The effect of multiple sclerosis therapy on gut microbiota dysbiosis: a longitudinal prospective study.

Gut microbiota has complex immune functions, related to different pathologies, including multiple sclerosis (MS).This study evaluated the influence of treatments on gut microbiota in people with MS (PwMS). The research comprised 60 participants, including 39 PwMS and 21 healthy controls (HC). Among the PwMS, 20 were prescribed a disease-modifying therapy (DMT), either interferon beta1a or teriflunomide, while 19 received a combination of classical DMT and an immunoglobulin Y (IgY) supplement. For each participant, two sets of gut samples were collected: one at the study's outset and another after two months. Alpha and beta diversity analyses revealed no significant differences between groups. In comparison to the HC, the MS group exhibited an increase in Prevotella stercorea and a decrease in Faecalibacterium prausnitzii. Following treatment, individuals with MS showed enrichment in Lachnospiraceae and Streptococcus. The second sample, compared to the first one, demonstrated an increase in Bifidobacterium angulatum and a decrease in Oscillospira for individuals with MS. Gut microbiota diversity in PwMS is not significantly different to HC.However, specific taxonomic changes indicate the presence of a dysbiosis state. The use of DMTs and immunoglobulin Y supplements may contribute to alterations in microbial composition, potentially leading to the restoration of a healthier microbiome.

Levodopa-Carbidopa-Entacapone Intestinal Gel in Advanced Parkinson Disease: A Multicenter Real-Life Experience.

BACKGROUND: For Parkinson disease (PD) patients who have been diagnosed with advanced disease that can no longer be effectively controlled with optimized oral or transdermal medications, a range of device-aided therapies (DAT) are available, comprising either deep brain stimulation or infusion therapies providing continuous dopaminergic stimulation. Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is the latest DAT for advanced PD (APD) that was approved in Romania in 2021. STUDY QUESTION: What is the experience to date in real-world clinical practice in Romania regarding the efficacy and tolerability of LECIG in APD? STUDY DESIGN: A retrospective evaluation of 74 APD patients treated with LECIG at 12 specialized APD centers in Romania. MEASURES AND OUTCOMES: Demographic data and various clinical parameters were recorded, including Mini Mental State Evaluation score or Montreal Cognitive Assessment Test score. Levodopa-equivalent daily dose and the administered doses of levodopa and other PD medications were evaluated at baseline and after starting LECIG treatment. The efficacy of LECIG in reducing daily hours of off time, motor fluctuations, and dyskinesias were assessed. Any percutaneous endoscopic gastrojejunostomy system or device complications after starting LECIG treatment were noted. RESULTS: At baseline, patients were taking oral levodopa for a mean of 5.3 times per day, with a high proportion also taking concomitant add-on therapies (dopamine agonists, 86%, monoamine oxidase type-B inhibitors, 53%; catechol-O-methyltransferase inhibitors, 64%). LECIG treatment significantly reduced daily off time versus baseline from 5.7 h/d to 1.7 hours per day ( P < 0.01). Duration and severity of dyskinesias was also significantly reduced versus baseline, and improvements were observed in Hoehn and Yahr Scale scores. LECIG treatment also allowed a significant reduction in the use of concomitant oral medications. CONCLUSIONS: These findings suggest that LECIG treatment is an effective DAT option in APD that can simplify the treatment regimen.

Pre-operative high-frequency ultrasound: a reliable management tool in auricular and nasal non-melanoma skin cancer.

BACKGROUND AND OBJECTIVES: The knowledge of depth infiltration in non-melanoma skin cancer (NMSC) using pre-operative ultrasound could enable clinicians to choose the most adequate therapeutic approach, avoiding unnecessary surgeries and expensive imaging methods, delaying diagnosis and treatment. Our single-center retrospective study determined the usefulness of high-frequency ultrasound (HFUS) for depth infiltration assessment in auricular and nasal NMSC and assessed the subsequent change in therapeutic approach. PATIENTS AND METHODS: In 60 NMSC cases, we assessed the accuracy of HFUS in cartilaginous/bone infiltration detection as well as the correlation of sonographic and histological parameters. RESULTS: In 16.6% of cases, a deep cartilaginous/bone involvement or locoregional disease was identified pre-operatively, resulting in a changed therapeutical scheme of radio-immunological treatment rather than surgery. In two cases, pre-operative HFUS identified local cartilage infiltration, reducing the number of surgical procedures. Forty-eight remaining lesions with no depth infiltration were excised; a correlation of > 99% between the histologic and sonographic tumor depth (p<0.001) was found. CONCLUSIONS: Pre-surgical HFUS influences the therapeutic management in NMSC by detecting subclinical involvement of deeper structures, avoiding more extensive diagnostics, reducing costs, and improving healthcare quality. High-frequency ultrasound should be implemented in dermatosurgery before tumor excision for optimized therapy and improved patient counseling.

Oral health, the patients' perspective during the COVID 19 pandemic.

Background and aims: On March 16, 2020, the state of emergency was established with drastic measures of isolation and quarantine. Among the measures taken in the context of the state of emergency was the closure of dental offices throughout the country. The aim of our questionnaire-based cross-sectional study was to identify the psycho-affective implications of the Romanian citizens induced by the COVID-19 pandemic period as well as their opinion related to the self-perceived oral health status during this period. Methods: An original questionnaire was designed consisting of 41 questions, which were distributed to the general population via the Internet. The first part of the questionnaire investigated the respondents' opinion regarding the impact of this COVID-19 pandemic period of isolation on their oral health and the attention paid by the subjects to oral hygiene during restrictions. The second part refers to their addressability to the dental services during this pandemic and the third part interrogates different characteristics, namely the presence of comorbidities, possible anxiety, and stress. Results: A total of 769 participants answered the questionnaire online. Conclusion: According to their responses most of the respondents were not afraid of the possibility of contracting Sars-Cov-2 during dental treatments, but were in certain periods deprived of accessing dental services due to lockdown restrictions. They are aware of their oral health problems and pay more attention to oral hygiene so that they do not get worse during restrictions.

Eyes on dementia: an overview of the interplay between eye movements and cognitive decline.

The economic and disease burden of dementia is forecasted to continue increasing. Considering its cognitive effects, timely diagnosis is important in developing a stage-based treatment plan and gathering data to support advocacy efforts and plan healthcare and social services. Eye-tracking technology has emerged as an efficient diagnostic tool in clinical practice and experimental studies. This review aimed to comprehensively analyze various aspects of eye-tracking technology, including pupillometry parameters, eye movements, eye-tracking devices, and neuropsychological tools. We conducted a systematic review retrieving articles published in the last ten years from six databases. Our results provide a complex overview for each included form of dementia/cognitive decline in terms of patient characteristics (age, sex-disaggregated by included pathologies), inclusion and exclusion criteria, devices, and neuropsychological tools. We also summarized findings on fixation stability tasks, saccadic evaluation, pupillometry, scene perception, object recognition, spatial memory, eye-tracking video tasks, and visual search. The eye-tracking method has become more common in cognitive assessments.

Cerebrolysin and repetitive transcranial magnetic stimulation (rTMS) in patients with traumatic brain injury: a three-arm randomized trial.

Introduction: Traumatic brain injury (TBI) is a major public health problem affecting millions worldwide. Despite significant advances in medical care, there are limited effective interventions for improving cognitive and functional outcomes in TBI patients. Methods: This randomized controlled trial investigated the safety and efficacy of combining repetitive transcranial magnetic stimulation (rTMS) and Cerebrolysin in improving cognitive and functional outcomes in TBI patients. Ninety-three patients with TBI were randomized to receive either Cerebrolysin and rTMS (CRB + rTMS), Cerebrolysin and sham stimulation (CRB + SHM), or placebo and sham stimulation (PLC + SHM). The primary outcome measures were the composite cognitive outcome scores at 3 and 6 months after TBI. Safety and tolerability were also assessed. Results: The study results demonstrated that the combined intervention of rTMS and Cerebrolysin was safe and well-tolerated by patients with TBI. Although no statistically significant differences were observed in the primary outcome measures, the descriptive trends in the study support existing literature on the efficacy and safety of rTMS and Cerebrolysin. Discussion: The findings of this study suggest that rTMS and Cerebrolysin may be effective interventions for improving cognitive and functional outcomes in TBI patients. However, limitations of the study, such as the small sample size and exclusion of specific patient populations, should be considered when interpreting the results. This study provides preliminary evidence for the safety and potential efficacy of combining rTMS and Cerebrolysin in improving cognitive and functional outcomes in TBI patients. The study highlights the importance of multidisciplinary approaches in TBI rehabilitation and the potential for combining neuropsychological measurements and interventions to optimize patient outcomes. Conclusion: Further research is needed to establish these findings' generalizability and identify the optimal dosages and treatment protocols for rTMS and Cerebrolysin.

Cost-Effectiveness of Cerebrolysin after Ischemic Stroke: Secondary Analysis of the CARS Study.

The cost-effectiveness of Cerebrolysin as an add-on therapy for moderate-severe acute ischemic stroke is a topic that remains understudied. This study aims to address this gap by performing a comprehensive cost-utility analysis using both deterministic and probabilistic methods from a payer perspective and within the Romanian inpatient care setting. Quality-adjusted life years (QALYs) were calculated using partial individual patient data from the 2016 Cerebrolysin and Recovery After Stroke (CARS) trial, utilizing three different health state valuation models. Cost data was extracted from actual acute care costs reported by Romanian public hospitals for reimbursement purposes for patients included in the CARS study. Incremental cost-effectiveness ratios were calculated for each treatment arm for the duration of the clinical trial. Deterministic analysis based on sample mean values indicates Cerebrolysin would be cost-effective at a threshold between roughly 18.8 and 29.9 thousand EUR, depending on valuation techniques. Probabilistic sensitivity analysis results indicate an 80% chance probability of cost-effectiveness of Cerebrolysin as an add-on therapy for acute ischemic stroke, considering a willingness-to-pay threshold of 50,000 EUR in a 90-day timeframe after stroke. Further economic evaluations of Cerebrolysin are needed to strengthen these findings, covering a timeframe of at least 12 months after the acute incident, which would account for treatment effects spanning beyond the first 90 days after ischemic stroke. These should be conducted to determine its cost-effectiveness under various care settings and patient pathways. Most importantly, modelling techniques are needed to answer important questions such as the estimates of population gain in QALYs after acute administration of Cerebrolysin and the potential offsetting of direct medical costs as a result of administering the intervention.

MRI Radiomics and Predictive Models in Assessing Ischemic Stroke Outcome-A Systematic Review.

Stroke is a leading cause of disability and mortality, resulting in substantial socio-economic burden for healthcare systems. With advances in artificial intelligence, visual image information can be processed into numerous quantitative features in an objective, repeatable and high-throughput fashion, in a process known as radiomics analysis (RA). Recently, investigators have attempted to apply RA to stroke neuroimaging in the hope of promoting personalized precision medicine. This review aimed to evaluate the role of RA as an adjuvant tool in the prognosis of disability after stroke. We conducted a systematic review following the PRISMA guidelines, searching PubMed and Embase using the keywords: 'magnetic resonance imaging (MRI)', 'radiomics', and 'stroke'. The PROBAST tool was used to assess the risk of bias. Radiomics quality score (RQS) was also applied to evaluate the methodological quality of radiomics studies. Of the 150 abstracts returned by electronic literature research, 6 studies fulfilled the inclusion criteria. Five studies evaluated predictive value for different predictive models (PMs). In all studies, the combined PMs consisting of clinical and radiomics features have achieved the best predictive performance compared to PMs based only on clinical or radiomics features, the results varying from an area under the ROC curve (AUC) of 0.80 (95% CI, 0.75-0.86) to an AUC of 0.92 (95% CI, 0.87-0.97). The median RQS of the included studies was 15, reflecting a moderate methodological quality. Assessing the risk of bias using PROBAST, potential high risk of bias in participants selection was identified. Our findings suggest that combined models integrating both clinical and advanced imaging variables seem to better predict the patients' disability outcome group (favorable outcome: modified Rankin scale (mRS) ≤ 2 and unfavorable outcome: mRS > 2) at three and six months after stroke. Although radiomics studies' findings are significant in research field, these results should be validated in multiple clinical settings in order to help clinicians to provide individual patients with optimal tailor-made treatment.

Circadian Rhythm and Risk of Hemorrhagic Transformation after Acute Ischemic Stroke Treated with Intravenous Thrombolysis - A Systematic Review.

BACKGROUND: A circadian pattern for the onset of acute ischemic stroke (AIS) has been described, with a higher risk in the early morning and a lower risk during nighttime. However, data assessing the circadian distribution of hemorrhagic transformation after intravenous thrombolysis (ivT) are still incongruent. OBJECTIVES: This review aimed to evaluate whether the time interval based on AIS onset or ivT time could influence the occurrence of intracranial hemorrhage (ICH) related to ivT and if the circadian rhythm of endogenous production of tissue plasminogen activator (t-PA) favors ICH occurrence. METHODS: We conducted a systematic review following the PRISMA guidelines, searching PubMed and Embase for articles in English using the keywords: 'stroke', 'thrombolysis', and 'circadian'. Articles investigating the AIS onset or ivT time effects on circadian variations of ICH in AIS adult patients treated with ivT were included. Based on ICH's incidence and odds ratio, time intervals associated with higher risk and time intervals associated with lower risk were defined. The Newcastle-Ottawa Scale was used to assess the risk of bias. The resulting data were reported in a qualitative narrative synthesis. RESULTS: From the 70 abstracts returned by electronic literature search, six studies with 33,365 patients fulfilled the inclusion criteria, out of which three were retrospective analysis studies, one case-control study, one prospective study, and one post hoc analysis of a multicentre trial. Some studies assessed the relationship between ICH occurrence and circadian rhythm depending on AIS onset time (n = 2), treatment time (n = 2), or both (n = 4). All studies investigated the patients' comorbidities as confounding variables for the circadian pattern of symptomatic ICH (sICH). Two studies found no association between AIS onset or ivT time and patient risk factors, but the other four found several differences and used multivariate logistic regression models to balance these covariates. The overall score of the Newcastle- Ottawa scale was 83.3%, which might be interpreted as overall high quality. CONCLUSION: ICH occurred after ivT seems to follow a circadian pattern; the 18:00-00:00 time frame was the safest one, and patients with AIS onset or ivT time between these hours had the lowest incidence of any ICH, including sICH. The 06:00-12:00 block was associated with the highest incidence of ICH and sICH. However, the analysis is limited by the small number of included studies and the heterogeneous findings reported. Further homogenized studies using comparable time frames and sICH definitions are needed to demonstrate this circadian pattern. The review protocol was registered in the OSF database under reference UHNF, doi:10.17605/OSF.IO/UHNF6.

The Burden of Cerebral Venous Thrombosis in a Romanian Population across a 5-Year Period.

Health policies in transitioning health systems are rarely informed by the social burden and the incidence shifts in disease epidemiology. Cerebral venous thrombosis (CVT) is a type of stroke more often affecting younger adults and women, with higher incidences being reported in recent studies. A retrospective, hospital-based population study was conducted at Cluj-Napoca Emergency County Hospital across a 5-year period between 2017 and 2021. The overall incidence and the rates in distinctive gender and age groups were assessed. Length of hospital stay (LHS), modified Rankin score (mRS) and mortality at discharge and at 3 months were calculated. Fifty-three patients were included. The median age was 45 years, and 64.2% were women. In our population of 3,043,998 person-years, 53 CVT cases resulted in an incidence of 1.74 per 100,000 (95% CI 1.30-2.27). CVT incidence was higher in women (2.13 per 100,000, 95% CI 1.47-2.07). There was a statistically significant difference in LHS between patients with different intracranial complications (Kruskal-Wallis, p = 0.008). The discharge mRS correlated with increasing age (rs = 0.334, p = 0.015), transient risk factors (Fisher's exact test, p = 0.023) and intracranial complications (Fisher's exact test, p = 0.022). In addition, the mRS at 3 months was statistically associated with increasing age (rs = 0.372, p = 0.006) and transient risk factors (Fisher's exact test, p = 0.012). In-hospital mortality was 5.7%, and mortality at follow up was 7.5%, with higher rates in women (5.9% and 8.8%, respectively). Our findings may provide insight regarding the epidemiological features of certain patient groups more prone to developing CVT and its complications, informing local and central stakeholders' efforts to improve standards of care.

N-Pep-12 supplementation after ischemic stroke positively impacts frequency domain QEEG.

BACKGROUND: N-Pep-12 is a dietary supplement with neuroprotective and pro-cognitive effects, as shown in experimental models and clinical studies on patients after ischemic stroke. We tested the hypothesis that N-Pep-12 influences quantitative electroencephalography (QEEG) parameters in patients with subacute to chronic supratentorial ischemic lesions. METHODS: We performed secondary data analysis on an exploratory clinical trial (ISRCTN10702895), assessing the efficacy and safety of 90 days of once-daily treatment with 90 mg N-Pep-12 on neurocognitive function and neurorecovery outcome in patients with post-stroke cognitive impairment against a control group. All participants performed two 32-channel QEEG in resting and active states at baseline (30-120 days after stroke) and 90 days later. Power spectral density on the alpha, beta, theta, delta frequency bands, delta/alpha power ratio (DAR), and (delta+theta)/(alpha+beta) ratio (DTABR) were computed and compared across study groups using means comparison and descriptive methods. Secondarily, associations between QEEG parameters and available neuropsychological tests were explored. RESULTS: Our analysis showed a statistically significant main effect of EEG segments (p<0.001) in alpha, beta, delta, theta, DA, and DTAB power spectral density. An interaction effect between EEG segments and time was noticed in the alpha power. There was a significant difference in theta spectral power between patients with N-Pep-12 supplementation versus placebo at 0.05 alpha level (p=0.023), independent of time points. CONCLUSION: A 90-day, 90 mg daily administration of N-Pep-12 had significant impact on some QEEG indicators in patients after supratentorial ischemic stroke, confirming possible enhancement of post-stroke neurorecovery. Further research is needed to consolidate our findings.

Safety of Cerebrolysin for Neurorecovery after Acute Ischemic Stroke: A Systematic Review and Meta-Analysis of Twelve Randomized-Controlled Trials.

We performed a systematic search and meta-analysis of available literature to determine the safety profile of Cerebrolysin in acute ischemic stroke, filling existing safety information gaps and inconsistent results. We searched EMBASE, PubMed, and Cochrane Databases of Systematic Reviews and Clinical Trials up to the end of February 2021. Data collection and analysis were conducted using methods described in the Cochrane Handbook for Systematic Reviews of Interventions. All safety outcomes were analyzed based on risk ratios (RR) and their 95% confidence intervals. The meta-analysis pooled 2202 patients from twelve randomized clinical trials, registering non-statistically significant (p > 0.05) differences between Cerebrolysin and placebo throughout main and subgroup analyses. The lowest rate of Serious Adverse Events (SAE), as compared to placebo, was observed for the highest dose of Cerebrolysin (50 mL), highlighting a moderate reduction (RR = 0.6). We observed a tendency of superiority of Cerebrolysin regarding SAE in high dose treatment courses for moderate-severe ischemic stroke, suggesting some effect of the agent against adverse events. This comprehensive safety meta-analysis confirms the safety profile for patients treated with Cerebrolysin after acute ischemic stroke, as compared to placebo.

European Academy of Neurology and European Federation of Neurorehabilitation Societies guideline on pharmacological support in early motor rehabilitation after acute ischaemic stroke.

BACKGROUND AND PURPOSE: Early pharmacological support for post-stroke neurorehabilitation has seen an abundance of mixed results from clinical trials, leaving practitioners at a loss regarding the best options to improve patient outcomes. The objective of this evidence-based guideline is to support clinical decision-making of healthcare professionals involved in the recovery of stroke survivors. METHODS: This guideline was developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. PubMed, Cochrane Library and Embase were searched (from database inception to June 2018, inclusive) to identify studies on pharmacological interventions for stroke rehabilitation initiated in the first 7 days (inclusive) after stroke, which were delivered together with neurorehabilitation. A sensitivity analysis was conducted on identified interventions to address results from breaking studies (from end of search to February 2020). RESULTS: Upon manually screening 17,969 unique database entries (of 57,001 original query results), interventions underwent meta-analysis. Cerebrolysin (30 ml/day, intravenous, minimum 10 days) and citalopram (20 mg/day, oral) are recommended for clinical use for early neurorehabilitation after acute ischaemic stroke. The remaining interventions identified by our systematic search are not recommended for clinical use: amphetamine (5, 10 mg/day, oral), citalopram (10 mg/day, oral), dextroamphetamine (10 mg/day, oral), Di-Huang-Yi-Zhi (2 × 18 g/day, oral), fluoxetine (20 mg/day, oral), lithium (2 × 300 mg/day, oral), MLC601(3 × 400 mg/day, oral), phosphodiesterase-5 inhibitor PF-03049423 (6 mg/day, oral). No recommendation 'for' or 'against' is provided for selegiline (5 mg/day, oral). Issues with safety and tolerability were identified for amphetamine, dextroamphetamine, fluoxetine and lithium. CONCLUSIONS: This guideline provides information for clinicians regarding existing pharmacological support in interventions for neurorecovery after acute ischaemic stroke. Updates to this material will potentially elucidate existing conundrums, improve current recommendations, and hopefully expand therapeutic options for stroke survivors.

Societal Cost of Ischemic Stroke in Romania: Results from a Retrospective County-Level Study.

BACKGROUND: Health policies in transitioning health systems are rarely informed by the economic burden of disease due to scanty access to data. This study aimed to estimate direct and indirect costs for first-ever acute ischemic stroke (AIS) during the first year for patients residing in Cluj, Romania, and hospitalized in 2019 at the County Emergency Hospital (CEH). METHODS: The study was conducted using a mixed, retrospective costing methodology from a societal perspective to measure the cost of first-ever AIS in the first year after onset. Patient pathways for AIS were reconstructed to aid in mapping inpatient and outpatient cost items. We used anonymized administrative and clinical data at the hospital level and publicly available databases. RESULTS: The average cost per patient in the first year after stroke onset was RON 25,297.83 (EUR 5226.82), out of which 80.87% were direct costs. The total cost in Cluj, Romania in 2019 was RON 17,455,502.7 (EUR 3,606,505.8). CONCLUSIONS: Our costing exercise uncovered shortcomings of stroke management in Romania, particularly related to acute care and neurorehabilitation service provision. Romania spends significantly less on healthcare than other countries (5.5% of GDP vs. 9.8% European Union average), exposing stroke survivors to a disproportionately high risk for preventable and treatable post-stroke disability.