Category: Nevin Manimala

Pain. 2021 Sep 2. doi: 10.1097/j.pain.0000000000002470. Online ahead of print.

ABSTRACT

Patients with chronic pain syndromes, such as those with painful peripheral neuropathy due to diabetes mellitus, have limited treatment options and suffer ongoing attrition of their quality of life. Safer and more effective treatment options are needed. One therapeutic approach encompasses phenotypic characterization of the neuropathic pain subtype, combined with the selection of agents that act on relevant mechanisms. ISC 17536 is a novel, orally available inhibitor of the widely expressed pain receptor, Transient Receptor Potential Ankyrin 1 (TRPA1), which mediates nociceptive signaling in peripheral small nerve fibers (SNF). In this randomized, placebo-controlled, proof-of-concept trial, we assessed the safety and efficacy of 28 day administration of ISC 17536 in 138 patients with chronic, painful diabetic peripheral neuropathy, and utilized Quantitative Sensory Testing (QST) to characterize the baseline phenotype of patients. The primary endpoint was change from baseline to end of treatment in the mean 24-hour average pain intensity (API) score based on an 11-point pain intensity numeric rating scale (NRS). The study did not meet the primary end-point in the overall patient population. However, statistically significant and clinically meaningful improvement in pain were seen with ISC 17536 in an exploratory hypothesis generating sub-population of patients with preserved SNF function defined by QST. These results may provide a mechanistic basis for targeted therapy in specific pain phenotypes in line with current approaches of “precision medicine” or personalized pain therapeutics. The hypothesis is planned to be tested in a larger Phase 2 study.

PMID:34490850 | DOI:10.1097/j.pain.0000000000002470

Epilepsia. 2021 Sep 7. doi: 10.1111/epi.17032. Online ahead of print.

ABSTRACT

OBJECTIVE: Drug-resistant temporal lobe epilepsy (TLE) is typically associated with hippocampal pathology. However, widespread network alterations are increasingly recognized and suggested to perturb cognitive function in multiple domains. Here we tested (1) whether TLE shows atypical cortical hierarchical organization, differentiating sensory and higher order systems; and (2) whether atypical hierarchy predicts cognitive impairment.

METHODS: We studied 72 well-characterized drug-resistant TLE patients and 41 healthy controls, statistically matched for age and sex, using multimodal magnetic resonance imaging analysis and cognitive testing. To model cortical hierarchical organization in vivo, we used a bidirectional stepwise functional connectivity analysis tapping into the differentiation between sensory/unimodal and paralimbic/transmodal cortices. Linear models compared patients to controls. Finally, we assessed associations of functional anomalies to cortical atrophy and microstructural anomalies, as well as clinical and cognitive parameters.

RESULTS: Compared to controls, TLE presented with bidirectional disruptions of sensory-paralimbic functional organization. Stepwise connectivity remained segregated within paralimbic and salience networks at the top of the hierarchy, and sensorimotor and dorsal attention at the bottom. Whereas paralimbic segregation was associated with atypical cortical myeloarchitecture and hippocampal atrophy, dysconnectivity of sensorimotor cortices reflected diffuse cortical thinning. The degree of abnormal hierarchical organization in sensory-petal streams covaried, with broad cognitive impairments spanning sensorimotor, attention, fluency, and visuoconstructional ability and memory, and was more marked in patients with longer disease duration and Engel I outcome.

SIGNIFICANCE: Our findings show atypical functional integration between paralimbic/transmodal and sensory/unimodal systems in TLE. Differential associations with paralimbic microstructure and sensorimotor atrophy suggest that system-level imbalance likely reflects complementary structural processes, but ultimately accounts for a broad spectrum of cognitive impairments. Hierarchical contextualization of cognitive deficits promises to open new avenues for personalized counseling in TLE.

PMID:34490890 | DOI:10.1111/epi.17032

Immunol Invest. 2021 Sep 7:1-15. doi: 10.1080/08820139.2020.1828911. Online ahead of print.

ABSTRACT

BACKGROUND: Peritoneal fibrosis (PF) can reduce the efficiency of peritoneal dialysis and eventually lead to ultrafiltration failure. Epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) is the start of PF. Macrophages are involved in the process. This study was to investigate the effect of macrophage polarization on EMT of PMCs.

METHODS: Monocyte-macrophage cells (THP-1) were treated to induce macrophage subsets (M1, M2a, M2c). The inducing was assessed by detecting protein and mRNA expression of cytokines using ELISA and RT-PCR. Subsequently, PMCs were co-cultured with M1, M2a and M2c, respectively, in Transwell chambers for 48 h and then expressions of E-cadherin and α-SMA were determined in PMCs. The PMCs that were not co-cultured with macrophages served as control PMCs. One-way ANOVA and SNK-q test were used to conduct statistics and P < .05 as significant.

RESULTS: Detection of the cytokines, including IL-6, IL-10, IL-12, TGF-β1, CCL17 and CXCL13, verified that the inducting of macrophage subtypes was successful. Compared to control, E-cadherin protein expression was significantly decreased and α-SMA protein expression increased in M1-treated PMCs (P < .05); M2a-treated PMCs had an increased gene expression of α-SMA (P < .05); E-cadherin protein and gene expression were decreased and α-SMA protein and gene expression increased significantly in M2c-treated PMCs (P < .05 or P < .01).

CONCLUSIONS: EMT of PMCs is enhanced by M2c macrophage polarization; meanwhile, M1 and M2a polarization may have the effect to some extent, but not as definite as M2c.

PMID:34490837 | DOI:10.1080/08820139.2020.1828911

Elife. 2021 Sep 7;10:e67455. doi: 10.7554/eLife.67455.

ABSTRACT

Bacteria live in environments that are continuously fluctuating and changing. Exploiting any predictability of such fluctuations can lead to an increased fitness. On longer timescales, bacteria can ‘learn’ the structure of these fluctuations through evolution. However, on shorter timescales, inferring the statistics of the environment and acting upon this information would need to be accomplished by physiological mechanisms. Here, we use a model of metabolism to show that a simple generalization of a common regulatory motif (end-product inhibition) is sufficient both for learning continuous-valued features of the statistical structure of the environment and for translating this information into predictive behavior; moreover, it accomplishes these tasks near-optimally. We discuss plausible genetic circuits that could instantiate the mechanism we describe, including one similar to the architecture of two-component signaling, and argue that the key ingredients required for such predictive behavior are readily accessible to bacteria.

PMID:34490844 | DOI:10.7554/eLife.67455

Nutr Cancer. 2021 Sep 7:1-10. doi: 10.1080/01635581.2021.1974894. Online ahead of print.

ABSTRACT

In recent years, Controlling Nutritional Status (CONUT) Score has become widely recognized as a novel index to evaluate the survival in urological neoplasms patients, especially with renal cell carcinoma (RCC) and upper tract urothelial carcinoma (UTUC). The aim of this meta-analysis is to evaluate the prognostic value of CONUT score in patients with RCC and UTUC. PubMed, Web of Science and Embase were searched for data on the association between CONUT score and RCC/UTUC prognosis up to July 29, 2021. Duplicates were excluded, and inclusion/exclusion criteria were applied to all abstracts. We sorted out relevant studies and extracted the risk ratios (RRs) and its 95% confidence interval (CI) for recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). The relationship between gender and survival outcomes was analyzed using univariate cox regression. We analyzed seven studies including 5410 patients in the meta-analysis. A high CONUT score was associated with poor 5-year RFS (RR = 1.27, 95% CI = 1.13-1.43, P = 0.0001), CSS (RR = 1.22, 95% CI = 1.07-1.39, P = 0.003) and OS (RR = 1.24, 95% CI = 1.10-1.41, P = 0.0005). As a result, the association between CONUT score and survival was statistically significant. In addition, gender was not related to survival outcomes. Our results show that the CONUT score is associated with RCC and UTUC outcomes and can serve as a readily available biomarker for managing this disease.

PMID:34490808 | DOI:10.1080/01635581.2021.1974894

Curr Med Res Opin. 2021 Sep 7:1. doi: 10.1080/03007995.2021.1976125. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the effects of metreleptin in distinct subgroups of patients with generalized lipodystrophy (GL) and partial lipodystrophy (PL), using multivariate linear regression modeling to account for the role patients’ baseline usage of concomitant glucose and lipid-lowering medications and other covariates on their outcomes.

MATERIALS AND METHODS: A post-hoc statistical analysis of two published single-arm, interventional, phase 2 clinical trials at NIH was conducted. Concomitant medication use was assessed for the clinical trial population using prescription fill data, measured at baseline and post-one year following metreleptin initiation. Pre-specified co-primary efficacy endpoints measured were change from baseline in HbA1c at month 12, and the percent change from baseline in fasting serum triglycerides (TG) at month 12. Descriptive and statistical analyses were conducted for the overall population, the separate populations with GL and PL, and additional PL subgroups defined by baseline metabolic markers of elevated HbA1c and elevated fasting TG.

RESULTS: As previously reported, improvement in HbA1c and fasting TG from baseline to 12 months on metreleptin were observed in the overall population (mean change -1.57 percentage points and median change -37.9%, respectively) and subgroups. For both HbA1c and TG, baseline levels were significant predictors of changes after metreleptin. After considering baseline characteristics such as disease type, age, sex, and baseline HbA1c, baseline insulin use was not found to be a significant predictor of HbA1c improvement following metreleptin initiation. Similar results were seen for TG levels, with use of any lipid-lowering medications at baseline not found to be a significant predictor of reductions in fasting TG levels.

CONCLUSIONS: Patients treated with metreleptin experienced statistically significant improvement in metabolic markers of glycemic and hypertriglyceridemic control – e.g. HbA1c and triglyceride levels -across various subgroups after controlling for baseline characteristics and concomitant medication usage.

PMID:34490811 | DOI:10.1080/03007995.2021.1976125

Nutr Cancer. 2021 Sep 7:1-4. doi: 10.1080/01635581.2021.1974499. Online ahead of print.

ABSTRACT

Pakistani females are at elevated risk of breast cancer, hence there is a need to explore every possible potential contributing factor. The present study was performed to analyze the perception of women about their Vit-D levels in both urban and rural areas. Women included 154 clinically diagnosed breast cancer patients from different hospitals and 248 randomly selected females as control group were recruited from Punjab, Pakistan. Statistical analysis was done using SPSS to find the association of Vit-D deficiency with breast carcinoma in different age groups. Out of a total of 402 respondent, 51.5% were completely ignorant of their Vit-D level. Pearson’s Chi- square test for those who had perception about Vit-D deficiency among the breast cancer patients and control group revealed asymptotic 2-sided significance of 0.004 while among different age groups, 41 to 50 years were most prone to deficiency with P = 0.003. Urban women were found to had 12% greater association of Vit-D deficiency as compared to women living in rural areas. It was concluded that Vit-D deficiency is a highly contributing factor for breast cancer so every female must be aware of the importance of Vit-D and should maintain a sufficient level of this crucially important vitamin.

PMID:34490801 | DOI:10.1080/01635581.2021.1974499

Curr Med Res Opin. 2021 Sep 7:1. doi: 10.1080/03007995.2021.1976126. Online ahead of print.

ABSTRACT

OBJECTIVE: The aim of this study was to investigate the time use and both direct and indirect costs associated with subcutaneous immunotherapy (SCIT) for adults with allergic rhinitis (AR) and caregivers of children with AR in the US.

METHODS: We conducted a survey to assess the retrospective time use and direct costs of SCIT. The populations surveyed included adults and caregivers of children (aged 5-17) with symptomatic AR of moderate or higher severity who are currently receiving or have previously started allergy immunotherapy (AIT). The retrospectively collected, self-reported time consumption and direct costs per clinic visit when receiving SCIT were assessed as well as the productivity loss associated with SCIT. Data were analyzed using univariate descriptive statistics.

RESULTS: The study included 106 adults with AR and 191 caregivers of children with AR. We found that the median time spent per visit to the clinic was 50 minutes for both groups, including travel time and time at the clinic. The direct costs related to each visit included parking fees, road tolls and other costs. Adults spent $10 on parking, $9 on tolls and $10 on other costs. Finally, a median 4 hours of work was missed for both the adult patients and the adults accompanying a child.

CONCLUSIONS: We found that SCIT is associated with substantial direct patient costs and productivity loss for both adults with AR and caregivers of children with AR.

PMID:34490806 | DOI:10.1080/03007995.2021.1976126

Bone Jt Open. 2021 Sep;2(9):745-751. doi: 10.1302/2633-1462.29.BJO-2021-0083.R1.

ABSTRACT

AIMS: This study assesses patient barriers to successful telemedicine care in orthopaedic practices in a large academic practice in the COVID-19 era.

METHODS: In all, 381 patients scheduled for telemedicine visits with three orthopaedic surgeons in a large academic practice from 1 April 2020 to 12 June 2020 were asked to participate in a telephone survey using a standardized Institutional Review Board-approved script. An unsuccessful telemedicine visit was defined as patient-reported difficulty of use or reported dissatisfaction with teleconferencing. Patient barriers were defined as explicitly reported barriers of unsatisfactory visit using a process-based satisfaction metric. Statistical analyses were conducted using analysis of variances (ANOVAs), ranked ANOVAs, post-hoc pairwise testing, and chi-squared independent analysis with 95% confidence interval.

RESULTS: The survey response rate was 39.9% (n = 152). The mean age of patients was 51.1 years (17 to 85), and 55 patients (38%) were male. Of 146 respondents with completion of survey, 27 (18.5%) reported a barrier to completing their telemedicine visit. The majority of patients were satisfied with using telemedicine for their orthopaedic appointment (88.8%), and found the experience to be easy (86.6%). Patient-reported barriers included lack of proper equipment/internet connection (n = 13; 8.6%), scheduling difficulty (n = 2; 1.3%), difficulty following directions (n = 10; 6.6%), and patient-reported discomfort (n = 2; 1.3%). Barriers based on patient characteristics were age > 61 years, non-English primary language, inexperience with video conferencing, and unwillingness to try telemedicine prior to COVID-19.

CONCLUSION: The barriers identified in this study could be used to screen patients who would potentially have an unsuccessful telemedicine visit, allowing practices to provide assistance to patients to reduce the risk of an unsuccessful visit. Cite this article: Bone Jt Open 2021;2(9):745-751.

PMID:34490783 | DOI:10.1302/2633-1462.29.BJO-2021-0083.R1

Sci Prog. 2021 Jul-Sep;104(3):368504211038186. doi: 10.1177/00368504211038186.

ABSTRACT

OBJECTIVE: It is aimed to examine the tooth sizes of digital models of patients with different malocclusions with the help of three-dimensional measurement software.

METHODS: Digital models of 252 patients aged between 13 and 25 years of age were included. According to the Angle classification, three different malocclusion groups were allocated such that there were 84 patients in each group, plaster models of patients scanned with the three-dimensional model browser 3Shape R700 3D Scanner (3Shape A/S Copenhagen, Denmark) and transferred to the digital format. 3Shape Ortho Analyzer (3Shape A/S Copenhagen, Denmark) software was used for making the necessary tooth size measurements.

RESULTS: When the measurements were evaluated, it was determined that significant changes occurred between tooth sizes of individuals with different malocclusions. Generally, higher values were observed in mesiodistal and buccolingual tooth dimensions of class II individuals compared to other groups. There was no difference between the groups in the anterior ratio values, but when the overall ratio values were evaluated among the groups, a statistically significant difference was determined. Class II malocclusion group was found to have a significantly lower overall ratio of occurrence.

CONCLUSION: Individuals with different malocclusions differ in tooth size.

PMID:34490798 | DOI:10.1177/00368504211038186