Endovascular Versus Medical Management in Distal Medium Vessel Occlusion Stroke: The DUSK Study.

BACKGROUND: Endovascular treatment (EVT) is part of the usual care for proximal vessel occlusion strokes. However, the safety and effectiveness of EVT for distal medium vessel occlusions remain unclear. We sought to compare the clinical outcomes of EVT to medical management (MM) for isolated distal medium vessel occlusions. METHODS: This is a retrospective analysis of prospectively collected data from seven comprehensive stroke centers. Patients were included if they had isolated distal medium vessel occlusion strokes due to middle cerebral artery M3/M4, anterior cerebral artery A2/A3, or posterior cerebral artery P1/P2 segments. Patients treated with EVT or MM were compared with multivariable logistic regression and inverse probability of treatment weighting. The primary outcome was the shift in the degree of disability as measured by the modified Rankin Scale (mRS) at 90 days. Secondary outcomes included 90-day good (mRS score, 0-2) and excellent (mRS score, 0-1) outcomes. Safety measures included symptomatic intracranial hemorrhage and 90-day mortality. RESULTS: A total of 321 patients were included in the analysis (EVT, 179; MM, 142; 40.8% treated with intravenous thrombolysis). In the inverse probability of treatment weighting model, there were no significant differences between EVT and MM in terms of the overall degree of disability (mRS ordinal shift; adjusted odds ratio [aOR], 1.25 [95% CI, 0.95-1.64]; P=0.110), rates of good (mRS score, 0-2; aOR, 1.32 [95% CI, 0.97-1.80]; P=0.075) and excellent (aOR, 1.32 [95% CI, 0.94-1.85]; P=0.098) outcomes, or mortality (aOR, 1.20 [95% CI, 0.78-1.85]; P=0.395) at 90 days. The multivariable regression model showed similar findings. Moreover, there was no difference between EVT and MM in rates of symptomatic intracranial hemorrhage in the multivariable regression model (aOR, 0.57 [95% CI, 0.21-1.58]; P=0.277), but the inverse probability of treatment weighting model showed a lower likelihood of symptomatic intracranial hemorrhage (aOR, 0.46 [95% CI, 0.24-0.85]; P=0.013) in the EVT group. CONCLUSIONS: This multicenter study failed to demonstrate any significant outcome differences among patients with isolated distal medium vessel occlusions treated with EVT versus MM. These findings reinforce clinical equipoise. Randomized clinical trials are ongoing and will provide more definite evidence.

Clinging on the brink: Whole genomes reveal human-induced population declines and severe inbreeding in the Critically Endangered Emirati Leaf-toed Gecko (Asaccus caudivolvulus).

Human-mediated habitat destruction has had a profound impact on increased species extinction rates and population declines worldwide. The coastal development in the United Arab Emirates (UAE) over the last two decades, serves as an example of how habitat transformation can alter the landscape of a country in just a few years. Here, we study the genomic implications of habitat transformation in the Critically Endangered Emirati Leaf-toed Gecko (Asaccus caudivolvulus), the only endemic vertebrate of the UAE. We generate a high-quality reference genome for this gecko, representing the first reference genome for the family Phyllodactylidae, and produce whole-genome resequencing data for 23 specimens from 10 different species of leaf-toed geckos. Our results show that A. caudivolvulus has consistently lower genetic diversity than any other Arabian species of Asaccus, suggesting a history of ancient population declines. However, high levels of recent inbreeding are recorded among populations in heavily developed areas, with a more than 50% increase in long runs of homozygosity within a 9-year period. Moreover, results suggest that this species does not effectively purge deleterious mutations, hence making it more vulnerable to future stochastic threats. Overall, results show that A. caudivolvulus is in urgent need of protection, and habitat preservation must be warranted to ensure the species' survival.

Mild hypophosphatasia may be twice as prevalent as previously estimated: an effective clinical algorithm to detect undiagnosed cases.

OBJECTIVES: Since the prevalence of hypophosphatasia (HPP), a rare genetic disease, seems to be underestimated in clinical practice, in this study, a new diagnostic algorithm to identify missed cases of HPP was developed and implemented. METHODS: Analytical determinations recorded in the Clinical Analysis Unit of the Hospital Universitario Clínico San Cecilio in the period June 2018 - December 2020 were reviewed. A new clinical algorithm to detect HPP-misdiagnosed cases was used including the following steps: confirmation of persistent hypophosphatasemia, exclusion of secondary causes of hypophosphatasemia, determination of serum pyridoxal-5'-phosphate (PLP) and genetic study of ALPL gene. RESULTS: Twenty-four subjects were selected to participate in the study and genetic testing was carried out in 20 of them following clinical algorithm criteria. Eighty percent of patients was misdiagnosed with HPP following the current standard clinical practice. Extrapolating these results to the current Spanish population means that there could be up to 27,177 cases of undiagnosed HPP in Spain. In addition, we found a substantial proportion of HPP patients affected by other comorbidities, such as autoimmune diseases (∼40 %). CONCLUSIONS: This new algorithm was effective in detecting previously undiagnosed cases of HPP, which appears to be twice as prevalent as previously estimated for the European population. In the near future, our algorithm could be globally applied routinely in clinical practice to minimize the underdiagnosis of HPP. Additionally, some relevant findings, such as the high prevalence of autoimmune diseases in HPP-affected patients, should be investigated to better characterize this disorder.

Retinal shadows produced by myopia control spectacles.

PURPOSE: To analyse ocular coherence tomography (OCT) images of the retinal shadows caused by defocus and diffusion optics spectacles. METHODS: One eye was fitted successively with the Hoya Defocus Incorporated Multiple Segments (DIMS) spectacle lens, two variations of the +3.50 D peripheral add spectacle (DEFOCUS) and the low-contrast dot lens (Diffusion Optics Multiple Segments, DOMS); each at a vertex distance of 12 mm. Simultaneously, a retinal image of the macular region with central fixation was obtained using infrared OCT. The corneal power and intraocular distances were determined using an optical biometer. RESULTS: The retinal images for the DIMS and DOMS lenses showed patterns of obvious retinal shadows in the periphery, while the central 10-11° remained clear. The DEFOCUS lens produced a darkened peripheral area. Dividing the size of the retinal pattern, measured with the calliper of the OCT software, by the actual size on the spectacle lens gave a magnification of -0.57 times. This is consistent with the incoming OCT beam being imaged to a position approximately 31 mm beyond the front of the eye. [Correction added on 26 October 2023 after first online publication: The preceding paragraph was corrected.] CONCLUSION: With device-specific correction, retinal OCT images can help visualise the regions affected by the defocus or lowered contrast induced by myopia control spectacles. This is of potential value for improving myopia therapies.

Survival and neurological outcomes following management of intramedullary spinal metastasis patients: a case series with comprehensive review of the literature.

Intramedullary spinal cord metastasis (ISCM), though rare, represents a potentially debilitating manifestation of systemic cancer. With emerging advances in cancer care, ISCMs are increasingly being encountered in clinical practice. Herein, we describe one of the larger retrospective single institutional case series on ISCMs, analyze survival and treatment outcomes, and review the literature. All surgically evaluated ISCMs at our institution between 2005 and 2023 were retrospectively reviewed. Demographics, tumor features, treatment, and clinical outcome characteristics were collected. Neurological function was quantified via the Frankel grade and the McCormick score (MCS). The pre- and post-operative Karnofsky performance scores (KPS) were used to assess functional status. Descriptive statistics, univariate analysis, log-rank test, and the Kaplan-Meier survival analysis were performed. A total of 9 patients were included (median age 67 years (range, 26-71); 6 were male). Thoracic and cervical spinal segments were most affected (4 patients each). Six patients (75%) underwent surgical management (1 biopsy and 5 resections), and 3 cases underwent chemoradiation only. Post-operatively, 2 patients had an improvement in their neurological exam with one patient becoming ambulatory after surgery; three patients maintained their neurological exam, and 1 had a decline. There was no statistically significant difference in the pre- and post-operative MCS and median KPS scores in surgically treated patients. Median OS after ISCM diagnosis was 7 months. Absence of brain metastasis, tumor histology (renal and melanoma), cervical/thoracic location, and post-op KPS ≥ 70 showed a trend toward improved overall survival. The incidence of ISCM is increasing, and earlier diagnosis and treatment are considered key for the preservation of neurological function. When patient characteristics are favorable, surgical resection of ISCM can be considered in patients with rapidly progressive neurological deficits. Surgical treatment was not associated with an improvement in overall survival in patients with ISCMs.

Outcomes of Corrective, Concentric (C2) Glenoid Reaming combined with Pyrocarbon Hemiarthroplasty for B2, B3 Glenoid Arthritis.

BACKGROUND: Posterior humeral subluxation (PHS) in B2/B3 glenoid is a cause of asymmetric long-term stress on the glenoid and the potential reason for glenoid loosening in anatomic total shoulder arthroplasty (ATSA) and painful glenoid erosion in hemiarthroplasty with metallic heads (HA-Metal). We hypothesized that corrective and concentric reaming (CCR) of the glenoid associated with pyrocarbon hemiarthroplasty (HA-PYC) could improve the centering of the humeral head and decrease the risk of persistent painful glenoid erosion in young/active patients with B2/B3 glenoid. METHODS: Between 2014 and 2020, 41shoulders (in 35 patients, mean age of 57.9 years) underwent HA-PYC combined with CCR reaming for B2 (n=30) or B3 (n=11) osteoarthritis. Patients were prospectively followed with computed tomography (CT) scans performed preoperatively, immediate postoperatively and at last follow-up (> 2 years). The primary outcomes were 3D-corrected CT-scan measurements of glenoid version, PHS, progression of glenoid erosion. Secondary outcomes included functional outcome scores, return to activities, and revision rate and complications. RESULTS: At a mean follow-up of 4.5 years (2 to 9.5 years), the prosthesis survival was 95% (39/41). No patient has been reoperated for painful glenoid erosion. The mean glenoid retroversion decreased from 17.1° ± 7.5 preoperatively to 8.3° ± 8.2 at last follow-up (p=0.001), and the mean PHS from 74% to 56.5% (p=0.001) based on the scapular plane and from 59.9% to 50.3% based on the glenoid plane. The humeral head was recentered in 97% according to the glenoid surface and 71% according to the scapular plane. Correction of PHS in the scapular plane was highly correlated to correction of glenoid retroversion (p<0.001). CT-scan measurements showed that the average total medialization was 3.7 ± 3.2 mm (2.0 ± 1.8 mm due to reaming and only 1.7 ± 2.4 mm due to erosion). The Adjusted Constant score increased from 43% ± 13 to 97% ± 16 and the Subjective Shoulder Value from 38% ± 14 to 84 % ± 12 (p<0.001). Overall, 84% of active patients returned to work and all patients returned to sports. CONCLUSION: In B2/B3 glenoid arthritis, corrective, concentric glenoid reaming combined with HA-PYC improves centering of the humeral head and shows a low risk of painful glenoid erosion at mid-term follow-up. The combined procedure results in excellent functional outcomes and high prosthesis survivorship at mid-term follow-up. HA-PYC and CCR is offering an alternative shoulder arthroplasty for young/active patients with B2/B3 glenoid osteoarthritis who want to return to work or sports practice.

Inhibition of Adult Neurogenesis in Male Mice after Repeated Exposure to Paracetamol Overdose.

Paracetamol, or acetaminophen (N-acetyl-para-aminophenol, APAP), is an analgesic and antipyretic drug that is commonly used worldwide, implicated in numerous intoxications due to overdose, and causes serious liver damage. APAP can cross the blood-brain barrier and affects brain function in numerous ways, including pain signals, temperature regulation, neuroimmune response, and emotional behavior; however, its effect on adult neurogenesis has not been thoroughly investigated. We analyze, in a mouse model of hepatotoxicity, the effect of APAP overdose (750 mg/kg/day) for 3 and 4 consecutive days and after the cessation of APAP administration for 6 and 15 days on cell proliferation and survival in two relevant neurogenic zones: the subgranular zone of the dentate gyrus and the hypothalamus. The involvement of liver damage (plasma transaminases), neuronal activity (c-Fos), and astroglia (glial fibrillar acidic protein, GFAP) were also evaluated. Our results indicated that repeated APAP overdoses are associated with the inhibition of adult neurogenesis in the context of elevated liver transaminase levels, neuronal hyperactivity, and astrogliosis. These effects were partially reversed after the cessation of APAP administration for 6 and 15 days. In conclusion, these results suggest that APAP overdose impairs adult neurogenesis in the hippocampus and hypothalamus, a fact that may contribute to the effects of APAP on brain function.

Dental color measurement to estimate age in adults: a systematic review and meta-analysis.

Age estimation is a major challenge in anthropology and forensic odontology laboratories, as well as in judicial settings, as one of the tools used in human identification. The aim of this study was to evaluate the usefulness of age estimation methods based on the accurate measurement of tooth color changes. A systematic review was carried out following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and in compliance with Cochrane criteria recommendations (PROSPERO registration number CRD 42022343371). An electronic search was performed in the following databases: Pubmed, Web of Science, Medline, Current Contents Connect, SciELO, KCI-Korean Journal Database, Derwent Innovations Index and Russian Citation Index. The search strategy yielded a total of 18 articles. A randomized meta-analysis model of the results for the CIE L*a*b* color variables stratified by age (less than 30 years, 30-60 years, 60 years and older) was performed with 9 of the 18 studies included in this systematic review. According to our results, sex and location of color measurement are the most influential factors in color estimation. All studies were carried out in healthy anterior teeth by spectrophotometry as the most commonly used method for color measurement, with CIE L*a*b* being the most commonly analyzed parameters. Studies based on age as a dependent variable showed R2 values between 0.28 and 0.56, being higher in ex vivo teeth. Studies based on age as an independent variable showed R2 values ranging from 0.10 to 0.48. The random model showed high heterogeneity for the L*, a* and b* parameters in all age groups, which is explained by discrepancies in age range and non-standardized conditions for color measurement. This systematic review highlights the need to protocolize age estimation studies that measure tooth color, in order to apply this method in different forensic settings.

Apraisal of the diagnostic value of the gag reflex in patients with neurogenic oropharyngeal dysphagia / Evaluación del valor clínico del reflejo nauseoso en la disfagia orofaríngea neurogénica.

Introduction: The gag reflex is a protection mechanism that prevents food and unwanted agents from entering the lower airways. It is usually part of the physical examination of swallowing to detect oropharyngeal dysphagia, but it is a potentially ambiguous sign. Objective: To evaluate the diagnostic value of the gag reflex in patients with neurogenic oropharyngeal dysphagia and adults without it. Materials and methods: We conducted an analytical observational study in patients with neurogenic oropharyngeal dysphagia (cases) and patients without dysphagia (controls). We evaluated the absence or presence of the reflex bilaterally, by direct visualization, and adjusted it according to sex, age, and other interaction variables. Results: We included 86 patients with neurogenic oropharyngeal dysphagia and 80 control subjects. The gag reflex on swallowing physical examination showed a positive relationship with the patients (right side: OR = 3.97; 95 % CI: 2.01-7.84; left side: OR = 4.84; 95 % CI: 2.41-9.72), but a negative association with the control group. In both groups, neither sex, nor age, nor other interaction variables modified the gag reflex. Conclusions: The gag reflex absence or presence does not confirm or exclude the existence of oropharyngeal dysphagia due to neurological and neuromuscular causes. Therefore, health professionals must not rely on this reflex. Clinicians must go beyond a simple reflex revision, even in neurological patients where it is supposed to be absent.

Introducción. El reflejo nauseoso es un mecanismo de protección que impide que alimentos y agentes no deseados penetren en la vía aérea inferior. Usualmente, hace parte del examen físico de la deglución para detectar la disfagia orofaríngea, pero es un signo potencialmente ambiguo. Objetivo. Evaluar el valor diagnóstico del reflejo nauseoso en pacientes con disfagia orofaríngea neurogénica y en pacientes sin ella. Materiales y métodos. Se trata de un estudio observacional, analítico, en pacientes con disfagia orofaríngea neurogénica (casos) y en personas sin disfagia (controles), en el cual se evaluó por visualización directa la ausencia o la presencia del reflejo nauseoso de forma bilateral. Este resultado se ajustó por sexo, edad y otras variables de interacción. Resultados. Se evaluaron 86 pacientes con disfagia orofaríngea neurogénica y 80 personas sin ella. En el examen físico de la deglución, la presencia del reflejo mostró una relación positiva con los pacientes (lado derecho: OR = 3,97; IC95%: 2,01-7,84; lado izquierdo: OR = 4,84; IC95%: 2,41-9,72), pero una asociación negativa con los controles. En ambos grupos, ni el sexo ni la edad, ni otras variables de interacción modificaron el reflejo nauseoso. Conclusiones. La ausencia o la presencia del reflejo nauseoso no confirma ni excluye la existencia de una disfagia orofaríngea por causas neurológicas o neuromusculares; por lo tanto, no es recomendable que los profesionales de la salud se fíen del resultado de este reflejo. Los médicos tratantes deben ir más allá de una simple revisión del reflejo nauseoso, incluso en pacientes neurológicos en quienes se supone que debería estar ausente.

Evaluation of a Pilot Spanish Language Program for Student Pharmacists.

OBJECTIVE: This study aimed to present findings from an evaluation of the Spanish Language Track (SLT) for student pharmacists, which assessed student outcomes and feedback. METHODS: A mixed-methods program evaluation was conducted with the first cohort of the SLT members (N = 10). Participants completed pre/post-surveys and focus groups. Quantitative data analysis used descriptive and frequency analysis, while qualitative data were thematically analyzed. RESULTS: With a focus on qualitative themes, quantitative results support themes 1, 2, and 3 on the basis of findings from the self-assessment of participants' ability to speak and use the Spanish language. The following 5 themes were identified: (1) initial involvement and motivation to engage; (2) language skill development; (3) health-focused language immersion; (4) strong relationships within the SLT cohort; and (5) opportunities for improvement. CONCLUSION: Findings demonstrate students' active engagement with SLT while enhancing language skills through immersive experiences. Their connections with other cohort members, SLT team members, and Colombian pharmacists, and biweekly patient appointment simulations were key contributors to learning outcomes while offering suggestions for programming. The SLT provides a foundational model for health professional programs to offer students opportunities to understand and practice language-concordant health care delivery and promote improved health outcomes in Spanish-speaking populations.

Intraventricular Pilocytic Astrocytoma in Adults: A 25-year Single-Center Case Series and Systematic Review of the Literature.

BACKGROUND: Pilocytic astrocytomas (PA) are the most common gliomas in children/adolescents but are less common and poorly studied in adults. Here, we describe the clinical presentation, surgical management, and outcomes of surgically treated adult patients with intraventricular (IV) PA and review the literature. METHODS: Consecutive adult patients treated for IV brain tumors at a tertiary academic center over 25 years (1997-2023) were identified. Clinical data were reviewed retrospectively for adult IV PA patients. A systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: Eight patients with IV PA were included. Median age was 25 years (range, 18-69 years), and 4 (50%) were female. The most common tumor location was the lateral ventricle (5, 63%), followed by the fourth ventricle (3, 37%). Subtotal and near total resection were the most common surgical outcomes (6 patients, 75%), followed by gross total resection in 2 (25%). Progression or recurrence occurred in 3 patients (37%), requiring repeat resection in 2 patients. The 5-year overall survival and progression-free survival were 67% and 40%, respectively. In addition, 42 cases were identified in the literature. CONCLUSIONS: PAs in adults are rare and an IV location is even more uncommon. The findings demonstrate the challenges in caring for these patients, with overall- and progression-free survival outcomes being poorer than the general adult PA population. Findings support the employment of surgical techniques and approaches that favor gross total resection when possible. Further studies are needed to better characterize this unique presentation.

Minimally Invasive Technique for Chiari I Decompression Without Durotomy: Surgical Technique and Preliminary Case Series.

BACKGROUND: Chiari I malformation, marked by severe headaches and potential brainstem/spinal cord issues, often requires surgical intervention when conservative methods fail. This study introduces a minimally invasive surgery (MIS) Chiari decompression technique utilizing a 3-blade retractor, aiming to reduce postoperative discomfort and optimize outcomes. METHODS: Chiari type I malformation patients who underwent a MIS technique were included. Technique consisted of a minimal-soft tissue opening using a 3-blade retractor, suboccipital craniectomy, C1 laminectomy, and resection of the atlantooccipital band without a durotomy. RESULTS: Ten patients were treated. Mean age was 43.3 years, with 7 female patients. All patients presented with occipital headaches; 50% retroorbital pain; 40% neck, upper back, or shoulder pain; and 30% limb paresthesias. Median pre-surgical modified Rankin Scale (mRS) was 3 (2-4) and pain visual analog score (VAS) was 7 (5-9). Mean operative time was 59 (59-71) minutes, with mean blood loss of 88.5 (50-140) mL. In our sample, 90% of patients were discharged the same surgical day (mean 7.2 [5.3-7.7] hours postoperative). No immediate or delayed postoperative complications were evidenced. At 6 months, 90% of patients had mRS 0-1. At last follow-up the mean VAS was 1.5 (range: 0-4, P < 0.001). CONCLUSIONS: The MIS 3-blade flexible retractor technique for Chiari decompression is feasible, provides wide visualization angles of the suboccipital region and C1 arch, allows 2-surgeon work, and minimizes skin and soft tissue disruption. This combination may diminish postoperative discomfort, reduce the risk of surgical site infections, and optimize outcomes.

Sex-based differences in growth-related IGF1 signaling in response to PAPP-A2 deficiency: comparative effects of rhGH, rhIGF1 and rhPAPP-A2 treatments.

BACKGROUND: Children with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations resulting in low levels of bioactive insulin-like growth factor-1 (IGF1) and progressive postnatal growth retardation have improved growth velocity and height following recombinant human (rh)IGF1 treatment. The present study aimed to evaluate whether Pappa2 deficiency and pharmacological manipulation of GH/IGF1 system are associated with sex-specific differences in growth-related signaling pathways. METHODS: Plasma, hypothalamus, pituitary gland and liver of Pappa2ko/ko mice of both sexes, showing reduced skeletal growth, and liver of these mice treated with rhGH, rhIGF1 and rhPAPP-A2 from postnatal day (PND) 5 to PND35 were analyzed. RESULTS: Reduced body and femur length of Pappa2ko/ko mice was associated with increases in: (1) components of IGF1 ternary complexes (IGF1, IGFBP5/Igfbp5, Igfbp3, Igfals) in plasma, hypothalamus and/or liver; and (2) key signaling regulators (phosphorylated PI3K, AKT, mTOR, GSK3ß, ERK1/2 and AMPKα) in hypothalamus, pituitary gland and/or liver, with Pappa2ko/ko females having a more prominent effect. Compared to rhGH and rhIGF1, rhPAPP-A2 specifically induced: (1) increased body and femur length, and reduced plasma total IGF1 and IGFBP5 concentrations in Pappa2ko/ko females; and (2) increased Igf1 and Igf1r levels and decreased Ghr, Igfbp3 and Igfals levels in the liver of Pappa2ko/ko females. These changes were accompanied by lower phospho-STAT5, phospho-AKT and phospho-ERK2 levels and higher phospho-AMPK levels in the liver of Pappa2ko/ko females. CONCLUSIONS: Sex-specific differences in IGF1 system and signaling pathways are associated with Pappa2 deficiency, pointing to rhPAPP-A2 as a promising drug to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.

Understanding the physiological role of pregnancy-associated plasma protein-A2 (PAPP-A2), a proteinase involved in the insulin-like growth factor-1 (IGF1) availability to regulate growth, could provide insight into new treatments for patients with short stature and skeletal abnormalities. Although progressive postnatal growth retardation in patients with PAPP-A2 mutations can differ between males and females, we do not know the underlying differences in IGF1 system and signaling, and their response to treatment that contribute to growth improvement. The present study examines whether Pappa2 deficiency and pharmacological administration of rhGH, rhIGF1 and rhPAPP-A2 are associated with sex-specific differences in IGF1 ternary complexes and IGF1 signaling pathways. Reduced body and femur length of Pappa2-deficient mice was associated with sex- and tissue-specific alteration of IGF ternary/binary complexes and IGF1 signaling pathways. rhPAPP-A2 treatment induced female-specific increase in body and femur length and reduction in IGF ternary/binary complexes through STAT5-AKT-ERK2-AMPK signaling pathways in liver. The involvement of PAPP-A2 in sex-based growth physiology supports the use of promising drugs to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.

Hydroxytyrosol Linoleoyl Ether Ameliorates Metabolic-Associated Fatty Liver Disease Symptoms in Obese Zucker Rats.

A main hepatic consequence of obesity is metabolic-associated fatty liver disease (MAFLD), currently treated by improving eating habits and administrating fibrates yet often yielding suboptimal outcomes. Searching for a new therapeutic approach, we aimed to evaluate the efficacy of hydroxytyrosol linoleoyl ether (HTLE), a dual Ppar-α agonist/Cb1 antagonist with inherent antioxidant properties, as an antisteatotic agent. Using lean and obese Zucker rats, they were administrated daily doses of HTLE (3 mg/kg) over a 15-day period, evaluating its safety profile, pharmacokinetics, impact on body weight, hepatic fat content, expression of key enzymes involved in lipogenesis/fatty acid oxidation, and antioxidant capacity. HTLE decreased the body weight and food intake in both rat genotypes. Biochemical analysis demonstrated a favorable safety profile for HTLE along with decreased concentrations of urea, total cholesterol, and aspartate aminotransferase AST transaminases in plasma. Notably, HTLE exhibited potent antisteatotic effects in obese rats, evidenced by a decrease in liver fat content and downregulation of lipogenesis-related enzymes, alongside increased expression of proteins controlling lipid oxidation. Moreover, HTLE successfully counteracted the redox imbalance associated with MAFLD in obese rats, attenuating lipid peroxidation and replenishing both glutathione levels and the overall antioxidant. Our findings highlight the effectiveness of triple-action strategies in managing MAFLD effectively. Based on our results in the Zucker rat model, HTLE emerges as a promising candidate with triple functionality as an anorexigenic, antisteatotic, and antioxidant agent, offering potential relief from MAFLD symptoms associated with obesity while exhibiting minimal side effects. In conclusion, our study positions HTLE as a highly promising compound for therapeutic intervention in MAFLD treatment, warranting further exploration in clinical trials.

Pharmacotherapeutic value of inflammatory and neurotrophic biomarkers in bipolar disorder: A systematic review.

BACKGROUND: The various pharmacological interventions, ranging from mood stabilizers and antipsychotics to antidepressants, reflect the diff/iculty of treating depressive/manic symptomatology of bipolar disorder (BD). Among a broad range of mechanisms implicated, immune dysregulation may contribute to the increased inflammation that influences the course of BD. Inflammatory, neurotrophic and oxidative stress factors may be identified as promising peripheral biomarkers in brain functioning, perhaps serving as predictors of an effective response to treatment for BD. The present systematic review aimed to examine the evidence supporting the pharmacotherapeutic value of inflammatory and neurotrophic biomarkers in BD. METHODS: PubMed, PsychINFO, Scopus and Web of Science were searched from inception to May 2024 by two independent reviewers. A total of 40 studies with 3371 patients with diagnosis and intervention of BD were selected. RESULTS: Inconsistencies in the effects of pharmacological treatments on the connection between the expected anti-inflammatory response and symptomatologic improvement were identified. Mood stabilizers (lithium), antipsychotics (quetiapine), antidepressants (ketamine) or their combination were described to increase both pro-inflammatory (TNFα, IL-6) and anti-inflammatory (IL-4, IL-8) factors. Other medications, such as memantine and dextromethorphan, autoimmune (infliximab) non-steroidal anti-inflammatory (aspirin, celecoxib) drugs, antidiabetics (pioglitazone), and even dietary supplementation (omega-3), or their combination, clearly decrease inflammatory factors (TNFα, IL-6, IL-1ß, C-reactive protein) and/or increase the neurotrophic factor BDNF in BD patients. CONCLUSION: Inflammation in BD requires further investigation to understand the underlying immunologic mechanism, to identify predictors of treatment response, and to make informed decisions about the use and development of more effective pharmacological interventions for BD.

Intrasaccular Flow Disruption: Examining Global Access and Research Trends.

The Woven EndoBridge (WEB) and other intrasaccular flow disruptors show promise in treating intracranial aneurysms. We performed a bibliometric analysis to provide novel insights into the trends and trajectory of these devices. We systematically assessed bibliometric data such as citations, journals, study designs, open access status, and multi-institutional involvement for the top-cited articles on WEB and other disruptors. The top 100 cited studies on the WEB had citations from 7 to 144 (mean ± standard deviation 35.6 ± 29.5), while only 33 studies were published for other intrasaccular flow disruptors (4.24 ± 8.45). Of the other devices, the Contour has the most publications (n = 21). Retrospective reviews were the most common study design for both WEB and other intrasaccular devices. France published the most studies in the top 100 WEB papers (n = 35), while Germany led for other flow disruptors (n = 10). In all studies analyzed, no senior authors from Africa are present. The top 100 WEB publications had a higher mean citation count (35.6 vs. 4.24, P<0.001), higher mean citations per year (5.24 vs. 1.03, P<0.01), and a higher proportion of multi-institutional collaborations (44.0% vs. 12.1%, P<0.01) than other intrasaccular flow disruptors. In conclusion, countries with the most publications on WEB are not necessarily the ones leading the way with newer intrasaccular devices, while study designs remain similar. There is a limited contribution to the literature outside of Europe and North America. Our findings identify notable collaborators and trends, providing a snapshot of the field and a roadmap for future research.

Woven EndoBridge versus stent-assisted coil embolization for the treatment of ruptured wide-necked aneurysms: A multicentric experience.

BACKGROUND: The potentially higher risk of hemorrhagic complications is of concern in stent-assisted coiling (SAC) of ruptured wide-necked intracranial aneurysms (IAs). The Woven EndoBridge (WEB) is considered an appealing alternative since antiplatelet therapy is not required. Herein, we aimed to compare the safety and effectiveness of WEB vs. SAC for the treatment of ruptured wide-necked IAs. METHODS: This was an international cross-sectional study of consecutive patients treated for ruptured wide-neck IAs with WEB or SAC at four high-volume neurovascular centers between 2019 and 2022. Primary and secondary efficacy outcomes were radiographic aneurysm occlusion at follow-up and functional status at last follow-up. Safety outcomes included periprocedural hemorrhagic/ischemia-related complications. RESULTS: One hundred five patients treated with WEB and 112 patients treated with SAC were included. The median procedure duration of endovascular treatment was shorter for WEB than for SAC (69 vs. 76 min; p = 0.04). There were no significant differences in complete aneurysm occlusion rates (SAC: 64.5% vs. WEB: 60.9%; adjusted OR [aOR] = 0.70; 95%CI 0.34-1.43; p = 0.328). SAC had a significantly higher risk of complications (23.2% vs. 9.5%, p = 0.009), ischemic events (17% vs. 6.7%, p = 0.024), and EVD hemorrhage (16% vs. 0%, p = 0.008). The probability of procedure-related complications across procedure time was significantly lower with WEB compared with SAC (aOR = 0.40; 95%CI 0.20-1.13; p = 0.03). CONCLUSION: WEB and SAC demonstrated similar obliteration rates at follow-up when used for embolization of ruptured wide-necked IAs. However, SAC showed higher rates of procedure-related complications primarily driven by ischemic events and higher rates of EVD hemorrhage. The overall treatment duration was shorter for WEB than for SAC.

Plasma Concentrations of High Mobility Group Box 1 Proteins and Soluble Receptors for Advanced Glycation End-Products Are Relevant Biomarkers of Cognitive Impairment in Alcohol Use Disorder: A Pilot Study.

Alcohol use disorder (AUD) is a major component in the etiology of cognitive decline and dementia. Underlying mechanisms by which long-term alcohol abuse causes cognitive dysfunction include excessive oxidative stress and inflammation in the brain, activated by increased reactive oxygen/nitrogen species (ROS/RNS), advanced glycation end-products (AGEs) and high-mobility group box 1 protein (HMGB1). In a pilot study, we examine the potential clinical value of circulating biomarkers of oxidative stress including ROS/RNS, HMGB1, the soluble receptor for AGE (sRAGE), the brain biomarker of aging apolipoprotein D (ApoD), and the antioxidant regulator nuclear factor erythroid 2-related factor 2 (NRF2) as predictive indices for cognitive impairment (CI) in abstinent patients with AUD (n = 25) compared to patients with established Alzheimer's disease (AD, n = 26) and control subjects (n = 25). Plasma concentrations of sRAGE were evaluated with immunoblotting; ROS/RNS with a fluorometric kit; and HMGB1, ApoD, and NRF2 by ELISA. Abstinent AUD patients had higher sRAGE, ROS/RNS (p < 0.05), and ApoD (p < 0.01) concentrations, similar to those of AD patients, and lower NRF2 (p < 0.01) concentrations, compared to controls. These changes were remarkable in AUD patients with CI. HMGB1, and sRAGE correlated positively with duration of alcohol use (rho = 0.398, p = 0.022; rho = 0.404, p = 0.018), whereas sRAGE correlated negatively with periods of alcohol abstinence (rho = -0.340, p = 0.045). A predictive model including ROS/RNS, HMGB1, sRAGE, alcohol use duration, and alcohol abstinence periods was able to differentiate AUD patients with CI (92.3% of correct predictions, ROC-AUC= 0.90) from those without CI. In conclusion, we propose ROS/RNS, HMGB1, and sRAGE as stress biomarkers capable of predicting cognitive impairment in AUD patients.

Update of the list of qualified presumption of safety (QPS) recommended microbiological agents intentionally added to food or feed as notified to EFSA 19: Suitability of taxonomic units notified to EFSA until September 2023.

The qualified presumption of safety (QPS) process was developed to provide a safety assessment approach for microorganisms intended for use in food or feed chains. The QPS approach is based on an assessment of published data for each taxonomic unit (TU), with respect to its taxonomic identity, the body of relevant knowledge and safety concerns. Safety concerns identified for a TU are, where possible, confirmed at the species/strain or product level and reflected by 'qualifications'. In the period covered by this Statement, no new information was found that would change the status of previously recommended QPS TUs. Of 71 microorganisms notified to EFSA between April and September 2023 (30 as feed additives, 22 as food enzymes or additives, 7 as novel foods and 12 from plant protection products [PPP]), 61 were not evaluated because: 26 were filamentous fungi, 1 was Enterococcus faecium, 5 were Escherichia coli, 1 was a bacteriophage (all excluded from the QPS evaluation) and 28 were TUs that already have a QPS status. The other 10 notifications belonged to 9 TUs which were evaluated for a possible QPS status: Ensifer adhaerens and Heyndrickxia faecalis did not get the QPS recommendation due to the limited body of knowledge about their occurrence in the food and/or feed chains and Burkholderia ubonensis also due to its ability to generate biologically active compounds with antimicrobial activity; Klebsiella pneumoniae, Serratia marcescens and Pseudomonas putida due to safety concerns. K. pneumoniae is excluded from future QPS evaluations. Chlamydomonas reinhardtii is recommended for QPS status with the qualification 'for production purposes only'; Clostridium tyrobutyricum is recommended for QPS status with the qualification 'absence of genetic determinants for toxigenic activity'; Candida oleophila has been added as a synonym of Yarrowia lipolytica. The Panel clarifies the extension of the QPS status for genetically modified strains.

Update of the list of qualified presumption of safety (QPS) recommended microbiological agents intentionally added to food or feed as notified to EFSA 20: Suitability of taxonomic units notified to EFSA until March 2024.

The qualified presumption of safety (QPS) process was developed to provide a safety assessment approach for microorganisms intended for use in food or feed chains. In the period covered by this statement, no new information was found that would change the status of previously recommended QPS TUs. The TUs in the QPS list were updated based on a verification, against their respective authoritative databases, of the correctness of the names and completeness of synonyms. A new procedure has been established to ensure the TUs are kept up to date in relation to recent taxonomical insights. Of 83 microorganisms notified to EFSA between October 2023 and March 2024 (47 as feed additives, 25 as food enzymes or additives, 11 as novel foods), 75 were not evaluated because: 15 were filamentous fungi, 1 was Enterococcus faecium, 10 were Escherichia coli, 1 was a Streptomyces (all excluded from the QPS evaluation) and 48 were TUs that already have a QPS status. Two of the other eight notifications were already evaluated for a possible QPS status in the previous Panel Statement: Heyndrickxia faecalis (previously Weizmannia faecalis) and Serratia marcescens. One was notified at genus level so could not be assessed for QPS status. The other five notifications belonging to five TUs were assessed for possible QPS status. Akkermansia muciniphila and Actinomadura roseirufa were still not recommended for QPS status due to safety concerns. Rhizobium radiobacter can be recommended for QPS status with the qualification for production purposes. Microbacterium arborescens and Burkholderia stagnalis cannot be included in the QPS list due to a lack of body of knowledge for its use in the food and feed chain and for B. stagnalis also due to safety concerns. A. roseirufa and B. stagnalis have been excluded from further QPS assessment.