.05). Subgroup analysis revealed that decreased risk estimates of restenosis rate were also observed in patients receiving open surgical interventions compared with endoscopic interventions (P < 0.05), based on prospective studies, Europe and America, < 2-year follow-up, laryngeal stenosis, stenotic length without inter-group difference or stenotic grade II alone. However, there were no statistically significant difference of recurrence rate between the two interventions (P > 0.05) based on retrospective studies, South Asia and Africa, ≥ 2-year follow-up, involving tracheal lesion, stenotic length with inter-group difference, or stenotic grades of I-IV. No notable difference in the incidence of complication or mortality were identified.

CONCLUSIONS: Open surgical interventions were more suitable for most laryngotracheal stenosis without contraindications. Endoscopic interventions are increasingly being used to treat simple laryngotracheal stenosis, as well as complex airway stenosis in carefully selected cases. Multi-center prospective randomized controlled trials should be conducted to search for the standard treatments for laryngotracheal stenosis.

PMID:36585989 | DOI:10.1007/s00405-022-07797-7

Eur J Pain. 2022 Dec 31. doi: 10.1002/ejp.2074. Online ahead of print.

ABSTRACT

BACKGROUND: A recent randomized controlled trial (N=140) was indicative of large and sustained average improvements of internet-based exposure for fibromyalgia, as compared to a waitlist. However, little is known about who benefits the most from this treatment.

OBJECTIVES: To test for potential moderating effects of age, educational attainment, the duration of fibromyalgia, baseline overall fibromyalgia severity, pain intensity, fibromyalgia-related avoidance behavior, and symptom preoccupation on the waitlist-controlled effect of 10-weeks of internet-based exposure for fibromyalgia.

METHODS: Secondary analysis of a randomized controlled trial (ClinicalTrials.gov NCT02638636). We used linear mixed effects models to determine whether the waitlist-controlled effect of exposure therapy on overall fibromyalgia severity (Fibromyalgia Impact Questionnaire) differed as a function of the potential moderators.

RESULTS: Only pain intensity (0-10) was found to be a significant moderator, where a higher baseline pain intensity predicted a more limited waitlist-controlled effect of internet-based exposure (B=3.48, 95% CI: 0.84 – 6.13). Standardized point estimates of effects were small for the sociodemographic variables, and in the moderate range for some clinical variables that did not reach statistical significance such as behavioral avoidance and time with the fibromyalgia diagnosis.

CONCLUSIONS: Results suggest that internet-based exposure treatment was more useful for participants with lower baseline levels of pain, and less so for participants with higher baseline levels of pain. The treatment had relatively similar effects across the other tested moderators.

PMID:36585933 | DOI:10.1002/ejp.2074

Biometrics. 2022 Dec 31. doi: 10.1111/biom.13818. Online ahead of print.

ABSTRACT

In recent years, the field of precision medicine has seen many advancements. Significant focus has been placed on creating algorithms to estimate individualized treatment rules (ITRs), which map from patient covariates to the space of available treatments with the goal of maximizing patient outcome. Direct Learning (D-Learning) is a recent one-step method which estimates the ITR by directly modeling the treatment-covariate interaction. However, when the variance of the outcome is heterogeneous with respect to treatment and covariates, D-Learning does not leverage this structure. Stabilized Direct Learning (SD-Learning), proposed in this paper, utilizes potential heteroscedasticity in the error term through a residual reweighting which models the residual variance via flexible machine learning algorithms such as XGBoost and random forests. We also develop an internal cross-validation scheme which determines the best residual model amongst competing models. SD-Learning improves the efficiency of D-Learning estimates in binary and multi-arm treatment scenarios. The method is simple to implement and an easy way to improve existing algorithms within the D-Learning family, including original D-Learning, Angle-based D-Learning (AD-Learning), and Robust D-Learning (RD-Learning). We provide theoretical properties and justification of the optimality of SD-Learning. Head-to-head performance comparisons with D-Learning methods are provided through simulations, which demonstrate improvement in terms of average prediction error (APE), misclassification rate, and empirical value, along with a data analysis of an AIDS randomized clinical trial. This article is protected by copyright. All rights reserved.

PMID:36585916 | DOI:10.1111/biom.13818

Ann Neurol. 2022 Dec 31. doi: 10.1002/ana.26593. Online ahead of print.

ABSTRACT

OBJECTIVE: To explore longitudinal changes in synaptic density after ischemic stroke in vivo with synaptic vesicle protein 2A (SV2A) PET.

METHODS: We recruited patients with an ischemic stroke to undergo ¹¹ C-UCB-J PET/MR within the first month and 6 months after stroke. We investigated longitudinal changes of partial volume corrected ¹¹ C-UCB-J SUVR (standardized uptake value ratio; relative to centrum semiovale) within the ischemic lesion, peri-ischemic area and unaffected ipsilesional and contralesional grey matter. We also explored crossed cerebellar diaschisis at 6 months. Additionally, we defined brain regions potentially influencing upper limb motor recovery after stroke and studied ¹¹ C-UCB-J SUVR evolution in comparison to baseline.

RESULTS: In 13 patients (age = 67±15 years) we observed decreasing ¹¹ C-UCB-J SUVR in the ischemic lesion (ΔSUVR = -1.0, p=0.001) and peri-ischemic area (ΔSUVR = -0.31, p=0.02) at 6 months after stroke compared to baseline. Crossed cerebellar diaschisis as measured with ¹¹ C-UCB-J SUVR was present in 11/13 (85%) patients at 6 months. ¹¹ C-UCB-J SUVR did not augment in ipsilesional or contralesional brain regions associated with motor recovery. On the contrary, there was an overall trend of declining ¹¹ C-UCB-J SUVR in these brain regions, reaching statistical significance only in the non-lesioned part of the ipsilesional supplementary motor area (ΔSUVR = -0.83, p=0.046).

INTERPRETATION: At 6 months after stroke, synaptic density further declined in the ischemic lesion and peri-ischemic area compared to baseline. Brain regions previously demonstrated to be associated with motor recovery after stroke did not show increases in synaptic density. This article is protected by copyright. All rights reserved.

PMID:36585914 | DOI:10.1002/ana.26593

J Clin Endocrinol Metab. 2022 Dec 31:dgac758. doi: 10.1210/clinem/dgac758. Online ahead of print.

ABSTRACT

AIMS/HYPOTHESIS: Hyperinsulinemia and adiposity are associated with one another, but the directionality of this relation is debated. Here, we tested the direction of the causal effects of fasting insulin (FI) levels, body fat accumulation/distribution using two-sample bidirectional Mendelian randomization (MR).

METHODS: We included summary statistics from large-scale genome-wide association studies for body mass index (BMI, n=806,834), waist-to-hip ratio adjusted for BMI (WHRadjBMI, n=694,649), abdominal subcutaneous, visceral, and gluteofemoral adipose tissue (n=38,965), FI levels (n=98,210), pancreatic islets gene expression (n=420) and hypothalamus gene expression (n=155). We used inverse variance-weighted and robust MR methods that relied on statistically and biologically driven genetic instruments.

RESULTS: Both BMI and WHRadjBMI were positively associated with FI. Results were consistent across all robust MR methods and when variants mapped to the hypothalamus (presumably associated with food behaviour) were included. In multivariable MR analyses, when waist circumference and BMI were mutually adjusted, the direct effect of waist circumference on FI was 2.43 times larger than the effect of BMI on FI. FI was not associated with adiposity. By contrast, using genetic instruments mapped to gene expression in pancreatic islets (presumably more specific to insulin secretion), insulin was positively associated with BMI and abdominal subcutaneous and gluteofemoral adipose tissue, but not with visceral adipose tissue.

CONCLUSIONS/INTERPRETATION: Although these results will need to be supported by experimental investigations, results of this MR study suggest that abdominal adiposity may be a key determinant of circulating insulin levels. Alternatively, insulin secretion may promote peripheral adipose tissue accumulation.

PMID:36585897 | DOI:10.1210/clinem/dgac758

J Am Geriatr Soc. 2022 Dec 31. doi: 10.1111/jgs.18166. Online ahead of print.

ABSTRACT

BACKGROUND: Primary care is essential for persons with Alzheimer’s disease and related dementias (ADRD). Prior research suggests that the propensity to provide high-quality, continuous primary care varies by provider setting, but the settings used by Medicare-Medicaid dual-eligibles with ADRD have not been described at the population level.

METHODS: Using 2012-2018 Medicare data, we identified dual-eligibles with ADRD. For each person-year, we identified primary care visits occurring in six settings. We calculated descriptive statistics for beneficiaries with a majority of visits in each setting, and conducted a k-means cluster analysis to determine utilization patterns, using the standardized count of primary care visits in each setting.

RESULTS: Each year from 2012 to 2018, at least 45.6% of dual-eligibles with ADRD received a majority of their primary care in nursing facilities, while at least 25.2% did so in physician offices. Over time, the share relying on nursing facilities for primary care decreased by 5.2 percentage points, offset by growth in Federally Qualified Health Centers (FQHCs) and miscellaneous settings (2.3 percentage points each). Dual-eligibles relying on nursing facilities had more annual primary care visits (16.1) than those relying on other settings (range: 6.8-10.7 visits). Interpersonal care continuity was also higher in nursing facilities (97.0%) and physician offices (87.9%) than in FQHCs (54.2%), rural health clinics (RHCs, 46.6%), or hospital-based clinics (56.8%). Among dual-eligibles without care continuity, 82.7% were assigned to a cluster with few primary care visits.

CONCLUSIONS: A trend toward care in different settings likely reflects improved access to patient-centered primary care. Low rates of interpersonal care continuity in FQHCs, RHCs, and physician offices may warrant concern, unless providers in these settings function as a care team. Nonetheless, every healthcare system encounter presents an opportunity to designate a primary care provider for dual-eligibles with ADRD who use little or no primary care.

PMID:36585893 | DOI:10.1111/jgs.18166