Metabolic-Associated Fatty Liver Disease and Cognitive Performance in Type 2 Diabetes: Basal Data from the Phytate, Neurodegeneration and Diabetes (PHYND) Study.

The effect of liver fibrosis on mild cognitive impairment (MCI) and dementia risk in type 2 diabetes mellitus (T2DM) patients is unclear. Therefore, we performed a prospective cross-sectional study on 219 patients with T2DM and older than 60 years to evaluate the association between liver fibrosis, liver steatosis, and cognitive impairment. The Montreal Cognitive Assessment (MoCA) was used to screen for MCI or dementia. Liver fibrosis was estimated using the non-invasive Fibrosis-4 (FIB-4) score, and liver steatosis was assessed with the hepatic steatosis index. The mean age was 71 ± 6 years, 47% were women and according to MoCA cut-off values, 53.88% had MCI and 16.43% had dementia. A moderate or high risk of advanced fibrosis was significantly higher in patients with MCI or dementia compared to those with normal cognition (p < 0.001). After adjusting for confounders, a FIB-4 score greater than 1.54 was associated with MCI or dementia (p = 0.039). Multivariate analysis identified age over 70.5 years, antiplatelet medication use, and a FIB-4 score above 1.54 as the most relevant risk factors. Liver fibrosis, but not liver steatosis, is associated with MCI or dementia in older T2DM patients, suggesting that FIB-4 score might be a simple biomarker for the detection of cognitive impairment.

Systematic review of subjective validation methods for computerized colonoscopy simulators.

Introduction: In recent years, different approaches have been used to conduct a subjective assessment of colonoscopy simulators. The purpose of this paper is to review these different approaches, specifically the ones used for computerized simulators, as the first step for the design of a standard validation procedure for this type of simulators. Methods: A systematic review was conducted by searching papers after 2010 in PubMed, Google Scholar, ScienceDirect, and IEEE Xplore databases. Papers were screened and reviewed for procedures regarding the subjective validation of computerized simulators for traditional colonoscopy with an endoscope. Results: An initial search in the databases identified 2094 papers, of which 7 remained after exhaustive review and application of exclusion criteria. All studies used questionnaires for subjective validation, with "face" being the most common validity type tested, while "content" validity and "usability" were less prominent. Conclusions: A classification of subscales for testing face validity was derived from the studies. The Colonoscopy Simulator Realism Questionnaire (CSRQ) was selected as the guide to follow for the development of future questionnaires related to subjective validation. Mislabeling of the validity tested in the studies due to ambiguous interpretations of the validity types was a common occurrence observed in the reviewed studies.

Prodromal Alzheimer's Disease: Global Cognition, Cue Efficiency, and Cerebrospinal Fluid Neurofilament Light Values Predict Short-Term Conversion to Dementia.

Background: Predicting which patients with prodromal AD (pAD) will imminently convert to dementia may be paramount in a memory clinical setting, especially with potential disease-modifying therapies on the horizon. Objective: To explore a practical tool for this prediction, combining cognitive tests and cerebrospinal fluid (CSF) biomarkers. Methods: We designed a longitudinal prospective, observational, and multicenter study, enrolling patients with pAD. Inclusion criteria comprised memory complaints, Mini-Mental State Examination (MMSE) score of≥22, memory impairment as indicated by the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT + IR) and/or TMA-93, Clinical Dementia Rating-Global Score (CDR-GS) of 0.5, and positive CSF Aß42/Aß40 ratio (<0.095, Euroimmun). The primary outcome was the conversion to dementia (CDR-GS≥1) within the first year of follow-up, referred to as "short-term conversion". A multiple regression logistic model was adopted to design the "Predict Short-Term Conversion" (PSTC) score. Results: Between 2020 and 2022, 83 patients were recruited. The median age was 74, with 49.4% being women. Twenty-five (30.1%) patients were classified as short-term converters. The PSTC score incorporated baseline scores on MMSE ( ≤24 = 3, >24 = 0) and FCSRT + IR Total Recall ( ≤14 = 4, >14 = 0), and CSF neurofilament light chains (NfLs) concentrations (ß=0.001299). The PSTC score demonstrated an area under the curve of 0.78 (95% CI: 0.67-0.90, p < 0.001), with a cutoff value of 5.14 presenting 76% sensitivity and 80% specificity. Conclusions: The PSTC score, comprising two relatively brief cognitive test scores and NfLs CSF concentrations, could be useful for predicting short-term converters among patients diagnosed with pAD.

Effect of the addition of exogenous progesterone and the progesterone receptor inhibitor (RU 486) on boar cryopreservation semen extenders.

Cryopreservation of porcine spermatozoa is detrimental due to their high sensitivity to cold shock, leading to changes akin to capacitation, known as cryocapacitation. These changes, including the acrosomal reaction, hypermotility induction, and protein phosphorylation, might be influenced by the presence of progesterone in seminal plasma and egg yolk, used in most freezing extenders. We tested the effect of various progesterone concentrations added to the freezing extenders (1, 10, and 100 µg/mL). At 100 µg/mL, progesterone decreased the proportion of straightness and tended to reduce viability and the proportion of progressive motility (p < 0.1). At 10 µg/mL, it increased reacted acrosomes in dead sperm (p < 0.05), protein phosphorylation rate (p < 0.05), and tended (p < 0.1) to enhance linear movement compared to the control. To counteract the capacitating effect of progesterone, we examined the effect of antiprogesterone mifepristone (RU 486) at concentrations of 5, 10, 20, 50, 100, and 200 µM, and co-incubated 10 µM of RU 486 with 10 µg/mL of progesterone. RU 486 maintained capacitation levels and motility parameters similar to the control, although high concentrations (100 µM) tended (p = 0.152) to increase protein phosphorylation. Co-incubation reduced the acrosome reaction in dead sperm, and RU 486 appeared to prevent hypermotility stabilizing motility and viability parameters compared to samples with progesterone alone. Protein phosphorylation increased and RU 486 could not restore capacitation to control levels due to its competitive antagonism for progesterone receptors, having less affinity than progesterone, which displaces RU 486 at high concentrations, allowing normal sperm capacitation.

Evaluation of the effects of a gamified, fully immersive and stroke-specific virtual reality intervention for improving disability and quality of life in patients with stroke in the subacute phase: study protocol of the RESET randomised trial.

Stroke is the leading cause of disability and the second cause of death worldwide. The increasing burden of stroke underscores the importance of optimising rehabilitation protocols. Virtual reality (VR) can improve poststroke prognosis. A VR software combining gamification, full immersion and stroke specificity (ie, the Development and validation of a novel viRtual rEality software for improving diSability and quality of lifE in patients with sTroke (RESET) software) might substantially improve disability and quality of life (QoL). However, this technology is still very scarce. The RESET trial aims to assess the effects of an early 10-week gamified, fully immersive and stroke-specific VR intervention (ie, starting at week 3 poststroke) on disability and QoL in people with stroke in the subacute phase. People with ischaemic or haemorrhagic stroke (n=94) aged ≥ 18 years will be randomised to receive (1) usual care (UC), (2) commercial VR or (3) gamified, fully immersive and stroke-specific VR (RESET). The three groups will receive UC (ie, three sessions/week of 90 min of standard rehabilitation). The VR groups will additionally receive three VR sessions of 20 min per week. The outcome measures will be assessed at baseline (week 2 from stroke occurrence), week 13 (approximately 90 days from the event) and week 26 (approximately 6 months from the event). The primary outcome is disability measured with the Barthel Index. Secondary outcomes include QoL, upper-extremity and lower-extremity motor function, gross manual dexterity, handgrip strength and cognitive function. This study will unravel the effects of a gamified, fully immersive and stroke-specific VR software on disability and QoL in patients with stroke in the early subacute phase.Trial registration number: NCT06132399.

Impact of Driver Mutations on Metastasis-Free Survival in Uveal Melanoma: A Meta-Analysis.

The prognosis of uveal melanoma is significantly influenced by the risk of metastasis, which varies according to clinical and genetic features. Driver mutations can predict the likelihood of disease progression and survival, although the data in the literature are inconsistent. This meta-analysis aimed to evaluate the prognostic significance of driver mutations, including GNAQ, GNA11, BAP1, and SF3B1, in the advancement of uveal melanoma. A comprehensive search of databases yielded relevant studies, and data from 13 studies (848 eyes) were synthesized to assess the impact of these mutations on metastasis-free survival. The BAP1 mutation and negative immunohistochemistry were associated with a higher risk of metastasis (logHR = 1.44, 95% CI 1.05-1.83). GNAQ, GNA11, and SF3B1 mutations did not show a significant increase in risk. In summary, BAP1 has proven to reliably predict the likelihood of disease progression in uveal melanoma, while further studies are needed to establish the significance of other driver mutations.

Distribution and habitat database of fluvial Plecoptera, Trichoptera and Coleoptera from Sierra Nevada, Spain.

Sierra Nevada (southern Iberian Peninsula) harbours a great biodiversity and the studies on some aquatic insect groups have been and continue to be numerous there. This database brings together information on Plecoptera, Trichoptera and Coleoptera inhabiting running waters of this mountain system above 800 m of altitude. It includes data on the number, life stage and sex of individuals as well as the available information on abiotic characteristics of their habitats. The dataset is composed of 1,718 sampling events carried out between 1901 and 2022 in approximately 60 different water bodies, 15,347 occurrences pertaining to more than 203,000 individuals, and 10,173 records of associated measurements (23 physico-chemical parameters). The dataset is the result of a comprehensive review of scientific literature and of integrating data from recent research projects and the Sierra Nevada Global-Change Observatory's long-term monitoring data. This information is valuable for those studying past distributions and abundances of the species in the dataset, for building predictive models or just studying temporal trends in the current context of climate change.

Selective Synthesis of Boron-Functionalized Indenes and Benzofulvenes by BCl3-Promoted Cyclizations of ortho-Alkynylstyrenes.

A selective, metal-free synthesis of boron-functionalized indenes and benzofulvenes via BCl3-mediated cyclization of o-alkynylstyrenes is described. The method allows precise control over product formation by adjusting reaction conditions. These borylated products were utilized in diverse C-B bond derivatizations and in the total synthesis of Sulindac, a nonsteroidal anti-inflammatory drug, demonstrating the versatility and practicality of the developed methodology for synthetic applications.

Ensemble machine learning using hydrometeorological information to improve modeling of quality parameter of raw water supplying treatment plants.

Source and raw water quality may deteriorate due to rainfall and river flow events that occur in watersheds. The effects on raw water quality are normally detected in drinking water treatment plants (DWTPs) with a time-lag after these events in the watersheds. Early warning systems (EWSs) in DWTPs require models with high accuracy in order to anticipate changes in raw water quality parameters. Ensemble machine learning (EML) techniques have recently been used for water quality modeling to improve accuracy and decrease variance in the outcomes. We used three decision-tree-based EML models (random forest [RF], gradient boosting [GB], and eXtreme Gradient Boosting [XGB]) to predict two critical parameters for DWTPs, raw water Turbidity and UV absorbance (UV254), using rainfall and river flow time series as predictors. When modeling raw water turbidity, the three EML models (rRF-Tu2=0.87, rGB-Tu2=0.80 and rXGB-Tu2=0.81) showed very good performance metrics. For raw water UV254, the three models (rRF-UV2=0.89, rGB-UV2=0.85 and rXGB-UV2=0.88) again showed very good performance metrics. Results from this study suggest that EML approaches could be used in EWSs to anticipate changes in the quality parameters of raw water and enhance decision-making in DWTPs.

Preserved VPS13A distribution and expression in Huntington's disease: divergent mechanisms of action for similar movement disorders?

VPS13A disease and Huntington's disease (HD) are two basal ganglia disorders that may be difficult to distinguish clinically because they have similar symptoms, neuropathological features, and cellular dysfunctions with selective degeneration of the medium spiny neurons of the striatum. However, their etiology is different. VPS13A disease is caused by a mutation in the VPS13A gene leading to a lack of protein in the cells, while HD is due to an expansion of CAG repeat in the huntingtin (Htt) gene, leading to aberrant accumulation of mutant Htt. Considering the similarities of both diseases regarding the selective degeneration of striatal medium spiny neurons, the involvement of VPS13A in the molecular mechanisms of HD pathophysiology cannot be discarded. We analyzed the VPS13A distribution in the striatum, cortex, hippocampus, and cerebellum of a transgenic mouse model of HD. We also quantified the VPS13A levels in the human cortex and putamen nucleus; and compared data on mutant Htt-induced changes in VPS13A expression from differential expression datasets. We found that VPS13A brain distribution or expression was unaltered in most situations with a decrease in the putamen of HD patients and small mRNA changes in the striatum and cerebellum of HD mice. We concluded that the selective susceptibility of the striatum in VPS13A disease and HD may be a consequence of disturbances in different cellular processes with convergent molecular mechanisms already to be elucidated.

Tirofiban versus aspirin to prevent in-stent thrombosis after emergent carotid artery stenting in acute ischemic stroke.

BACKGROUND: Several antithrombotic treatments during emergent carotid artery stenting (eCAS) have been proposed, but an appropriate protocol to balance risk-benefit is not well known. OBJECTIVE: To investigate the efficacy and safety of tirofiban compared with aspirin in patients with acute ischemic stroke undergoing eCAS. METHODS: We conducted a retrospective single-center study of the prospective ARTISTA Registry, including patients with atherosclerotic internal carotid artery occlusion treated with eCAS. Two groups, according to antiplatelet drug, were studied: aspirin (250-500 mg single-dose) versus tirofiban (500 µg bolus+200 µg/h). Primary outcomes were the rate of in-stent thrombosis and symptomatic intracranial hemorrhage (sICH) within the first 24 hours. RESULTS: During the period 2019-2023, 181 patients were included, 103 received aspirin, 78 tirofiban; 149 (82.3%) had tandem lesions. The primary efficacy outcome occurred in 9 (9.4%) in the aspirin group, as compared with 1 (1.3%) in the tirofiban group (adjusted odds ratio (aOR)=0.11, 95% CI 0.01 to 0.98; P=0.048). The primary safety outcome was detected in 12 (11.7%) in the aspirin group, as compared with 2 (2.6%) in the tirofiban group (aOR=0.16, 95% CI 0.03 to 0.87; P=0.034). The tirofiban group presented a lower risk of parenchymal hemorrhage (18 (17.4%) vs 4 (5.2%), aOR=0.27, 95% CI 0.09 to 0.88; P=0.029) and an increased rate of excellent recanalization (expanded Treatment in Cerebral Infarction (eTICI) 2c-3) (50 (48.5%) vs 54 (69.2%); aOR=2.15, 95% CI 1.12 to 4.13; P=0.02). There were no differences in functional outcomes or mortality at 3 months. CONCLUSIONS: Periprocedural antithrombotic therapy with tirofiban was associated with a lower risk of in-stent thrombosis and sICH at 24 hours from eCAS compared with aspirin. Prospective randomized clinical trials are needed to confirm our results.

Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.

A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.

Domestic access to water in a decentralized truck-to-cistern system: a case study in the Northern Village of Kangiqsualujjuaq, Nunavik (Canada).

Municipal water supply through truck-to-cistern systems is common in northern Canada. Household satisfaction and concerns about water services likely impact user preferences and practices. This case study explores household perspectives and challenges with regard to domestic access to water in a decentralized truck-to-cistern system. A case study was conducted in the Northern Village of Kangiqsualujjuaq, Nunavik (Quebec, Canada). A paper-based questionnaire was completed by 65 households (one quarter of the population). Many households (37%) reported not drinking tap water from the truck-to-cistern system. Chlorine taste was a frequently reported concern, with those households being significantly less likely to drink water directly from the tap (p = 0.002). Similarly, households that reported a water shortage in the previous week (i.e., no water from the tap at least once) (33%) were more likely to express dissatisfaction with delivered water quantity (rs = 0.395, p = 0.004). Interestingly, 77% of households preferred using alternative drinking water sources for drinking purposes, such as public tap at the water treatment plant, natural sources or bottled water. The study underscores the importance of considering household perspectives to mitigate the risks associated with service disruptions and the use of alternative sources for drinking purposes.

Oral Exposure to Titanium Dioxide E171 and Zinc Oxide Nanoparticles Induces Multi-Organ Damage in Rats: Role of Ceramide.

Food-grade titanium dioxide (E171) and zinc oxide nanoparticles (ZnO NPs) are common food additives for human consumption. We examined multi-organ toxicity of both compounds on Wistar rats orally exposed for 90 days. Rats were divided into three groups: (1) control (saline solution), (2) E171-exposed, and (3) ZnO NPs-exposed. Histological examination was performed with hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM). Ceramide (Cer), 3-nitrotyrosine (NT), and lysosome-associated membrane protein 2 (LAMP-2) were detected by immunofluorescence. Relevant histological changes were observed: disorganization, inflammatory cell infiltration, and mitochondrial damage. Increased levels of Cer, NT, and LAMP-2 were observed in the liver, kidney, and brain of E171- and ZnO NPs-exposed rats, and in rat hearts exposed to ZnO NPs. E171 up-regulated Cer and NT levels in the aorta and heart, while ZnO NPs up-regulated them in the aorta. Both NPs increased LAMP-2 expression in the intestine. In conclusion, chronic oral exposure to metallic NPs causes multi-organ injury, reflecting how these food additives pose a threat to human health. Our results suggest how complex interplay between ROS, Cer, LAMP-2, and NT may modulate organ function during NP damage.

Oral phytate supplementation on the progression of mild cognitive impairment, brain iron deposition and diabetic retinopathy in patients with type 2 diabetes: a concept paper for a randomized double blind placebo controlled trial (the PHYND trial).

Type 2 diabetes mellitus has a worldwide prevalence of 10.5% in the adult population (20-79 years), and by 2045, the prevalence is expected to keep rising to one in eight adults living with diabetes. Mild cognitive impairment has a global prevalence of 19.7% in adults aged 50 years. Both conditions have shown a concerning increase in prevalence rates over the past 10 years, highlighting a growing public health challenge. Future forecasts indicate that the prevalence of dementia (no estimations done for individuals with mild cognitive impairment) is expected to nearly triple by 2050. Type 2 diabetes mellitus is a risk factor for the development of cognitive impairment, and such impairment increase the likelihood of poor glycemic/metabolic control. High phytate intake has been shown to be a protective factor against the development of cognitive impairment in observational studies. Diary phytate intake might reduce the micro- and macrovascular complications of patients with type 2 diabetes mellitus through different mechanisms. We describe the protocol of the first trial (the PHYND trial) that evaluate the effect of daily phytate supplementation over 56 weeks with a two-arm double-blind placebo-controlled study on the progression of mild cognitive impairment, cerebral iron deposition, and retinal involvement in patients with type 2 diabetes mellitus. Our hypothesis proposes that phytate, by inhibiting advanced glycation end product formation and chelating transition metals, will improve cognitive function and attenuate the progression from Mild Cognitive Impairment to dementia in individuals with type 2 diabetes mellitus and mild cognitive impairment. Additionally, we predict that phytate will reduce iron accumulation in the central nervous system, mitigate neurodegenerative changes in both the central nervous system and retina, and induce alterations in biochemical markers associated with neurodegeneration.

Squeezed from the top: "Social Outburst" (2019) and elite overproduction. A study of the dynamics of Chilean political instability from the approach of Structural Demographic Theory.

On October 18, 2019, Chile experienced the most important social upheaval since the country regained democracy in the late 1980s. The "Social Outbreak" surprised economic and political elites and seemed paradoxical to the international community who had often praised Chile as a model of successful development. In this paper, we used structural-demographic theory to analyze the interaction between the overproduction of elites and the stagnation in the relative income of the population as the underlying structural cause of Chilean political instability. This theory was able to predict the three most significant instances of political tension in the recent history of Chile: the crisis of the late 1960s that culminated in the coup d'état of 1973, popular mobilizations during the 1980s, and the recent student mobilizations and social upheaval. Our results suggest that, at least during the period 1938-2019, Chilean sociopolitical dynamics is determined by the same structural drivers.

Multiple neoplasms in patients with uveal melanoma: a systematic review.

PURPOSE: Uveal melanoma is the most prevalent intraocular malignancy in adults, derived from uveal tract melanocytes. This study focuses on the frequency and risk of second primary malignancies in UM patients. METHODS: A PubMed search (1980-2023) identified studies on SPM incidence in UM patients. From 191 references, 14 studies were chosen, focusing on UM, SPMs, and analysing data on demographics and types of neoplasms. RESULTS: Among 31,235 UM patients in 14 studies, 4695 had 4730 SPMs (15.03% prevalence). Prostate (15%), breast (12%), and colorectal (9%) cancers were most common. Digestive system malignancies were highest (19%), with colorectal cancer leading (51%). Breast and prostate cancers were prevalent in respective systems. Lung, bladder, and non-Hodgkin's lymphoma were also notable. The study observed an increasing trend in the frequency of SPMs over time, reflecting broader trends in cancer survivorship and the growing prevalence of multiple malignancies. CONCLUSION: The study highlights a significant presence of SPMs in UM patients, with an increasing trend in frequency over time, emphasizing prostate and breast cancers. This underscores the need for focused surveillance and tailored follow-up for UM survivors, considering their higher risk of additional malignancies. Future research should further investigate SPM aetiology in UM patients.