Category: Nevin Manimala

J Pharm Biomed Anal. 2023 Oct 4;237:115765. doi: 10.1016/j.jpba.2023.115765. Online ahead of print.

ABSTRACT

Alzheimer’s disease (AD) threatens elderly human health and still lacks effective treatment. Our previous work showed that LGZGD possessed a neuroprotective effect on the Aβ_25-35-induced neurotoxicity in differentiated PC12 cells, indicating that LGZGD may be a potential drug for treatment of AD. However, its pharmacodynamic substances which show anti-inflammatory and anti-oxidant stress activities are still unrevealed. This research aims to reveal the pharmacodynamic substances of LGZGD on Aβ_25-35-induced PC12 cell model of AD based on a spectrum-effect relationship study by using HPLC-FT-ICR-MS method and multivariate statistical analysis. Firstly, the chemical composition spectra of different combinations of LGZGD were recorded by HPLC-FT-ICR MS. Subsequently, Aβ_25-35-induced PC12 cell model of AD was established and pharmacodynamic experiments were conducted to evaluate their anti-inflammatory and anti-oxidant activities, respectively. Finally, the potential pharmacodynamic substances were screened out through spectrum-effect relationship study accompanied by multivariate statistical analysis including bivariate correlation analysis (BCA), grey relational analysis (GRA), principal component analysis (PCA), partial least squares regression analysis (PLSR). As a result, a total of 96 chemical consistents in different combinations of LGZGD were discovered. Among them, 7 components such as isoglabrolide, licorice saponin E2, licorice saponin N2 and licoisoflavanone were directly linked with the anti-inflammatory effects, and 14 constituents such as tumulosic acid, polyporenic acid C, dehydrotumulosic acid, dehydropachymic acid, and pachymic acid were directly correlated with the anti-oxidative stress activities. In conclusion, we combined the HPLC-FT-ICR-MS spectra with pharmacodynamic indicators to develop the spectrum-effect relationships of LGZGD for the first time, and successfully revealed its potential pharmacodynamic substances in the treatment of AD from the anti-inflammatory and antioxidant pathways in the cell model.

PMID:37844366 | DOI:10.1016/j.jpba.2023.115765

J Pharm Biomed Anal. 2023 Oct 10;237:115777. doi: 10.1016/j.jpba.2023.115777. Online ahead of print.

ABSTRACT

In pharmaceutical analysis using a high-performance liquid chromatography (HPLC) system, repeatability assessment is significant to obtain reliable and precise quantitative results. The purpose of the present study is to experimentally show the statistical reliability of a relative standard deviation (RSD) of peak area estimated by a chemometric tool based on probability theory, called the function of mutual information (FUMI) theory, which stochastically provided an RSD of peak area and SD of baseline areas with width k (s(k)) from noises and a signal on a single chromatogram. An ultra-high-performance liquid chromatography with ultraviolet detection (UHPLC-UV) for determining ergosterol was applied as an example of the repeatability assessment. In addition, the statistical reliability of an RSD of peak area in the UHPLC-UV system was certified according to a chi-square (χ²) distribution. The 712 values of s(k) were experimentally obtained from a data series of 1001 points in the noise regions of 712 chromatograms. The histogram of χ² of s(k) was well-fitted to the χ² distribution curve (freedom degree, ν = 50), indicating that the statistical reliability of an RSD of the peak area in the UHPLC-UV estimated by the FUMI theory (n = 1) was equivalent to that estimated by 50 runs of chromatographic measurements.

PMID:37844361 | DOI:10.1016/j.jpba.2023.115777

Clin Exp Optom. 2023 Oct 16:1-6. doi: 10.1080/08164622.2023.2266498. Online ahead of print.

ABSTRACT

CLINICAL RELEVANCE: Currently eye examinations are usually based on autorefraction followed by subjective refraction (SR) with a phoropter. An automated phoropter that can also perform autorefraction may facilitate the optometric workflow.

BACKGROUND: The efficiency and feasibility of an objective autorefraction and correction system are assessed by comparing objective refractive measurements with SR on the same subjects and evaluating the visual acuity (VA) values obtained after the objective refractive measurement and correction.

METHODS: Objective autorefraction and correction was performed on 41 subjects using an automated binocular phoropter system. The auto-phoropter performs autorefraction by wavefront measurement and corrects the spherical and cylindrical errors with tunable fluidic lenses while the patient looks at a visual display inside the instrument. The instrument outputs are optometric constants of spherical and cylindrical aberrations. After measurement and automated correction of the refractive errors, the VA values were assessed by having the subjects look at an integrated Snellen chart. The objective measurement results were statistically compared with their SR.

RESULTS: The correlations between SR and objective autorefraction and correction spherical equivalents (M) were 0.98 (0.97-0.99) and 0.96 (0.93-0.98), the vertical Jackson cross cylinder (J₀) were 0.96 (0.92-0.98) and 0.95 (0.91-0.97), and the oblique Jackson cross cylinder (J₄₅) were 0.73 (0.55-0.85) and 0.82 (0.69-0.90), for the right and left eyes, respectively, with the 95% confidence interval (CI) values in parentheses. 89.0% of the 82 eyes had at least 6/7.5 VA.

CONCLUSIONS: A significant agreement between the SR and objective autorefraction and correction was observed. An all-objective refractive assessment with instantaneous verification may improve the precision of eye prescriptions and possibly reduce the procedure time.

PMID:37844333 | DOI:10.1080/08164622.2023.2266498

Ann Intern Med. 2023 Oct;176(10):1413-1418. doi: 10.7326/M23-0623.

ABSTRACT

The speed of drug regulatory agencies in the United States and Europe is often a source of discussion. The objective of this research was to assess regulatory review duration of first and supplementary indications approved between 2011 and 2020 in the United States and Europe (European Union [EU] and Switzerland) and differences in submission times between the United States and Europe. Descriptive statistics were applied to review times between the jurisdictions and across the therapeutic areas. A regression analysis was done to estimate the association between approval agency and review times. The primary analysis cohort included 241 drugs approved in the United States, the EU, and Switzerland. Of these, 128 drugs had supplemental indications (331 in total) in the United States and 87 had supplemental indications (206 in total) in the EU. Overall median review duration from submission to approval subtracting the clock stop period was 39 weeks in the United States, 44 weeks in the EU, and 44 weeks in Switzerland. When review times within each drug were compared, the European Medicines Agency took a median of 3.7 weeks (IQR, -6.7 to 14.9 weeks) longer than the U.S. Food and Drug Administration and Swissmedic a median of 0.3 weeks (IQR, -10.6 to 15.3 weeks) longer. Median total review duration for supplemental indications was 26 weeks in the United States and 40 weeks in the EU. Applications were submitted a median of 1.3 and 17.9 weeks later in the EU and Switzerland, respectively, than in the United States. The regression analysis showed small differences in submission times between the United States and the EU (-2.1 weeks [95% CI, -11.7 to 7.6 weeks]) and larger differences between the United States and Switzerland (33.0 weeks [CI, 23.1 to 42.8 weeks]). It would be beneficial for patients if differences in submission times between the United States and Europe continue to be minimized.

PMID:37844306 | DOI:10.7326/M23-0623

Transl Vis Sci Technol. 2023 Oct 3;12(10):13. doi: 10.1167/tvst.12.10.13.

ABSTRACT

PURPOSE: Circumpapillary retinal nerve fiber layer thickness (RNFLT) measurement aids in the clinical diagnosis of glaucoma. Spectral domain optical coherence tomography (SD-OCT) machines measure RNFLT and provide normative color-coded plots. In this retrospective study, we investigate whether normative percentiles of RNFLT (pRNFLT) from Spectralis SD-OCT improve prediction of glaucomatous visual field loss over raw RNFLT.

METHODS: A longitudinal database containing OCT scans and visual fields from Massachusetts Eye & Ear glaucoma clinic patients was generated. Reliable OCT-visual field pairs were selected. Spectralis OCT normative distributions were extracted from machine printouts. Supervised machine learning models compared predictive performance between pRNFLT and raw RNFLT inputs. Regional structure-function associations were assessed with univariate regression to predict mean deviation (MD). Multivariable classification predicted MD, pattern standard deviation, MD change per year, and glaucoma hemifield test.

RESULTS: There were 3016 OCT-visual field pairs that met the reliability criteria. Spectralis norms were found to be independent of age, sex, and ocular magnification. Regional analysis showed significant decrease in R2 from pRNFLT models compared to raw RNFLT models in inferotemporal sectors, across multiple regressors. In multivariable classification, there were no significant improvements in area under the curve of receiver operating characteristic curve (ROC-AUC) score with pRNFLT models compared to raw RNFLT models.

CONCLUSIONS: Our results challenge the assumption that normative percentiles from OCT machines improve prediction of glaucomatous visual field loss. Raw RNFLT alone shows strong prediction, with no models presenting improvement by the manufacturer norms. This may result from insufficient patient stratification in tested norms.

TRANSLATIONAL RELEVANCE: Understanding correlation of normative databases to visual function may improve clinical interpretation of OCT data.

PMID:37844261 | DOI:10.1167/tvst.12.10.13

J Pediatr Endocrinol Metab. 2023 Oct 18. doi: 10.1515/jpem-2023-0303. Online ahead of print.

ABSTRACT

OBJECTIVES: Greulich-Pyle (GP) is one of the most used method for bone age determination (BAD) in various orthopedic, pediatric, radiological, and forensic situations. We aimed to investigate the inter- and intra-observer reliability of the GP method between the most relevant disciplines and its applicability to the Turkish population.

METHODS: One-hundred and eighty (90 boys, 90 girls) patients with a chronological age younger than 18 (mean 9.33) were included. X-rays mixed by the blinded investigator were evaluated by two orthopedists, two radiologists, and two pediatric endocrinologists to determine skeletal age according to the GP atlas. A month later the process was repeated. As a statistical method, Paired t-test was used for comparison, an Intraclass Correlation Coefficients test was used for reliability and a 95 % confidence interval was determined. Results were classified according to Landis-Koch.

RESULTS: All results were consistent with chronological age (p<0.001), according to the investigators’ evaluations compared with chronological age. At the initial evaluation, the interobserver reliability of the method was 0.999 (excellent); at the second evaluation, the interobserver reliability was 0.997 (excellent). The intra-observer reliability of the method was ‘excellent’ in all observers. When results were separately evaluated by gender, excellent intraobserver correlation and excellent correlation with chronological age were found among all researchers (>0.9). When X-rays were divided into three groups based on age ranges and evaluated, ‘moderate’ and ‘good’ correlations with chronological age were obtained during the peripubertal period.

CONCLUSIONS: The GP method used in skeletal age determination has excellent inter- and intra-observer reliability. During the peripubertal period, potential discrepancies in bone age assessments should be kept in mind. This method can be used safely and reproducibly by the relevant specialists.

PMID:37844258 | DOI:10.1515/jpem-2023-0303

Elife. 2023 Oct 16;12:e52599. doi: 10.7554/eLife.52599. Online ahead of print.

ABSTRACT

Visual neurons respond selectively to features that become increasingly complex from the eyes to the cortex. Retinal neurons prefer flashing spots of light, primary visual cortical (V1) neurons prefer moving bars, and those in higher cortical areas favor complex features like moving textures. Previously, we showed that V1 simple cell tuning can be accounted for by a basic model implementing temporal prediction – representing features that predict future sensory input from past input (Singer et al., 2018). Here we show that hierarchical application of temporal prediction can capture how tuning properties change across at least two levels of the visual system. This suggests that the brain does not efficiently represent all incoming information; instead, it selectively represents sensory inputs that help in predicting the future. When applied hierarchically, temporal prediction extracts time-varying features that depend on increasingly high-level statistics of the sensory input.

PMID:37844199 | DOI:10.7554/eLife.52599

J Strength Cond Res. 2023 Oct 16. doi: 10.1519/JSC.0000000000004602. Online ahead of print.

ABSTRACT

Costello II, JP, Wagner, JD, Dahl, VA, Cohen, JL, Reuter, AM, and Kaplan, LD. Effects of COVID-19 on rate of injury and position-specific injury during the 2020 National Football League season. J Strength Cond Res XX(X): 000-000, 2023-Because of the COVID-19 pandemic, the National Football League (NFL) made changes to its operations for the 2020 season. We hypothesize an increase in the rate of injuries during the 2020 season. Publicly available data were reviewed to identify NFL injuries from the 2015-2020 seasons. Player position, description of injury, date of injury, and injury setting were recorded. p ≤ 0.05 was considered statistically significant. For the 2020 season, compared with the 2015-2019 seasons, there was an increased risk of injury during the regular season overall relative risk (RR) = 1.308 (p < 0.05), week (W)1 RR = 7.33 (p < 0.05), W1-6 RR = 1.964 (p < 0.05), W7-12 RR = 1.8909 (p < 0.05), and during the postseason overall RR = 1.1444 (p < 0.05), calculated using analysis of variance. There was an overall increased risk of abdominal or core injuries RR = 1.248 (p < 0.05), groin or hip injuries RR = 2.534 (p < 0.05), and hamstring injuries RR = 3.644 (p < 0.05). There was an increased risk of hamstring injuries in cornerbacks RR = 3.219 (p < 0.05) and running backs RR = 1.1394 (p < 0.05), hip or groin injuries in guards RR = 1.105 (p < 0.05), Achilles tendon injuries in safeties RR = 1.6976 (p < 0.05), quadriceps injuries in running backs RR = 1.6191 (p < 0.05), and arm injuries in defensive tackles RR = 1.221 (p < 0.05). There was an increase in the overall rate of injuries in the 2020 NFL season, both in the regular season and postseason, compared with the 2015-2019 seasons. The overall rate of abdominal or core, groin or hip, and hamstring injuries increased. Specific player positions saw unique increases in rates of injuries. These findings may be due to numerous operational changes implemented, such as reduced in-person training and the elimination of the preseason, leading to suboptimal, sports-specific conditioning and increased risk of musculoskeletal injury.

PMID:37844189 | DOI:10.1519/JSC.0000000000004602

J Am Chem Soc. 2023 Oct 16. doi: 10.1021/jacs.3c06799. Online ahead of print.

ABSTRACT

High-mobility group box 1 (HMGB1) is a multifunctional protein. Upon injury or infection, HMGB1 is passively released from necrotic and activated dendritic cells and macrophages, where it functions as a cytokine, acting as a ligand for RAGE, a major receptor of innate immunity stimulating inflammation responses including the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Blocking the HMGB1/RAGE axis offers a therapeutic approach to treating these inflammatory conditions. Here, we describe a synthetic antibody (SA), a copolymer nanoparticle (NP) that binds HMGB1. A lightly cross-linked N-isopropylacrylamide (NIPAm) hydrogel copolymer with nanomolar affinity for HMGB1 was selected from a small library containing trisulfated 3,4,6S-GlcNAc and hydrophobic N–tert-butylacrylamide (TBAm) monomers. Competition binding experiments with heparin established that the dominant interaction between SA and HMGB1 occurs at the heparin-binding domain. In vitro studies established that anti-HMGB1-SA inhibits HMGB1-dependent ICAM-1 expression and ERK phosphorylation of HUVECs, confirming that SA binding to HMGB1 inhibits the proteins’ interaction with the RAGE receptor. Using temporary middle cerebral artery occlusion (t-MCAO) model rats, anti-HMGB1-SA was found to accumulate in the ischemic brain by crossing the blood-brain barrier. Significantly, administration of anti-HMGB1-SA to t-MCAO rats dramatically reduced brain damage caused by cerebral ischemia/reperfusion. These results establish that a statistical copolymer, selected from a small library of candidates synthesized using an “informed” selection of functional monomers, can yield a functional synthetic antibody. The knowledge gained from these experiments can facilitate the discovery, design, and development of a new category of drug.

PMID:37844138 | DOI:10.1021/jacs.3c06799

PLoS Negl Trop Dis. 2023 Oct 16;17(10):e0011696. doi: 10.1371/journal.pntd.0011696. Online ahead of print.

ABSTRACT

INTRODUCTION: Melioidosis is a deadly endemic disease in northern Australia and Southeast Asia, including Sabah, Malaysia, which is caused by the bacterium Burkholderia pseudomallei. It contributes to high fatality rates, mainly due to misdiagnosis leading to the wrong treatment being administered to the patients. Local epidemiology and data on clinical features could assist clinicians during diagnosis and treatment. However, these details are still scarce, particularly in Sabah.

METHODS: A retrospective study of 246 culture-confirmed melioidosis cases in Queen Elizabeth Hospital, Sabah, Malaysia was performed between 2016 and 2018. The epidemiological data and clinical and laboratory findings were extracted and analysed.

RESULTS: The annual incidence of culture-confirmed melioidosis cases was estimated to be 4.97 per 100,000 people. The mean age of the patients was 50±15 years. Males and members of the Kadazan-Dusun ethnic group accounted for the majority of the melioidosis cases. The odds ratio analysis indicated that bacteraemic melioidosis in this region was significantly associated with fever (76%), and patients having at least one underlying illness (43%), including diabetes mellitus (32%). Sixty-eight patients (28%) succumbed to melioidosis. Contrary to what is known regarding factors that promote bacteraemic melioidosis, neither patients with fever nor patients with at least one comorbid disease, including diabetes mellitus, were significantly associated with death from melioidosis. There was no statistically significant difference between patients without comorbidities (24, 27%) and those with at least one comorbid disease (26, 25%), including diabetes mellitus (18, 23%). The odds ratios indicate that melioidosis mortality in this region is related to patients showing respiratory organ-associated symptoms (29%), bacteraemia (30%), and septic shock (47%). Burkholderia pseudomallei isolates in this study were highly susceptible to ceftazidime (100%), imipenem (100%), and trimethoprim-sulfamethoxazole (98%).

CONCLUSIONS: Information obtained from this study can be used by clinicians to recognise individuals with the highest risk of acquiring melioidosis, estimate an accurate prognosis, and provide effective treatment for melioidosis patients to reduce death from melioidosis.

PMID:37844130 | DOI:10.1371/journal.pntd.0011696