Nevin Manimala

Expert Rev Mol Diagn. 2023 Feb 6. doi: 10.1080/14737159.2023.2176223. Online ahead of print.

ABSTRACT

BACKGROUND: : Colorectal cancer (CRC) is the most common cancer and the second leading cause of cancer deaths in Hong Kong. We tested the hypothesis that circulating tumor cell (CTC) analysis by ARB101 antibody could be used as a tool for CRC detection, progression, and therapy response.

RESEARCH DESIGN AND METHODS: : ARB101 antibody was used for investigation of CDH17 expression in formalin-fixed, paraffin-embedded (FFPE) tissue sections and circulating tumor cells (CTCs) of CRC patients.

RESULTS: Using ARB101, highest sensitivity was observed in 98/100 (98%) colorectal cancer tissue compared to 72/100 gastric cancer (72%) and 27/32 pancreatic cancer (84%). Immunoreactivity of CDH17 was significantly higher in distant metastatic (tumor-node-metastasis [TNM] stage IV) than non-distant metastatic (TNM stage I to III) colorectal cancer. ARB101 antibody also manifested the higher sensitivity than c-erbB2 (8%) and epidermal growth factor receptor (EGFR)-targeting antibodies (37%) with the significance (p < 0.0001). ARB101 positive CTCs were detected in 64/83 (77%) TNM stage I to IV colorectal cancer patients. Detailed analysis showed that ARB101 positive CTCs (threshold ⩾1) were identified in 17/25 stage I (68%), 14/21 stage II (67%), 18/21 stage III (86%) and 15/16 stage IV (94%) colorectal cancer patients. Furthermore, ARB101 positive CTCs were detected in TNM stage I to III colorectal cancer patients before and after surgical operation. The difference of ARB101 positive CTCs between those 2 groups of matched patient samples are statistically significant (p < 0.0001).

CONCLUSIONS: CTC detection by ARB101 antibody could serve as a potential non-invasive approach for CRC detection, progression, and monitoring treatment response of colorectal cancers.

PMID:36744385 | DOI:10.1080/14737159.2023.2176223

Work. 2023 Feb 2. doi: 10.3233/WOR-220189. Online ahead of print.

ABSTRACT

BACKGROUND: Vehicular emissions on long-term exposure predispose metropolitan bus drivers to cardiorespiratory ailments.

OBJECTIVE: To evaluate the cardiorespiratory risk of urban metropolitan bus drivers related to vehicular emission exposure.

METHODS: Bus drivers (with service >5 years, n = 254) and their administrative controls (primarily engaged in indoor white collared jobs, n = 73) were recruited. Demographic, occupational and clinical details were collected through pre-validated standardized format. Pulmonary Function Test (PFT) and lipid profile were carried out with standard protocol. Risk for cardiovascular events for preceding 10-years was estimated with WHO/ISH risk prediction chart and QRISK3 score. Exposure assessments for particulate matter (PM) were performed for both groups while duty hours.

RESULTS: Exposure of drivers to PM2.5 six times and PM10 five times higher in comparison to administration staff (PM2.5- 970.9 v/s 145.0μg/m3 TWA and PM10- 1111.7 v/s 233.8μg/m3 TWA). Bus drivers exhibited significantly higher prevalence of respiratory symptoms (dyspnea-25% v/s 6.8% and cough-20.1% v/s 9.8%) and compromised PFT (obstructive-21% v/s 5.7% and restrictive-4.2% v/s 2.9%) in comparison to controls. Multivariate regression statistics reveal a significant decline for FEV1/FVC and FEV25-75 % among bus drivers compared to controls, controlling the influence of physiological and environmental factors. The difference between predicted cardiac age and their respective chronological age was twice higher (8.3 v/s 4.3 years) among drivers compared to their administration staff.

CONCLUSION: Bus drivers were exposed to high levels of outdoor air pollutants. Further, the drivers exhibited higher risk for ischemic attack and obstructive airway diseases as compared to administration staff.

PMID:36744353 | DOI:10.3233/WOR-220189

J Alzheimers Dis. 2023 Jan 28. doi: 10.3233/JAD-220894. Online ahead of print.

ABSTRACT

BACKGROUND: Diabetes increases the risk for cognitive decline, but the mechanisms behind this association remain unknown. Impaired early insulin secretion in elderly men and insulin resistance, both of which are pathophysiological features of type 2 diabetes, have previously been linked to Alzheimer’s disease.

OBJECTIVE: To examine if the early insulin response to oral glucose load predicts cognitive performance after 10 years in men and women aged 45-74 years.

METHODS: This study was based on a subpopulation of the Health 2000 Survey, a Finnish nationwide, population-based health examination study, and its follow-up, the Health 2011 Study. In total, 961 45-74-year-old individuals (mean age at baseline 55.6 years, 55.8% women) were examined. An oral glucose tolerance test was performed in 2001-2002, and early insulin response was defined as the ratio of the 30-min increment in insulin concentration to that of glucose concentration. Cognitive function was evaluated at baseline and follow-up with categorical verbal fluency, word-list learning, and word-list delayed recall. Statistical analyses were performed using multivariable linear models adjusted for age, sex, education, APOE&z.epsi;4 genotype, vascular risk factors including diabetes, and depressive symptoms.

RESULTS: A lower early insulin response to glucose load predicted lower performance (β: 0.21, p = 0.03) and greater decline (β: 0.19, p = 0.03) in the word-list delayed recall test. Baseline early insulin response did not predict verbal fluency or word-list learning (all p-values≥0.13).

CONCLUSION: Our results suggest that decreased early insulin secretion predicts episodic memory decline in middle-aged to elderly men and women.

PMID:36744339 | DOI:10.3233/JAD-220894

J Alzheimers Dis. 2023 Feb 2. doi: 10.3233/JAD-220727. Online ahead of print.

ABSTRACT

BACKGROUND: The oxidative stress hypothesis is challenging the dominant position of amyloid-β (Aβ) in the field of understanding the mechanisms of Alzheimer’s disease (AD), a complicated and untreatable neurodegenerative disease.

OBJECTIVE: The goal of the present study was to uncover the oxidative stress mechanisms causing AD, as well as the potential therapeutic targets and neuroprotective drugs against oxidative stress mechanisms.

METHODS: In this study, a systematic workflow combining pharmacological experiments and computational prediction were proposed. 222 drugs and natural products were collected first and then tested on SH-SY5Y cells to obtain phenotypic screening data on neuroprotection. The preliminary screening data were integrated with drug-target interactions (DTIs) and multi-scale biomedical data, which were analyzed with statistical tests and gene set enrichment analysis. A polypharmacology network was further constructed for investigation.

RESULTS: 340 DTIs were matched in multiple databases, and 222 cell viability ratios were calculated for experimental compounds. We identified significant potential therapeutic targets based on oxidative stress mechanisms for AD, including NR3C1, SHBG, ESR1, PGR, and AVPR1A, which might be closely related to neuroprotective effects and pathogenesis. 50% of the top 14 enriched pathways were found to correlate with AD, such as arachidonic acid metabolism and neuroactive ligand-receptor interaction. Several approved drugs in this research were also found to exert neuroprotective effects against oxidative stress mechanisms, including beclometasone, methylprednisolone, and conivaptan.

CONCLUSION: Our results indicated that NR3C1, SHBG, ESR1, PGR, and AVPR1A were promising therapeutic targets and several drugs may be repurposed from the perspective of oxidative stress and AD.

PMID:36744334 | DOI:10.3233/JAD-220727

J Alzheimers Dis. 2023 Feb 2. doi: 10.3233/JAD-220599. Online ahead of print.

ABSTRACT

BACKGROUND: Our understanding of the pathophysiology underlying Alzheimer’s disease (AD) has benefited from genomic analyses, including those that leverage polygenic risk score (PRS) models of disease. The use of functional annotation has been able to improve the power of genomic models.

OBJECTIVE: We sought to leverage genomic functional annotations to build tissue-specific AD PRS models and study their relationship with AD and its biomarkers.

METHODS: We built 13 tissue-specific AD PRS and studied the scores’ relationships with AD diagnosis, cerebrospinal fluid (CSF) amyloid, CSF tau, and other CSF biomarkers in two longitudinal cohort studies of AD.

RESULTS: The AD PRS model that was most predictive of AD diagnosis (even without APOE) was the liver AD PRS: n = 1,115; odds ratio = 2.15 (1.67-2.78), p = 3.62×10-9. The liver AD PRS was also statistically significantly associated with cerebrospinal fluid biomarker evidence of amyloid-β (Aβ 42:Aβ 40 ratio, p = 3.53×10-6) and the phosphorylated tau:amyloid-β ratio (p = 1.45×10-5).

CONCLUSION: These findings provide further evidence of the role of the liver-functional genome in AD and the benefits of incorporating functional annotation into genomic research.

PMID:36744333 | DOI:10.3233/JAD-220599

Biomed Mater Eng. 2023 Jan 31. doi: 10.3233/BME-222513. Online ahead of print.

ABSTRACT

BACKGROUND: Acrylic resins used in dental and biomedical applications do not have antimicrobial properties, their surface is susceptible to colonization of microorganisms.

OBJECTIVE: The aim of this study was to evaluate the antibiofilm properties of silver nanoparticles (AgNPs) deposited in a polymethyl methacrylate (PMMA) surface against a Staphylococcus aureus biofilm.

METHODS: The PMMA was impregnated with AgNPs by using the in-situ polymerization method. To determine the solubility of the incorporated silver (Ag+) atomic absorption spectrophotometry was used (AAS) at 24 h, 48 h, 7 days, and 30 days. Thirty specimens of PMMA with AgNPs and without NP (control group) were assembled in the CDC Biofilm Bioreactor system with a cell suspension of S. aureus. The specimens were removed at 6, 12, 24, 48, and 72 h to determine the viability profile and quantify the Arbitrary Fluorescence Units (AFU).

RESULTS: The AgNPs showed an irregular and quasispherical shape with an average size of 25 nm. AAS analysis demonstrated a low solubility of Ag+. The formation of the S. aureus biofilm increased as the evaluation periods continued up to 72 h. The experimental group showed poor growth, and a decrease in the intensity of the fluorescence demonstrated a statistically significant inhibition of the formation of the biofilm (P < 0.05) in relation to the control group at 6, 12, 24, 48, and 72 h.

CONCLUSION: AgNPs incorporated into PMMA decreased the growth and maturation of S. aureus biofilm.

PMID:36744329 | DOI:10.3233/BME-222513

Cardiol Young. 2023 Feb 6:1-4. doi: 10.1017/S1047951123000136. Online ahead of print.

ABSTRACT

OBJECTIVES: When cardiac muscle damage occurs, cardiac troponins are released to blood and their detection is used as a marker in clinical setting. The prognostic value of the quantitative levels of blood troponin I in cases of myocarditis and myopericarditis is unclear. The aim of this study was to analyse whether troponin quantitative blood levels can be correlated with the course of hospitalisation and prognosis.

METHODS: Retrospective data was collected from all consecutive patients aged ≤30 hospitalised with a diagnosis of acute myocarditis or acute myopericarditis in our health Care Campus between the years 2010-2016.

RESULTS: Ninety-three patients with myocarditis and myopericarditis were identified. Higher peak troponin levels correlated with longer hospitalisation times in the cardiac or paediatric wards (p = 0.03, Pearson correlation: r -0.23), and median troponin level at admission correlated with longer overall hospitalisation (p = 0.026, Pearson correlation: r = 0.23). Patients admitted to ICU, received oral cardiac supportive therapy or that were discharged with cardiac drugs had higher median troponin compared to patients who were not but this was not statistically significant. A small group of patients that needed intravenous cardiac support had significantly lower median peak troponin levels (n = 4, 0.375ng/ml, p = 0.048). Only two patients needed extracorporeal membrane oxygenation support, and one died. The small number of patients precludes statistical analysis.

CONCLUSION: Higher troponin levels correlated significantly with longer hospitalisation, lower troponin values correlated with intravenous cardiac support, while other variables related to the severity of disease could not be significantly related to higher troponin levels.

PMID:36744328 | DOI:10.1017/S1047951123000136

Med Educ Online. 2023 Dec;28(1):2172744. doi: 10.1080/10872981.2023.2172744.

ABSTRACT

PURPOSE: International studies document that lesbian, gay, bisexual, transgender, queer and intersex (LGBTQI+) patients face significant health disparities. Studies exploring the attitudes, knowledge, preparedness and comfort levels of healthcare students towards LGBTQI+ health have been conducted in the United States, United Kingdom and Malaysia. This study aims to investigate stigma in healthcare for LGBTQI+ patients in Singapore, and possible upstream factors within medical education.

METHODS: This mixed-methods study adopts a convergent parallel design. The Health Stigma and Discrimination Framework was referenced to devise in-depth interviews with representatives from 13 LGBTQI-affirming non-governmental organisations, analysed through thematic analysis. 320 clinical medical students were surveyed about attitudes, knowledge, comfort, preparedness, and perceived importance of/towards LGBTQI+ health, analysed via descriptive statistics and multivariate regression.

RESULTS: Prevailing stigma in Singaporean society against LGBTQI+ individuals is exacerbated in healthcare settings. Doctors were cited as unfamiliar or uncomfortable with LGBTQI+ health, possibly from lack of training. Among medical students surveyed, the median composite attitudes, comfort and preparedness index was 3.30 (Interquartile Range (IQR) = 0.50), 3.17 (IQR = 0.83), 2.50 (IQR = 1.00) respectively. Only 12.19% of students answered all 11 true-false questions about LGBTQI+ health correctly.

CONCLUSION: Medical students in Singapore have scored sub-optimally in their knowledge and preparedness towards LGBTQI+ health, while interpersonal and structural stigma in healthcare towards LGBTQI+ people in Singapore negatively affects health and wellbeing. These findings are an impetus to improve medical training in this area. High scores among medical students in attitudes, comfort and perceived importance of LGBTQI+ topics demonstrate that there is space for LGBTQI+ health in the local medical education curriculum. Curricular interventions can prioritise content knowledge, communication skills and sensitivity.

PMID:36744296 | DOI:10.1080/10872981.2023.2172744

Front Pharmacol. 2023 Jan 19;14:1081724. doi: 10.3389/fphar.2023.1081724. eCollection 2023.

ABSTRACT

Until recently, the most standard treatment for sensorineural or sudden hearing loss, which is caused by inner ear damage or deterioration, has been systemic oral steroid administration. In recent, intratympanic steroid injections such as dexamethasone have been used for the treatment of sudden hearing loss as well. It is injected into the tympanic cavity through its membrane and is expected to diffuse over the round window located between the tympanic cavity and the inner ear. However, in clinical situations, the delivery time of steroids to the inner ear is shorter than 24 h, which does not allow for a sufficient therapeutic effect. Therefore, we applied a previously invented dual viscosity mixture vehicle (DVV) for intratympanic dexamethasone to a guinea pig model, which could reduce the side effects of systemic steroid administration with sufficient dwelling time for the treatment of hearing loss, and we investigated the physiological changes with a global proteomic approach. In this study, we extracted perilymph in three different conditions from guinea pigs treated with dexamethasone-embedded DVV, dexamethasone mixed in saline, and control groups to compare proteomic changes using tandem mass spectrometry analysis. After liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) analysis, we first identified 46 differentially expressed proteins (DEPs) that were statistically significant after one-way ANOVA multiple-sample test. We also performed pairwise comparisons among each group to identify DEPs closely related to the treatment response of dexamethasone-embedded DVV. Gene ontology enrichment analysis showed that these DEPs were mostly related to inflammation, immune, actin remodeling, and antioxidant-related processes. As a result, the proteome changes in the DVV-treated groups revealed that most upregulated proteins activate the cell proliferation process, and downregulated proteins inhibit apoptosis and inflammatory reactions. Moreover, the reactive oxygen process was also regulated by DEPs after DVV treatment.

PMID:36744248 | PMC:PMC9892634 | DOI:10.3389/fphar.2023.1081724

Front Pharmacol. 2023 Jan 20;14:1024807. doi: 10.3389/fphar.2023.1024807. eCollection 2023.

ABSTRACT

Background: No consensus exists on the antibiotic treatment course for patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Former studies indicate that shorter courses might have the same efficacy with fewer adverse events, which is inconsistent with guidelines and general practice. Existing evidence allows us to conduct a systematic review and Bayesian analysis on this topic. Methods: Four databases were searched from their inception to January 5, 2023. All statistical estimations were performed using R. “Gemtc” was the core package of analysis. CINeMA was used to assess the grade of confidence of the results. Results: Fourteen studies were included in the Bayesian meta-analysis. No difference in the clinical success rate of antibiotic treatment was observed from a super short course (1-3 days) to a long course (≥10 days). Considering the adverse events, the short course (4-6 days) might be the safest. The majority of results were of high or moderate confidence grade. Conclusion: Short course might cause the fewest adverse events. The clinical efficacy of antibiotics might not depend on the course length. Undeniably, more systematic explorations are warranted to investigate the clinical application of a shorter course of antibiotic treatment.

PMID:36744244 | PMC:PMC9895851 | DOI:10.3389/fphar.2023.1024807