Long-term cardiovascular outcomes in a population-based multicentric cohort of northern Portugal: Validation of the ESC/EAS prognostic risk classification.

BACKGROUND: Cardiovascular (CV) risk scores identify individuals at higher long-term risk of CV events that may benefit from more aggressive preventive interventions. OBJECTIVE: To assess the association of CV-risk categories and criteria with long-term CV events. METHODS: Observational cohort study between 2000-2019 on patients aged 40-80 years, followed by 14 primary care centers assisted by 1 hospital in Portugal. Follow-up began when electronic health records data allowed for CV-risk classification and dynamic reassessment per 2019 ESC/EAS Guidelines. Inclusion criteria required at least one appointment with a primary care physician within three years before follow-up initiation. We assessed the 10-year adjusted hazard-ratio of combined CV death and non-fatal Atherosclerotic Cardiovascular Disease (ASCVD) hospitalization, across SCORE risk categories and criteria, using Cox proportional hazards models adjusted for sex, age, competing comorbidities, and medication. RESULTS: The study included 161 681 observations from 87 035 unique patients. During the observation period, 71 787 patients were classified as low/moderate, 51 476 as high and 38 418 as very-high CV-risk categories. In the very-high group, prevalent comorbidities were hypertension (69%), hypercholesterolemia (69%) and type 2 diabetes (61%), and 13% were hospitalized for ASCVD. The adjusted 10-year hazard ratio of the composite of CV death or ASCVD hospitalization was 2.10 (95% CI: 1.91-2.32) for high-risk and 3.56 (95% CI: 3.21-3.96) for very-high-risk patients (low-risk as reference). CONCLUSION: Our study reinforces the prognostic relevance of CV-risk stratification for long-term prediction of CV death and ASCVD hospitalization in an unselected cohort, independently of sex, age, competing comorbidities and medication.

Improved Chemical and Radiochemical Synthesis of Neuropeptide Y Y2 Receptor Antagonist N-Methyl-JNJ-31020028 and Preclinical Positron Emission Tomography Studies.

Neuropeptide Y (NPY) is one of the most abundant peptides in the central nervous system of mammals and is involved in several physiological processes through NPY Y1, Y2, Y4 and Y5 receptors. Of those, the Y2 receptor has particular relevance for its autoreceptor role in inhibiting the release of NPY and other neurotransmitters and for its involvement in relevant mechanisms such as feeding behaviour, cognitive processes, emotion regulation, circadian rhythms and disorders such as epilepsy and cancer. PET imaging of the Y2 receptor can provide a valuable platform to understand this receptor's functional role and evaluate its potential as a therapeutic target. In this work, we set out to refine the chemical and radiochemical synthesis of the Y2 receptor antagonist N-[11C]Me-JNJ31020028 for in vivo PET imaging studies. The non-radioactive reference compound, N-Me-JNJ-31020028, was synthesised through batch synthesis and continuous flow methodology, with 43% and 92% yields, respectively. N-[11C]Me-JNJ-31020028 was obtained with a radiochemical purity > 99%, RCY of 31% and molar activity of 156 GBq/µmol. PET imaging clearly showed the tracer's biodistribution in several areas of the mouse brain and gut where Y2 receptors are known to be expressed.

Characterization and LDL-C management in a cohort of high and very high cardiovascular risk patients: The PORTRAIT-DYS study.

AIM: This study aims to characterize sociodemographic and clinical characteristics, use of lipid-lowering therapies (LLTs), and low-density lipoprotein cholesterol (LDL-C) control in a population with increased cardiovascular (CV) risk. METHODS: A cross-sectional observational study that uses electronic health records of patients from one hospital and across 14 primary care health centers in the North of Portugal, spanning from 2000 to 2020 (index date). Patients presented at least (i) 1 year of clinical data before inclusion, (ii) one primary care appointment 3 years before the index date, and (iii) sufficient data for CV risk classification. Patients were divided into three cohorts: high CV risk; atherosclerotic cardiovascular disease (ASCVD) risk equivalents without established ASCVD; evidence of ASCVD. CV risk and LDL-C control were defined by the 2019 and 2016 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) dyslipidemia guidelines. RESULTS: A total of 51 609 patients were included, with 23 457 patients classified as high CV risk, 19 864 with ASCVD equivalents, and 8288 with evidence of ASCVD. LDL-C control with 2016 ESC/EAS guidelines was 32%, 10%, and 18% for each group, respectively. Considering the ESC/EAS 2019 guidelines control level was even lower: 7%, 3%, and 7% for the same cohorts, respectively. Patients without any LLT prescribed ranged from 37% in the high CV risk group to 15% in patients with evidence of ASCVD. CONCLUSION: We found that LDL-C control was very low in patients at higher risk of CV events. An alarming gap between guidelines on dyslipidemia management and clinical implementation persists, even in those at very high risk or with established ASCVD.

Racemose neurocysticercosis presenting with thalamic stroke: A case report and literature review.

Racemose neurocysticercosis is an uncommon type of neurocysticercosis that represents a particularly aggressive infection. It is characterized by the presence of multiple confluent cysts within the subarachnoid space and it carries unique diagnostic challenges. Clinical manifestations include headache, cerebrovascular events, and life-threatening hydrocephalus. A 56-year-old female presented with sudden onset headache and right-sided hemisensory loss. Brain MRI revealed multiple cystic lesions in the subarachnoid space consistent with racemose neurocysticercosis and left thalamus acute lacunar infarct. This case report emphasizes the clinical importance, unique characteristics, and imaging features of racemose neurocysticercosis and its complications.

Missed opportunities in the diagnosis of heart failure: a real-world assessment.

AIMS: Heart failure (HF) is a leading cause of hospitalization worldwide. An early HF diagnosis is key to reducing hospitalizations. We used electronic health records (EHRs) to characterize HF pathways at the primary care physician (PCP) level prior to a first HF hospitalization (hHF). This study aimed to identify missed opportunities for HF diagnosis and management at the PCP level before a first hHF. METHODS AND RESULTS: This cohort study used EHRs of a large health care organization in Portugal. Patients with incident hHF between 2017 and 2020 were identified. Missed opportunities were defined by the absence of any of the following work-up in the 6 months after signs or symptoms had been recorded: lab results and electrocardiogram, natriuretic peptides, echocardiogram, referral to HF specialist, or HF medication initiation. A total of 2436 patients with a first hHF were identified. The median (interquartile range) age at the time of hospitalization was 81 (14) years, and 1361 (56%) were women. Most patients were treated with cardiovascular drugs prior or at index event. A total of 720 (30%) patients had records of HF signs or symptoms, 94% (n = 674) within 6 months prior to hHF. Among patients with recorded HF signs or symptoms, 410 (57%) had clinical management considered adequate before signs and symptoms were recorded. Of the 310 remaining patients, 155 (50%) had a follow-up that was considered inadequate. CONCLUSIONS: Relatively few patients with a first hHF had primary care records of signs or symptoms prior to admission. Of these, nearly half had inadequate management considering diagnosis and treatment. These data suggest the need to improve PCP HF awareness.

Sex differences in LDL-C control in a primary care population: The PORTRAIT-DYS study.

BACKGROUND AND AIMS: Cardiovascular (CV) diseases show clear differences in clinical manifestation and treatment outcomes between men and women. To reduce sex disparities in achieving lipid-lowering therapy (LLT) goals, a sex-focused assessment is essential and more studies are needed to bring new evidence to clinicians. This study aims to assess the role of sex in attaining low-density lipoprotein cholesterol (LDL-C) goals, after correction for age, CV risk category, LLT intensity, and presence of mental health disorder and social deprivation. METHODS: A retrospective cohort analysis of patients aged 40-85, followed in 1 hospital and 14 primary care centers in Portugal, using electronic health records from 1/1/2012 to 31/12/2020, was performed. The analysis considered an episode-based design, where exposure consists of any time when LLT was started or intensity changed. The likelihood of reaching the LDL-C goal according to contemporary ESC/EAS guidelines was modeled using multivariate Cox regression. LDL-C goal achievement at 180 days was defined as the outcome. The analysis was repeated at 30-day follow-up intervals up to 360 days, and also stratified by CV risk category. RESULTS: We identified 40,032 exposure episodes (LLT initiation or intensity change) in 30,323 distinct patients. Male sex, older age, lower CV risk and increasing LLT intensity were associated with improved LDL-C control. Women were 22% less likely to reach the LDL-C goal than men (HR = 0.78, 95% CI:0.73, 0.82) independently of covariates. CONCLUSIONS: Women have a lower likelihood of attaining LDL-C goals than men after adjustment for LLT intensity, age, CV risk category, presence of mental health disorder and social deprivation. This finding underscores the need for further investigation and tailoring of LLT management strategies in women.

Metachronous lesions after gastric endoscopic submucosal dissection: first assessment of the FAMISH prediction score.

BACKGROUND: Surveillance after gastric endoscopic submucosal dissection (ESD) is recommended for all patients owing to the persistent risk of metachronous gastric lesions (MGLs). We developed and validated a prediction score to estimate MGL risk after ESD for early neoplastic gastric lesions, to define an individualized and cost-saving approach. METHODS: Clinical predictors and a risk score were derived from meta-analysis data. A retrospective, single-center, cohort study including patients with ≥ 3 years of standardized surveillance after ESD was conducted for score validation. Predictive accuracy of the score by the area under the receiver operating characteristic curve (AUC) was assessed and cumulative probabilities of MGL were estimated. RESULTS: The risk score (0-9 points) included six clinical predictors (scored 0-3): positive family history of gastric cancer, older age, male sex, corpus intestinal metaplasia, synchronous gastric lesions, and persistent Helicobacter pylori infection (FAMISH). The study population included 263 patients. The MGL rate was 16 %. The score diagnostic accuracy for predicting MGL at 3 years' follow-up, measured by the AUC, was 0.704 (95 %CI 0.603-0.806). At 3 years and a cutoff < 2, the score achieved maximal sensitivity and negative predictive value; 15 % of patients could be assigned to a low-risk group, in which the progression to MGL was significantly lower than for the high-risk group (P = 0.04). CONCLUSION: The FAMISH score might be a useful tool to accurately identify patients with low-to-intermediate risk for MGL at 3 years of follow-up who could have surveillance intervals extended to reduce the burden of care.

The combined effect of BMI and age on ART outcomes.

STUDY QUESTION: For a woman with infertility and overweight/obesity, can infertility treatment be postponed to first promote weight loss? SUMMARY ANSWER: Advice regarding a delay in IVF treatment to optimize female weight should consider female age, particularly in women over 38 years for whom only substantial weight loss in a short period of time (3 months) seems to provide any benefit. WHAT IS KNOWN ALREADY: Body weight excess and advanced age are both common findings in infertile patients, creating the dilemma of whether to promote weight loss first or proceed to fertility treatment immediately. Despite their known impact on fertility, studies assessing the combined effect of female age and BMI on cumulative live birth rates (CLBRs) are still scarce and conflicting. STUDY DESIGN, SIZE, DURATION: We performed a multicentre retrospective cohort study including 14 213 patients undergoing their first IVF/ICSI cycle with autologous oocytes and subsequent embryo transfers, between January 2013 and February 2018 in 18 centres of a multinational private fertility clinic. BMI was subdivided into the following subgroups: underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obesity (≥30.0 kg/m2). PARTICIPANTS/MATERIALS, SETTING, METHODS: The primary outcome was CLBR. The secondary outcome was time to pregnancy. To assess the influence of female age and BMI on CLBR, two multivariable regression models were developed with BMI being added in the models as either an ordinal categorical variable (Model 1) or a continuous variable (Model 2) using the best-fitting fractional polynomials. CLBR was estimated over 1-year periods (Model 1) and shorter timeframes of 3 months (Model 2). We then compared the predicted CLBRs according to BMI and age. MAIN RESULTS AND THE ROLE OF CHANCE: When compared to normal weight, CLBRs were lower in women who were overweight (adjusted odds ratio (aOR) 0.86, 95% CI 0.77-0.96) and obese (aOR 0.74, 95% CI 0.62-0.87). A reduction of BMI within 1 year, from obesity to overweight or overweight to normal weight would be potentially beneficial up to 35 years old, while only a substantial reduction (i.e. from obesity to normal BMI) would be potentially beneficial in women aged 36-38 years. Above 38 years of age, even considerable weight loss did not compensate for the effect of age over a 1-year span but may be beneficial in shorter time frames. In a timeframe of 3 months, there is a potential benefit in CLBR if there is a loss of 1 kg/m2 in BMI for women up to 33.25 years and 2 kg/m2 in women aged 33.50-35.50 years. Older women would require more challenging weight loss to achieve clinical benefit, specifically 3 kg/m2 in women aged 35.75-37.25 years old, 4 kg/m2 in women aged 37.50-39.00 years old, and 5 kg/m2 or more in women over 39.25 years old. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective design and lower number of women in the extreme BMI categories. The actual effect of individual weight loss on patient outcomes was also not evaluated, as this was a retrospective interpatient comparison to estimate the combined effect of weight loss and ageing in a fixed period on CLBR. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that there is potential benefit in weight loss strategies within 1 year prior to ART, particularly in women under 35 years with BMI ≥25 kg/m2. For those over 35 years of age, weight loss should be considerable or occur in a shorter timeframe to avoid the negative effect of advancing female age on CLBR. A tailored approach for weight loss, according to age, might be the best course of action. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. All authors have no conflicts to declare. TRIAL REGISTRATION NUMBER: N/A.

Sex Differences in Tryptophan Metabolism: A Systematic Review Focused on Neuropsychiatric Disorders.

Tryptophan (Tryp) is an essential amino acid and the precursor of several neuroactive compounds within the central nervous system (CNS). Tryp metabolism, the common denominator linking serotonin (5-HT) dysfunctions and neuroinflammation, is involved in several neuropsychiatric conditions, including neurological, neurodevelopmental, neurodegenerative, and psychiatric diseases. Interestingly, most of those conditions occur and progress in a sex-specific manner. Here, we explore the most relevant observations about the influence of biological sex on Tryp metabolism and its possible relation to neuropsychiatric diseases. Consistent evidence suggests that women have a higher susceptibility than men to suffer serotoninergic alterations due to changes in the levels of its precursor Tryp. Indeed, female sex bias in neuropsychiatric diseases is involved in a reduced availability of this amino acid pool and 5-HT synthesis. These changes in Tryp metabolism could lead to sexual dimorphism on the prevalence and severity of some neuropsychiatric disorders. This review identifies gaps in the current state of the art, thus suggesting future research directions. Specifically, there is a need for further research on the impact of diet and sex steroids, both involved in this molecular mechanism as they have been poorly addressed for this topic.

Osteosarcoma-Derived Exosomes as Potential PET Imaging Nanocarriers for Lung Metastasis.

Lung metastases represent the most adverse clinical factor and rank as the leading cause of osteosarcoma-related death. Nearly 80% of patients present lung micrometastasis at diagnosis not detected with current clinical tools. Herein, an exosome (EX)-based imaging tool is developed for lung micrometastasis by positron emission tomography (PET) using osteosarcoma-derived EXs as natural nanocarriers of the positron-emitter copper-64 (64 Cu). Exosomes are isolated from metastatic osteosarcoma cells and functionalized with the macrocyclic chelator NODAGA for complexation with 64 Cu. Surface functionalization has no effect on the physicochemical properties of EXs, or affinity for donor cells and endows them with favorable pharmacokinetics for in vivo studies. Whole-body PET/magnetic resonance imaging (MRI) images in xenografted models show a specific accumulation of 64 Cu-NODAGA-EXs in metastatic lesions as small as 2-3 mm or in a primary tumor, demonstrating the exquisite tropism of EXs for homotypic donor cells. The targetability for lung metastasis is also observed by optical imaging using indocyanine green (ICG)-labeled EXs and D-luciferin-loaded EXs. These findings show that tumor-derived EXs hold great potential as targeted imaging agents for the noninvasive detection of small lung metastasis by PET. This represents a step forward in the biomedical application of EXs in imaging diagnosis with increased translational potential.

Polyphenol Metabolite Pyrogallol-O-Sulfate Decreases Microglial Activation and VEGF in Retinal Pigment Epithelium Cells and Diabetic Mouse Retina.

(Poly)phenol-derived metabolites are small molecules resulting from (poly)phenol metabolization after ingestion that can be found in circulation. In the last decade, studies on the impact of (poly)phenol properties in health and cellular metabolism accumulated evidence that (poly)phenols are beneficial against human diseases. Diabetic retinopathy (DR) is characterized by inflammation and neovascularization and targeting these is of therapeutic interest. We aimed to study the effect of pyrogallol-O-sulfate (Pyr-s) metabolite in the expression of proteins involved in retinal glial activation, neovascularization, and glucose transport. The expression of PEDF, VEGF, and GLUT-1 were analyzed upon pyrogallol-O-sulfate treatment in RPE cells under high glucose and hypoxia. To test its effect on a diabetic mouse model, Ins2Akita mice were subjected to a single intraocular injection of the metabolite and the expression of PEDF, VEGF, GLUT-1, Iba1, or GFAP measured in the neural retina and/or retinal pigment epithelium (RPE), two weeks after treatment. We observed a significant decrease in the expression of pro-angiogenic VEGF in RPE cells. Moreover, pyrogallol-O-sulfate significantly decreased the expression of microglial marker Iba1 in the diabetic retina at different stages of disease progression. These results highlight the potential pyrogallol-O-sulfate metabolite as a preventive approach towards DR progression, targeting molecules involved in both inflammation and neovascularization.

Implementing a globally harmonized risk assessment-based approach for regulatory decision-making of crop protection products.

A global, harmonized evaluation system for crop protection chemicals based on exposure and risk will improve the ability to inform risk management decisions and better support innovation. This would be achieved through harmonized risk assessment-based regulatory decision-making realized through the application of the best available science, via integration of new methods and traditional data to create tailored exposure-driven risk assessments. A requirement to achieve success is a structure that encourages direct communication between the regulatory community and the regulated industry, which would enable a more rapid incorporation of new technologies and advancing science. An approach that emulates the International Conference of Harmonization (ICH) for pharmaceuticals would bring together regulatory authorities and the regulated industry along with relevant experts from academia and Non-Governmental Organizations to discuss scientific and technical advances and their implementation. These discussions would also encourage the elimination of outmoded practices that no longer serve a purpose resulting in more uniform testing requirements and best practices for data evaluation to support safe use and scientifically defensible human health and environmental risk assessments. New and developing technologies offer exciting opportunities to improve the current toxicity testing paradigms to provide better solutions and diminish animal testing. Implementation of a harmonized approach will increase the speed, efficiency and accuracy of regulatory decision-making for human health and environmental protection while increasing the efficiency of providing safe and effective innovative products to the agriculture community. © 2020 Society of Chemical Industry.

Single Low Dose of Cocaine-Structural Brain Injury Without Metabolic and Behavioral Changes.

Chronic cocaine use has been shown to lead to neurotoxicity in rodents and humans, being associated with high morbidity and mortality rates. However, recreational use, which may lead to addictive behavior, is often neglected. This occurs, in part, due to the belief that exposure to low doses of cocaine comes with no brain damage risk. Cocaine addicts have shown glucose metabolism changes related to dopamine brain activity and reduced volume of striatal gray matter. This work aims to evaluate the morphological brain changes underlying metabolic and locomotor behavioral outcome, in response to a single low dose of cocaine in a pre-clinical study. In this context, a Balb-c mouse model has been chosen, and animals were injected with a single dose of cocaine (0.5 mg/kg). Control animals were injected with saline. A behavioral test, positron emission tomography (PET) imaging, and anatomopathological studies were conducted with this low dose of cocaine, to study functional, metabolic, and morphological brain changes, respectively. Animals exposed to this cocaine dose showed similar open field activity and brain metabolic activity as compared with controls. However, histological analysis showed alterations in the prefrontal cortex and hippocampus of mice exposed to cocaine. For the first time, it has been demonstrated that a single low dose of cocaine, which can cause no locomotor behavioral and brain metabolic changes, can induce structural damage. These brain changes must always be considered regardless of the dosage used. It is essential to alert the population even against the consumption of low doses of cocaine.

Diarrhea as a form of presentation of medullary thyroid carcinoma.

A case is presented of a 57-year-old man consulting for chronic diarrhea. Based on subsequent findings (thyroid nodule and metastases), the possibility of metastatic medullary thyroid carcinoma (MTC) was raised. Thyroidectomy allowed diagnosing a multicentric left lobe MTC. MTC is a rare cause of diarrhea, but should be considered, especially in the presence of signs or symptoms of alarm or nonresponse to empirical therapy.

Guideline values and human risk assessment for the presence of anti-inflammatory drugs remaining in drinking water after lab scale treatment

This study aimed to determine whether the anti-inflammatory drugs that are most commonly consumed in Brazil, including diclofenac, ketoprofen, naproxen, indomethacin, ibuprofen and acetaminophen, are present in drinking water and to derive guideline values to characterize the human risk. These pharmaceuticals were quantified in surface waters by LC-MS/MS with solid phase extraction, both before and after conventional treatment on a laboratory scale, using a jar test assay. The methods used to quantify these drugs showed good results: the chromatographic analysis obtained correlation coefficients between 0.9952 and 0.9991, with limits of quantification of 0.5 ng.mL-1 - 50 ng.mL-1 and precision standard deviations (0.08 - 2.08). Only ketoprofen and ibuprofen were not completely removed through the jar test. Environmental samples were collected and handled by the same method; the values |for ketoprofen and ibuprofen after treatment were 18.67 - 19.65 ng.L-1 (±17%) and 166.70 - 244.73 ng.L-1 (±14%), respectively. Human risk was assessed by comparing the guideline values for each compound to the concentrations obtained in the environmental samples, considering the toxicological backgrounds, following WHO (2011) method. The results suggest that the concentrations of ketoprofen and ibuprofen found in drinking water do not pose a risk to human health, even with chronic consumption