Nevin Manimala

Iran Biomed J. 2023 Jun 22. doi: 10.52547/ibj.3862. Online ahead of print.

ABSTRACT

BACKGROUND: The aim of the present study was to evaluate alterations in the vegf gene expression as an angiogenic factor in mouse embryo fibroblasts seeded on the decellularized liver fragments.

METHODS: Liver tissue samples (n = 10) collected from adult male mice were randomly divided into decellularized and native control groups. Tissues were decellularized by treating with 1% Triton X-100 and 0.1% SDS for 24 hours and assessed by H&E staining and SEM. Then DNA content analysis and toxicity tests were performed. By centrifugation, DiI-labeled mouse embryo fibroblasts were seeded on each scaffold and cultured for one week. The recellularized scaffolds were studied by H&E staining, SEM, and LSCM. After RNA extraction and cDNA synthesis, the expression of the vegf gene in these samples was investigated using real-time RT-PCR.

RESULTS: Our observations showed that the decellularized tissues had morphology and porous structure similar to the control group, and their DNA content significantly reduced (p < 0.05) and reached to 4.12% of the control group. The MTT test indicated no significant cellular toxicity for the decellularized scaffolds. Light microscopy, SEM, and LSCM observations confirmed the attachment and penetration of embryonic fibroblast cells on the surface and into different depths of the scaffolds. There was no statistically significant difference in terms of vegf gene expression in the cultured cells in the presence and absence of a scaffold.

CONCLUSION: The reconstructed scaffold had no effect on vegf gene expression. Decellularized mouse liver tissue recellularized by embryonic fibroblasts could have an application in regenerative medicine.

PMID:37950395 | DOI:10.52547/ibj.3862

Subst Use Misuse. 2023 Nov 10:1-5. doi: 10.1080/10826084.2023.2275559. Online ahead of print.

ABSTRACT

BACKGROUND: Buprenorphine is a medication that is used to treat opioid use disorder by reducing withdrawal symptoms and cravings for opioids. Patients with poor adherence are at higher risk of relapse and overdose. Providers often test adherence through urine testing but are not aware of simulated adherence, where patients may directly add buprenorphine to the urine samples. As of now, there exists no literature on the simulated adherence practices for patients who stayed in the treatment for more than three months.

METHODS: This study is a cross-sectional analysis of simulated adherence through urine toxicology results of 3950 patients undergoing buprenorphine/naloxone treatment. Simulated adherence was measured by the ratio of norbuprenorphine and buprenorphine <0.02 in the urine sample. Descriptive statistics as well as multivariate analysis was conducted to examine the relationship between patient information and outcomes.

RESULTS: Out of 3950 patients, 411 (10.4%) had a history of one or more simulated adherence. On average, patients with multiple simulated adherences had 48.1% of their tests simulated, while on the contrary, patients with a single occurrence of simulated adherence had 17.6% of their tests simulated. Weekly testing and visit number of over 15 were associated with a higher likelihood of simulated adherence.

CONCLUSION: The study demonstrates that simulated adherence is a recurring phenomenon among buprenorphine/naloxone treatment patients regardless of the duration in the treatment. Utilization of quantitative urine toxicology to identify simulated adherence will enable healthcare providers to formulate a more precise and effective treatment plan tailored to support individual patient needs.

PMID:37950394 | DOI:10.1080/10826084.2023.2275559

Int J Stroke. 2023 Nov 10:17474930231216339. doi: 10.1177/17474930231216339. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Cerebral microbleeds are MRI markers of hemorrhage-prone cerebral small-vessel disease that predict future risk of ischemic stroke and intracranial hemorrhage (ICrH). There exists concerns about the net benefit of antithrombotic therapy in patients with microbleeds. We aimed to investigate the effects of an oral factor-XIa inhibitor (asundexian), that is hypothesized to inhibit thrombosis without compromising hemostasis, on the development of new microbleeds over time and interactions between microbleeds and asundexian treatment on clinical outcomes. We additionally assessed associations between baseline microbleeds and the risks of clinical and neuroimaging outcomes in patients with non-cardioembomic ischemic stroke.

METHODS: This is a subgroup analysis of the PACIFIC-STROKE, international, multi-center Phase 2b double-blind, randomized clinical trial. PACIFIC-STROKE enrolled patients aged ≥45 years with mild-to-moderate non-cardioembolic ischemic stroke who presented within 48 hours of symptom onset for whom antiplatelet therapy was intended. Microbleeds were centrally adjudicated, and participants with an interpretable T2*-weighted sequence at their baseline MRI were included in this analysis. Patients were randomized to asundexian (10/20/50mg daily) vs. placebo plus standard antiplatelet treatment. Regression models were used to estimate the effects of i) all pooled asundexian doses and ii) asundexian 50 mg daily on new microbleed formation on 26-week MRIs. Cox proportional hazards or regression models were additionally used to estimate interactions between treatment assignment and microbleeds for ischemic stroke/TIA (primary outcome), as well as ICrH, all-cause mortality, hemorrhagic transformation (HT), and new microbleeds (secondary outcomes).

RESULTS: Of 1746 participants (mean age, 67.0±10.0; 34% female) with baseline MRIs, 604 (35%) had microbleeds. During a median follow-up of 10.6 months, 7.0% (n=122) had ischemic stroke/TIA, 0.5% (n=8) ICrH, and 2.1% (n=37) died. New microbleeds developed in 10.3% (n=155) of participants with adequate up-MRIs and HT in 31.4% (n=345). In the total sample of patients with adequate baseline and 26-week follow-up MRIs (n=1507, ), new microbleeds occurred in 10.2% of patients assigned to any asundexian dose and 10.5% of patients assigned to placebo (OR 0.96, 95%CI 0.66-1.41). There were no interactions between microbleeds and treatment assignment for any of the outcomes (p for interaction>0.05). The rates of new microbleeds, HT and ICrH were numerically less in patients with microbleeds assigned to asundexian relative to placebo. The presence of microbleeds was associated with a higher risk of HT (aOR, 1.6; 95%CI, 1.2-2.1) and new microbleeds (aOR, 4.4; 95%CI, 3.0-6.3).

CONCLUSIONS: Factor XIa inhibition with asundexian appears safe in patients with non-cardioembolic ischemic stroke and hemorrhage-prone cerebral small-vessel disease marked by microbleeds on MRI. These preliminary findings will be confirmed in the ongoing OCEANIC-STROKE randomized trial.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04304508.

PMID:37950392 | DOI:10.1177/17474930231216339

Int J Stroke. 2023 Nov 10:17474930231216037. doi: 10.1177/17474930231216037. Online ahead of print.

ABSTRACT

BACKGROUND: Moyamoya disease is considered a progressive disease with an ongoing risk of recurrent stroke. However, there is a lack of long-term observational data to quantify the extent of the stroke risk.

METHODS: This study aimed to provide insight into the long-term stroke risk in MMD and explore possible risk factors for stroke. Records from all patients diagnosed with MMD in 13 clinical departments from six different Danish hospitals between 1994 and 2017 were retrospectively reviewed until 2021.

RESULTS: The cohort comprised 50 patients (33 females and 17 males). Patients were followed up for a median of 9.4 years, with more than 10 years of follow-up for 24 patients. Ten patients had 11 new stroke events – 6 ischemic strokes and 5 brain hemorrhages. Events occurred at a median of 7 years and up to 25 years after diagnosis. The overall Kaplan-Meier 5-year stroke risk was 10%. Patients with bypass performed had significantly fewer events than conservatively treated patients (HR 0.25, 95% CI 0.07 – 0.91, p<0.05). All but one event occurred in females, a difference that reached statistical significance.

CONCLUSIONS: The study provides data on the extent of the risk of recurrent stroke in MMD. Bypass surgery patients had fewer stroke events than those treated conservatively. There was a trend toward a higher stroke risk in females.

DATA ACCESS STATEMENT: The data supporting this study’s findings are available from the corresponding author upon reasonable request.

PMID:37950387 | DOI:10.1177/17474930231216037

Psychophysiology. 2023 Nov 10:e14474. doi: 10.1111/psyp.14474. Online ahead of print.

ABSTRACT

Hair cortisol concentration (HCC) has shown remarkable promise as a stable, non-invasive measure of systemic cortisol; however, despite methodological advances, the value that would typically be seen in healthy adults has not been established. Therefore, we sought to review the relevant literature to determine a reference value for HCC in healthy (i.e., non-clinical) adults. To this end, we conducted a systematic review of the PubMed, Scopus, and CINAHL databases for studies that measured healthy adult HCC using immunoassay methods, given that these are the most widely accessible analytical tools. To be eligible, studies were required to have been published in English, to have provided relevant descriptive statistics (i.e., means and standard deviations), and to have used a healthy adult human sample. We found 17 studies that met our inclusion criteria; the reports involved 1348 participants with a mean age of about 38 years. Since we identified a large amount of between-study heterogeneity, we completed a random-effect meta-regression analysis and found that test kit vendor was the only significant variable of the model. As a result, when using methodologies from traditional finite mixture distributions to determine reference values for mean and elevated HCC in individual healthy adults, we calculated these estimates for each of the major test kit vendors. Future work will need to determine whether our estimated reference values need to be modified, and these efforts will be greatly assisted by studies that account for potential moderating factors, such as age, sex, and ethnicity.

PMID:37950380 | DOI:10.1111/psyp.14474

Int J Stroke. 2023 Nov 10:17474930231215660. doi: 10.1177/17474930231215660. Online ahead of print.

ABSTRACT

BACKGROUND: Adverse non-motor outcomes are common after acute stroke and likely to substantially affect quality of life, yet few studies have comprehensively assessed their prevalence, patterns, and predictors across multiple health domains.

AIMS: We aim to identify the prevalence, patterns and the factors associated with non-motor outcomes 30 days after stroke.

METHODS: This prospective observational hospital cohort study (Stroke Investigation in North and Central London (SIGNAL) identified patients with acute ischaemic stroke or intracerebral haemorrhage (ICH) admitted to the Hyperacute Stroke Unit (HASU) University College Hospital (UCH), London, between August 1st 2018 and August 31st 2019. We assessed non-motor outcomes (anxiety, depression, fatigue, sleep, participation in social roles and activities, pain, bowel, and bladder function) at 30-day follow-up using the Patient Reported Outcome Measurement Information System-Version 29 (PROMIS-29) scale and Barthel Index scale.

RESULTS: We obtained follow-up data for 605/719 (84.1%) eligible patients (mean age 72.0 years; 48.3% female; 521 with ischaemic stroke, 84 with ICH). Anxiety (57.0%), fatigue (52.7%), bladder dysfunction (50.2%), reduced social participation (49.2%), and pain (47.9%) were the commonest adverse non-motor outcomes. The rates of adverse non-motor outcomes in ≥1, ≥2 and ≥3 domains were 89%, 66.3% and 45.8%, respectively; in adjusted analyses, stroke due to ICH (compared to ischaemic stroke) and admission stroke severity were the strongest and most consistent predictors. There were significant correlations between; bowel dysfunction and bladder dysfunction (κ= 0.908); reduced social participation and bladder dysfunction (κ= 0.844); and anxiety and fatigue (κ= 0.613). We did not identify correlation for other pairs of non-motor domains.

CONCLUSIONS: Adverse non-motor outcomes are very common at one month after stroke, affecting nearly 90% of evaluated patients in at least one health domain, about two-thirds in two or more domains, and almost 50% in three or more domains. Stroke due to ICH and admission stroke severity were the strongest and most consistent predictors. Adverse outcomes occur in pairs of domains such as with anxiety and fatigue.Our findings emphasise the importance of a multi-domain approach to effectively identify adverse non-motor outcomes after stroke to inform the development of more holistic patient recovery programs.

PMID:37950351 | DOI:10.1177/17474930231215660

J Pharm Biomed Anal. 2023 Oct 31;238:115838. doi: 10.1016/j.jpba.2023.115838. Online ahead of print.

ABSTRACT

Euphorbia pekinensis (EP), known for its diuretic properties, is clinically utilized for treating conditions such as edema and malignant tumors. However, in its raw form, Euphorbia pekinensis is toxic, and oral administration of this crude medicine can lead to gastrointestinal stimulation, resulting in abdominal pain and diarrhea. In Mongolian medicine’s ethnomedicinal system, a distinctive processing method called “Chebulae Fructus processing” is employed. Chebulae Fructus is used to mitigate the toxicity of EP and alleviate its purgative effects. Nevertheless, the detoxification mechanism associated with this processing method remains unexplored. It is hypothesized that processing with Chebulae Fructus may alter the chemical composition of EP, and the residual components of Chebulae Fructus within processed Chinese medicine might exhibit pharmacological antagonistic effects, thereby achieving the purpose of processing and reducing toxicity. To investigate this further, a combination of UPLC-QTOF-MS-based metabolomics technology and multivariate statistical analysis was employed to analyze and compare the chemical composition of raw and processed EP. Differential variables contributing to group separation were identified based on specific criteria, including VIP (Variable Importance in Projection) values of ≥ 1 in PLS-DA models, p-values < 0.05, and fold changes (FC) > 1.2 or < 0.8. The resulting differentially expressed features were then identified through database matching, literature review, or manual annotation. In total, 47 components were identified from the PEP samples in both positive and negative ionization modes, primarily belonging to flavonoids, terpenoids, organic acids, glycosides, and fatty acids. Among the raw EP group and PEP S4 group, 10 differential compounds were identified. Notably, one toxic terpene and one phenylpropanoid from EP were downregulated, while two bioactive components from Chebulae Fructus were upregulated in the processed group. The possible conversion reactions of these two processing Q-markers were also elucidated. The characteristic processing with Chebulae Fructus resulted in a change in the composition of this Mongolian medicine EP. Furthermore, this study provides a scientific foundation for optimizing the processing technology of EP and offers insights into the processing of other ethnomedicines with toxic properties.

PMID:37948776 | DOI:10.1016/j.jpba.2023.115838

Biomed Phys Eng Express. 2023 Nov 10. doi: 10.1088/2057-1976/ad0bb2. Online ahead of print.

ABSTRACT

Precise monitoring of the position and dwell time of iridium-192 (Ir-192) during high-dose-rate (HDR) brachytherapy is crucial to avoid serious damage to normal tissues. Source imaging using a compact gamma camera is a potential approach for monitoring. However, images from the gamma camera are affected by blurring and statistical noise, which impact the accuracy of source position monitoring. This study aimed to develop a deep-learning approach for estimating ideal source images that reduce the effect of blurring and statistical noise from experimental images captured using a compact gamma camera.&#xD;Approach: A double pix2pix model was trained using the simulated gamma camera images of an Ir-192 source. The first model was responsible for denoising the Ir-192 images, whereas the second model performed super resolution. Trained models were then applied to the experimental images to estimate the ideal images. &#xD;Main results: At a distance of 100 mm between the compact gamma camera and the Ir-192 source, the difference in full width at half maximum (FWHM) between the estimated and actual source sizes was approximately 0.5 mm for a measurement time of 1.5 s. This difference has been improved from approximately 2.7 mm without the use of DL. Even with a measurement time of 0.1 s, the ideal images could be estimated as accurately as in the 1.5 s measurements. This method consistently achieved accurate estimations of the source images at any position within the field of view; however, the difference increased with the distance between the Ir-192 source and the compact gamma camera.&#xD;Significance: The proposed method successfully provided estimated images from the experimental images within errors smaller than 0.5 mm at 100 mm. This method is promising for reducing blurring and statistical noise from the experimental images, enabling precise real-time monitoring of Ir-192 sources during HDR brachytherapy.

PMID:37948761 | DOI:10.1088/2057-1976/ad0bb2

J Infect Dis. 2023 Nov 9:jiad446. doi: 10.1093/infdis/jiad446. Online ahead of print.

ABSTRACT

BACKGROUND: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood.

METHODS: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and d-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models.

RESULTS: Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P < .001), and a steeper rate of decline through the first 5 days (P < .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale.

CONCLUSIONS: Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed.

CLINICAL TRIALS REGISTRATION: NCT04501978.

PMID:37948759 | DOI:10.1093/infdis/jiad446

Retina. 2023 Nov 7. doi: 10.1097/IAE.0000000000003987. Online ahead of print.

ABSTRACT

PURPOSE: The primary aim was to describe patterns of para macular involvement, not yet reported but that OCT-A can now detect in SCD patients. The secondary aim was to search arguments concerning the physio pathogeny of para macular involvement.

METHODS: This institutional cohort retrospective study was conducted in a Referral Center for Ophthalmological Rare Diseases. Follow-up included an ophthalmological examination with optical coherent tomography and optical coherent tomography angiography.

RESULTS: Hundred and thirty-two sickle cell patients were included. Typical sickle cell maculopathy was observed in temporal area in 84 eyes (40.0 %) of SS patients and 8 eyes (14.8 %) of SC patients (p < 0.001). Enlargement of the foveal avascular zone was observed in 10 eyes whom 8 of SS patients. Two atypical parafoveal abnormalities were found in SS patients only. The first one consisted in macular thinning with normal vascularization in 15 eyes of 11 patients. The second atypical maculopathy was large areas of loss of vascularization without retina thinning 10 eyes of six patients. Multivariate analysis did not show a statistically significant relation between the PSR stage and the different type of sickle cell maculopathy (p = 0.21).

CONCLUSION: Those atypical sickle cell maculopathy may correspond to early forms preceding a typical SCM. This would point towards several physiopathogenic mechanisms. The first one included the existence of ischemia which can be related to anemia. Presence of retinal thinning without vascular involvement point out to a neurogenic mechanism.

PMID:37948742 | DOI:10.1097/IAE.0000000000003987