Evidence of epigenetic landscape shifts in mucopolysaccharidosis IIIB and IVA.

Lysosomal storage diseases (LSDs) are a group of monogenic diseases characterized by mutations in genes coding for proteins associated with the lysosomal function. Despite the monogenic nature, LSDs patients exhibit variable and heterogeneous clinical manifestations, prompting investigations into epigenetic factors underlying this phenotypic diversity. In this study, we focused on the potential role of epigenetic mechanisms in the pathogenesis of mucopolysaccharidosis IIIB (MPS IIIB) and mucopolysaccharidosis IVA (MPS IVA). We analyzed DNA methylation (5mC) and histone modifications (H3K14 acetylation and H3K9 trimethylation) in MPS IIIB and MPS IVA patients' fibroblasts and healthy controls. The findings revealed that global DNA hypomethylation is present in cell lines for both diseases. At the same time, histone acetylation was increased in MPS IIIB and MPS IVA cells in a donor-dependent way, further indicating a shift towards relaxed open chromatin in these MPS. Finally, the constitutive heterochromatin marker, histone H3K9 trimethylation, only showed reduced clustering in MPS IIIB cells, suggesting limited alterations in heterochromatin organization. These findings collectively emphasize the significance of epigenetic mechanisms in modulating the phenotypic variations observed in LSDs. While global DNA hypomethylation could contribute to the MPS pathogenesis, the study also highlights individual-specific epigenetic responses that might contribute to phenotypic heterogeneity. Further research into the specific genes and pathways affected by these epigenetic changes could provide insights into potential therapeutic interventions for these MPS and other LSDs.

Frequency of Depressive Disorders in Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Depressive disorders are recognized as a common neuropsychiatric disorder of Parkinson's disease (PD). Reported frequencies vary widely among studies and depend on the diagnostic criteria, the methods of ascertainment used, and the population sampled. OBJECTIVE: We aimed to evaluate the frequency of depressive disorders in PD and to investigate the relationship with PD clinical variables. METHODS: A systematic review and meta-analysis of observational studies (community-based, prospective and retrospective cohort, case-control, and cross-sectional studies) reporting the frequency of depressive disorders in PD patients. RESULTS: Electronic database search wielded 3,536 articles; an additional 91 were identified through citation chaining. 163 full-text articles were assessed for eligibility. Of these, 49 met the inclusion criteria for our analysis. The pooled frequency of depressive disorders was 30.7% (95% confidence interval [CI] 25.6 to 36.2; I2 = 95%; 49 studies; combined n = 10,039). The pooled frequency of major depressive disorder was 14.0% (95% CI 10.5 to 18.5; I2 = 88%; 23 studies; combined n = 5,218). Subgroup/meta-regression analyses were conducted to investigate the relationship between frequency and study inclusion criteria, methodology used for diagnosis, and study design. We found a statistically significant correlation between study design and depressive disorders frequency (ranging from 8% in the community-based study to 44% in the retrospective studies) and a statistically significant positive correlation between mean baseline PD duration and major depressive disorder frequency. CONCLUSION: The current meta-analysis found a global frequency of depressive disorders of 30.7% and major depressive disorder of 14.0%. Study design influenced the frequency of depressive disorders in PD. Mean baseline PD duration and major depressive disorder frequency were positively correlated.

Systematic reviews and meta-analysis published in indexed Portuguese medical journals: time trends and critical appraisal.

INTRODUCTION: Over the last years, the number of systematic reviews published is steadily increasing due to the global interest in this type of evidence synthesis. However, little is known about the characteristics of this research published in Portuguese medical journals. This study aims to evaluate the publication trends and overall quality of these systematic reviews. MATERIAL AND METHODS: This was a methodological study. We aimed the most visible Portuguese medical journals indexed in MEDLINE. Systematic reviews were identified through an electronic search (through PUBMED). We included systematic reviews published up to August 2020. Systematic reviews selection and data extraction were done independently by three authors. The overall quality critical appraisal using the A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) was independently assessed by three authors. Disagreements were solved by consensus. RESULTS: Sixty-six systematic reviews published in 5 Portuguese medical journals were included. Most (n = 53; 80.3%) were systematic reviews without meta-analysis. Up to 2010 there was a steady increase in the number of systematic reviews published, followed by a period of great variability of publication, ranging from 1 to 10 in a given year. According to the systematic reviews' typology, most have been predominantly conducted to assess the effectiveness/efficacy of health interventions (n = 27; 40.9%). General and Internal Medicine (n = 20; 30.3%) was the most addressed field. Most systematic reviews (n = 46; 69.7%) were rated as being of "critically low-quality". CONCLUSIONS: There were consistent flaws in the methodological quality report of the systematic reviews included, particularly in establishing a prior protocol and not assessing the potential impact of the risk of bias on the results. Through the years, the number of systematic reviews published increased, yet their quality is suboptimal. There is a need to improve the reporting of systematic reviews in Portuguese medical journals, which can be achieved by better adherence to quality checklists/tools.

Frequency and Characteristics of Psychosis in Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Psychotic symptoms are highly frequent in Parkinson's disease (PD) patients and are associated with poor prognosis. They include hallucinations, delusions, and minor psychotic phenomena, including sense of presence, passage hallucinations, and illusions. OBJECTIVE: To evaluate the frequency of psychosis in PD patients. METHODS: A systematic review and meta-analysis of clinical trials, prospective and retrospective cohort studies, case-control studies, and cross-sectional studies reporting the frequency of psychosis, hallucinations, and delusions in PD. RESULTS: Electronic database search wielded 3536 articles, an additional 91 were identified through citation chaining. Of these, 163 were fully inspected, 57 removed, and 106 included as relevant for neuropsychiatric events frequency, with 32 meeting our inclusion criteria (psychosis and/or specific psychotic phenomena). The pooled frequency of psychosis was 20.7% (95% CI 14.5 to 28.6; I2 = 94%, 15 studies; combined n = 2919). None of the pre-defined meta-regressions or subgroup analyses were statistically significant or helped explain the statistical heterogeneity. The pooled frequency of any form of hallucination was 21.6% (95% CI 14.7 to 30.6; I2 = 95%; 18 studies; combined n = 3161). Duration of PD at baseline and mean baseline Hoehn & Yahr stage helped explain the statistical heterogeneity in the meta-analysis of hallucinations. CONCLUSION: Based on the available evidence, around a fifth of PD patients experience psychosis or hallucinations. The risk of developing hallucinations is likely moderated by the disease duration, Hoehn & Yahr stage, and the cognitive status.

Activity of the Giardia intestinalis proteasome during encystation and its connection with the expression of the cyst wall protein 1 (CWP1).

Giardia is a parasite whose life cycle is composed of two stages: replicative trophozoites, responsible for the symptoms of the disease, and infective cysts, resistant to adverse environments outside of hosts. Proteasomes are multicatalytic peptidase complexes responsible for the specific degradation of proteins in eukaryotic cells. This study assessed the proteasome activity in the trophozoite and during encystation. Strong activation of the proteasome was observed during the differentiation of trophozoites into cysts, reaching its maximum level 24 h after the stimulus. We also found that the Giardia proteasome presents unusual characteristics related to higher eukaryotic proteasomes, making it an eventual therapeutic target. Here we tested the effects on the synthesis of a cyst wall protein by chemical inactivation of the proteasome and by overexpression or partial inhibition of the deubiquitinating protein RPN11 in transfected cells. Moreover, an analysis of the intracellular localization of RPN11 (an integral part of the proteasome regulatory particle) revealed major changes associated with the differentiation of trophozoites into cysts. This evidence further supports the important role of the proteasome in Giardia encystation.

Risk of SARS-CoV-2 Infection and COVID-19 Severity Associated With Exposure to Nonsteroidal Anti-Inflammatory Drugs: Systematic Review and Meta-Analysis.

Nonsteroidal anti-inflammatory drugs (NSAIDs) were thought to increase the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus entrance into cells. Hence, it was suggested in the media that NSAIDs could lead to a higher risk of infection and/or disease severity. To determine the existence or absence of this association, we aimed to systematically evaluate the risk of SARS-CoV-2 infection and mortality and the risk of severe coronavirus disease 2019 (COVID-19) associated with previous exposure to NSAIDs. MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE were searched in February 2021 for controlled studies. The results were calculated through random-effect meta-analyses and reported in terms of odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity was assessed with I2 test. Eleven studies were included, comprising a total of 683 715 patients. NSAID exposure did not increase the risk of having a positive test for SARS-CoV-2 infection (OR, 0.97; 95%CI, 0.85-1.11, I2 = 24%; 5 studies). The exposure to NSAIDs did not increase the risk of severe/critical COVID-19 disease (OR, 0.92; 95%CI, 0.80-1.05; I2 = 0%; 5 studies) nor all-cause mortality among patients with COVID-19 (OR, 0.86; 95%CI, 0.75-0.99; I2 = 14%, 4 studies). Our data did not suggest that exposure to NSAIDs increases the risk of having SARS-CoV-2 infection or increases the severity of COVID-19 disease. Also, the fragility of the studies included precludes definite conclusions and highlights the need for further robust data.

TERTp mutations and p53 expression in head and neck cutaneous basal cell carcinomas with different aggressive features.

Cutaneous basal cell carcinoma (cBCC) is an economic burden to health services, due to its great morbidity and increasing incidence in old people. Infiltrative cBCCs and cBCCs with micronodular pattern are considered as more aggressive. The role of p53 expression and TERTp mutation on cBCC behavior remains to be clarified. We aimed to assess TERTp mutations and p53 expression in relation to the cBCC histological subtype in a cohort of patients referred to an ENT Department of a tertiary Hospital of Northern Portugal. We performed a retrospective clinicopathological and histological review of the head and neck cBCCs followed-up at the otorhinolaryngology department of Trás-os-Montes e Alto Douro hospital (January 2007-June 2018). We assessed TERTp mutations in 142 cBCCs and p53 protein expression, through immunohistochemistry, in 157 cBCCs. We detected TERTp mutations in 43.7% of cBCCs and p53 overexpression in 60.5% of cBCCs. We spotted association of p53 overexpression and TERTp mutation with necrosis. In the infitrative-growth pattern cBCCs, there was no significant association with the clinical and histological features evaluated, except for necrosis. In the indolent-growth cBCCs, we identified a significant association of TERTp mutation status with female sex, necrosis, multiple cBCCs, and p53 positive expression. Our results suggest that TERTp mutation may be useful to identify more aggressive features in the indolent-growth pattern cBCCs (nodular and superficial subtypes). Further studies with larger cohorts are warranted to clarify the relevance of TERTp mutation in cBCCs.

Antithrombotic Therapy Recommendations in the European Society of Cardiology Guidelines: How Robust Are the Randomized Controlled Trials Underpinning Them?

Introduction Criticisms have been raised against the sole use of p -value in interpreting results from randomized controlled trials (RCTs). Additional tools have been suggested, like the fragility index (FI), a measure of a trial's robustness/fragility, and derivative measures. The FI is the minimum number of patients who would have to be converted from nonevents to events, in the group with the least events, for a result to lose statistical significance. Objective This study aimed to evaluate RCT supporting European Society of Cardiology (ESC) guidelines regarding antithrombotics, using the FI and FI-related measures. Methods FI, fragility quotient (FQ), and FI minus LTF lost to follow-up (FI - LTF) were calculated for the RCT underpinning recommendations regarding antithrombotic therapy from the updated ESC guidelines. LTF was compared with FI. Results were calculated for the total group of studies, as per guideline and as per recommendation type. Results Overall, 61 studies were included. The median FI was 24.5 (interquartile range [IQR]: 9.0-60.0) and median FQ was 0.0035 (IQR: 0.0019-0.0056). Median FI - LTF was 2.0 (IQR: 0.0-38.0). Twenty (32.8%) of the studies had one primary or main safety outcome with LTF exceeding FI. Peripheral arterial disease guideline and chronic coronary syndrome guideline had the lowest (2.5; IQR: 1.8-3.3) and the highest (48.5; IQR: 23.8-73.0) FI, respectively. Conclusion The median FI suggests robustness of clinical trials evaluating antithrombotic drugs cited in the guidelines, but about one-third of them had LTF larger than FI. This emphasizes the need for assessing trials' robustness when constructing guidelines.

Analysis of clinical and methodological characteristics of early COVID-19 treatment clinical trials: so much work, so many lost opportunities.

BACKGROUND: The COVID-19 pandemic continues to rage on, and clinical research has been promoted worldwide. We aimed to assess the clinical and methodological characteristics of treatment clinical trials that have been set forth as an early response to the COVID-19 pandemic. METHODS: First, we reviewed all registered clinical trials on COVID-19. The World Health Organization International Trials Registry Platform and national trial registries were searched for COVID-19 trials through April 19th, 2020. For each record, independent researchers extracted interventions, participants, and methodological characteristics. Second, on September 14th, 2020 we evaluated the recruitment status and availability of the results of COVID-19 treatment trials previously identified. RESULTS: In April 2020, a total of 580 trials evaluating COVID-19 treatment were registered. Reporting quality was poor (core participant information was missing in 24.1 to 92.7%). Between 54.0 and 93.8% of the trials did not plan to include older people or those with a higher baseline risk. Most studies were randomised (67.9%), single-centre (58.3%), non-industry-funded (81.1%), to be conducted in China (47.6%), with a median duration of 184 days and a median sample size of 100 participants. Core endpoints (mortality, clinical status, and hospitalization length) were planned to be assessed in 5.2 to 13.1% of the trials. Five months later, 66 trials (11.4%) were reported as "Completed", and only 46 (7.9%) had public results available. One hundred forty-four of 580 trials (24.8%) either had the status "Not yet recruiting" or "Suspended", and 18 (3.1%) trials were prematurely stopped ("Terminated" or "Withdrawn") The number of completed trials and trials with results are much lower than anticipated, considering the planned follow-up. CONCLUSIONS: Our results raise concerns about the success of the initial global research effort on COVID-19 treatment. The clinical and methodological characteristics of early COVID-19 treatment trials limit their capability to produce clear answers to critical questions in the shortest possible time.

The impact of SSRIs on mortality and cardiovascular events in patients with coronary artery disease and depression: systematic review and meta-analysis.

BACKGROUND: Depression is common in patients after acute coronary syndromes (ACS) and with stable coronary artery disease (CAD) and has been associated with increased mortality and morbidity. However, it is unclear whether selective serotonin receptor inhibitors (SSRIs) reduce mortality or cardiac events in patients with CAD and depression. OBJECTIVE: We conducted a systematic review and meta-analysis to assess the effects of SSRIs on cardiovascular events in depressed CAD patients. METHODS: The CENTRAL, MEDLINE, and PsycINFO databases were searched (April 2020) for randomized controlled trials (RCTs) and extended follow-up analyses of RCTs that compared SSRIs with placebo or no intervention in patients with CAD and depression. The primary outcomes were all-cause mortality, cardiovascular mortality, and myocardial infarction incidence. The results were calculated through random-effect meta-analyses and reported in terms of risk ratio (RR) with 95% confidence intervals (CI). RESULTS: We retrieved 8 RCTs (2 of which with extended follow-up analyses), comprising a total of 1148 patients. 7 studies only included post-ACS patients. SSRIs were associated with a significantly lower risk of myocardial infarction in patients with CAD and depression (RR 0.54, 95% CI 0.34-0.86), and in post-ACS patients with depression (RR 0.56, 95% CI 0.35-0.90). We found no statistically significant difference in all-cause mortality, cardiovascular mortality, hospitalizations, angina, congestive heart failure, or stroke incidence. CONCLUSION: The use of SSRIs in post-ACS patients with depression was associated with a 44% relative risk reduction of myocardial infarction. No difference in mortality was found. Given that the quality of the evidence was low, further research is warranted.

Effect of oxygen supply on mortality in acute ST-elevation myocardial infarction: systematic review and meta-analysis.

Previous studies stated that high oxygen supply in patients with myocardial infarction (MI) was not associated with improved outcomes. However, the particularities of ST-elevation myocardial infarction (STEMI) and the results of a recent trial raised the question if this subgroup of patients benefits from high oxygen supply. This study aims to evaluate the clinical effect of high oxygen supply in patients with STEMI using a systematic review of the available literature. All randomized controlled trials (RCTs) evaluating the systematic use of high oxygen (6 L/min or higher) versus room air or lower oxygen supply in STEMI patients were included. Systematic review with meta-analysis of trials retrieved in July 2020. Six databases were searched. The confidence in the pooled estimates was ascertained through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Risk of bias was evaluated using the Cochrane risk of bias tool. There were five eligible RCTs (7703 patients). High oxygen supply was associated with a significant risk reduction of short-term mortality [risk ratio (RR) 0.83; 95% confidence interval (CI), 0.70-0.98; I2 = 0%]. Mortality (longest follow-up) (RR 0.83; 95% CI, 0.71-0.97; I2 = 0%) and heart failure (RR 0.84; 95% CI, 0.60-1.18; I2 = 0%) did not present a risk reduction. Recurrent MI presented a contradictory result, favouring the lower oxygen protocol (RR 1.47; 95% CI, 0.84-2.56; I2 = 0%). The GRADE analysis was very low. High oxygen supply may be associated with a decrease in short-term mortality in STEMI patients, but the pooled data are not robust enough to allow definitive conclusions.

Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers and the risk of COVID-19 infection or severe disease: Systematic review and meta-analysis.

OBJECTIVE: Animal studies suggested that angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB) facilitate the inoculation of potentially leading to a higher risk of infection and/or disease severity. We aimed to systematically evaluate the risk of COVID-19 infection and the risk of severe COVID-19 disease associated with previous exposure to (ACEi) and/or ARB). METHODS: MEDLINE, CENTRAL, PsycINFO, Web of Science Core Collection were searched in June 2020 for controlled studies. Eligible studies were included and random-effects meta-analyses were performed. The estimates were expressed as odds ratios (OR) and 95% confidence intervals (95%CI). Heterogeneity was assessed with I2 test. The confidence in the pooled evidence was appraised using the GRADE framework. RESULTS: Twenty-seven studies were included in the review. ACEi/ARB exposure did not increase the risk of having a positive test for COVID-19 infection (OR 0.99, 95%CI 0.89-1.11; I2 = 36%; 5 studies, GRADE confidence moderate). The exposure to ACEi/ARB did not increase the risk of all-cause mortality among patients with COVID-19 (OR 0.91, 95%CI 0.74-1.11; I2 = 20%; 17 studies; GRADE confidence low) nor severe/critical COVID-19 disease (OR 0.90, 95%CI 0.74-1.11; I2 = 55%; 17 studies; GRADE confidence very low). Exploratory analyses in studies enrolling hypertensive patients showed a association of ACEi/ARB with a significant decrease of mortality risk. CONCLUSIONS: ACEi/ARB exposure does not seem to increase the risk of having the SARS-CoV-2 infection or developing severe stages of the disease including mortality. The potential benefits observed in mortality of hypertensive patients reassure safety, but robust studies are required to increase the confidence in the results.

High-affinity free ubiquitin sensors for quantifying ubiquitin homeostasis and deubiquitination.

Ubiquitin (Ub) conjugation is an essential post-translational modification that affects nearly all proteins in eukaryotes. The functions and mechanisms of ubiquitination are areas of extensive study, and yet the dynamics and regulation of even free (that is, unconjugated) Ub are poorly understood. A major impediment has been the lack of simple and robust techniques to quantify Ub levels in cells and to monitor Ub release from conjugates. Here, we describe avidity-based fluorescent sensors that address this need. The sensors bind specifically to free Ub, have dissociation constant Kd values down to 60 pM and, together with a newly developed workflow, allow us to distinguish and quantify the pools of free, protein-conjugated and thioesterified forms of Ub from cell lysates. Alternatively, free Ub in fixed cells can be visualized microscopically by staining with a sensor. Real-time assays using the sensors afford unprecedented flexibility and precision to measure deubiquitination of virtually any (poly)Ub conjugate.

Percepción visual del rango de color: diferencias entre género y edad / Perception of the visible spectrum: differences among gender and age

La percepción del color constituye una de las ventajas de adaptación proporcionadas por el desarrollo evolutivo. Es uno de los mecanismos más importantes de señalización biológica y una auténtica fuente por medio de la cual los organismos obtienen información acerca del entorno. Existen factores como la edad y el sexo, ajenos al propio mecanismo fisiológico, que podrían afectar esta percepción, debido a la presencia de receptores de estrógeno en la retina. En este documento se presentan los resultados de un estudio de observación, diseñado para determinar la influencia del sexo, la edad y la presencia de defectos visuales en la percepción del color en los individuos. El montaje se basó en generar un efecto cromático en la mitad de una tarjeta trapezoidal blanca que recibe el reflejo de la otra cara, de color magenta, iluminada únicamente con luz blanca. Se tomaron datos de 561 personas (289 mujeres y 272 hombres), con edades entre 4 y 71 años. Tanto los hombres como las mujeres entre los 9 y 35 años percibieron tonalidades más claras que individuos de mayores edades (porcentaje magenta 50 por ciento), probablemente porque el proceso de oscurecimiento de la córnea y del cristalino en las personas mayores de 35 años ocasiona una tendencia a distinguir tonos más oscuros. Las mujeres distinguieron tonos más oscuros (46-50 por ciento magenta) que los hombres (38-44 por ciento), siendo significativas las diferencias en los intervalos de edad entre 9 y 13 años (p=0,04) y entre 14 y 18 años (p=0,03), que coinciden con el inicio de los cambios hormonales, en el primer caso para mujeres y en el segundo para hombres