A study protocol for a randomized clinical trial on exposure and effects of pesticides consumption - the PEST-EXPO Brazil study.

Randomized clinical trials are considered the gold standard for studies with dietary interventions, which is mainly due to the fact that they can establish causal relationships between food exposure and body composition measures or biomarkers. The aim of this study was to describe the details of a double-blind, randomized, clinical trial protocol to identify, characterize and evaluate the effects of human dietary exposure to pesticide residues in food. Specific aspects of planning (development of a research question, determination of objectives, selection of participants, randomization and blinding) and performance (recruitment of participants, measures to improve adherence, data collection, follow-up and evaluation of results) are addressed in this study. The study design proved effective in characterizing dietary patterns with foods originating from both conventional and organic agriculture. A total of 148 individuals were recruited for the study. The conventional group was represented by 47 % of the sample and the organic group was represented by 53 %. The practice of evidence-based nutrition has demanded that trials be well designed and systematically performed in the field of clinical nutrition. Therefore, this clinical trial emphasizes the importance of improving studies with toxicological nutrition that assess sources of exposure through food.•This double-blind, randomized clinical trial details the protocol for identifying, characterizing, and evaluating the effects of dietary exposure to pesticide residues.•The protocol demonstrates that well-designed and systematically conducted trials emphasize the importance of robust methodologies in evidence-based nutrition.•In the face of the global climate crisis, this clinical trial underscores the importance of enhancing studies in toxicological nutrition, particularly those evaluating sources of exposure through food, to better understand the dietary impacts on health.

Molecular detection of multiple arboviruses in the city of Goiânia-Goiás-Brazil.

BACKGROUND: Healthcare systems are currently ill-equipped to diagnose arboviruses rapidly and efficiently or to differentiate between various viruses. METHODS: Utilizing molecular techniques, this study examined arbovirus infections in 459 patients from a public health unit in Goiânia-Goiás, Brazil, a region where arbovirus infection poses a significant public health challenge. RESULTS: Nearly 60% of the analyzed samples tested positive for at least one arbovirus, and over 10% of the patients were co-infected with more than one virus. CONCLUSIONS: Fast and accurate diagnostic tools are essential for informing public health policy and enhancing epidemiological surveillance.

Epidemiological profile of malaria in a rural community in the Amazon, Mato Grosso State, Brazil, 2011.

BACKGROUND: More than 95% of malaria transmission in Brazil occurs in the Legal Amazon Region, which in 2010 recorded around 333,429 cases reported in the Epidemiological Surveillance Information System-Malaria (Sivep_malaria), presenting an annual parasitic incidence (IPA) of 13.1 cases/1000 inhabitants. METHODS: This was a descriptive study that measured the community prevalence of Plasmodium infection and its relationship with land use in Três Fronteiras District, Colniza Municipality, Mato Grosso State. Data were collected during household visits in July 2011, with blood collection from finger pricks for the preparation of thick smear slides, and completion of a standardized case notification form. A georeferenced database was analysed, with land use evaluated as categorical variables. A kernel density map was built to show the density of cases and their location. RESULTS: Of the 621 respondents, 68(11%) had Plasmodium infection: 39 (57.4%) with Plasmodium vivax, 27(39.7%) with Plasmodium falciparum and two (2.9%) with mixed infections. Among infected individuals, 49 (72.1%) were men. Cases of malaria were distributed over the district, with greater occurrence of cases per household in open areas close to the mining company and artisanal mining sites. The was a greater density of cases located in the gold mining region. CONCLUSION: Transmission of malaria in Três Fronteiras District has a heterogeneous distribution. Individuals residing in mining and timber extraction sites have increased occurrence of Plasmodium infection.

A randomised trial of short- vs long-term androgen deprivation with salvage radiotherapy for biochemical failure following radical prostatectomy: URONCOR 06-24.

BACKGROUND: Salvage radiotherapy (SRT) and androgen-deprivation therapy (ADT) are widely used in routine clinical practice to treat patients with prostate cancer who develop biochemical recurrence (BCR) after radical prostatectomy (RP). However, there is no standard-of-care consensus on optimal duration ADT. Investigators propose three distinct risk groups in patients with prostate cancer treated with SRT in order to better define the indications and duration of ADT combined with SRT. STUDY DESIGN: The URONCOR 06-24 trial (ClinicalTrials.gov identifier NCT05781217) is a prospective, multicentre, randomised, open-label, phase III, clinical trial. The aim of the trial is to determine the impact of short-term (6 months) vs long-term (24 months) ADT in combination with SRT on distant metastasis-free survival (MFS) in patients with prostate cancer with BCR after RP (intermediate and high risk). ENDPOINTS: The primary endpoint is 5-year MFS rates in patients with prostate cancer treated with long- vs short-term ADT in combination with SRT. Secondary objectives are biochemical-relapse free interval, pelvic progression-free survival, time to start of systemic treatment, time to castration resistance, cancer-specific survival, overall survival, acute and late toxicity, and quality of life. METHODS AND ANALYSIS: Total of 534 patients will be randomised 1:1 to ADT 6 months or ADT 24 months with a luteinizing hormone-releasing hormone analogue in combination with SRT, stratified by risk group and pathological lymph node status. ETHICS AND DISSEMINATION: The study is conducted under the guiding principles of the World Medical Association Declaration of Helsinki. The results will be disseminated at research conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EudraCT number 2021-006975-41.

Central line-associated bloodstream infections in patients with COVID-19.

OBJECTIVE: to investigate the association between central line-associated bloodstream infections and clinical and care variables of intensive care unit patients with COVID-19 hospitalized at a reference public health institution. METHOD: a case-control study. RESULTS: the study sample consisted of 70 patients diagnosed with central line-associated bloodstream infections (case group) and 70 non-infected patients (control group). Most patients were male, with mean age of 57.93±13.93 years old and provided with a double lumen catheter. Median time of central line-associated bloodstream infections onset was 11 (8-18) days. Longer time on mechanical ventilation ( P =0.014; OR: 1.79; 95% CI: 0.91-3.51) and prone position ( P =0.017; OR: 2.41; 95% CI: 1.22-4.81) were associated with central line-associated bloodstream infections onset. CONCLUSION: longer time on invasive mechanical ventilation and prone position contributed to central line-associated bloodstream infections onset in COVID-19 patients.

Visual detection of seizures in mice using supervised machine learning.

Seizures are caused by abnormally synchronous brain activity that can result in changes in muscle tone, such as twitching, stiffness, limpness, or rhythmic jerking. These behavioral manifestations are clear on visual inspection and the most widely used seizure scoring systems in preclinical models, such as the Racine scale in rodents, use these behavioral patterns in semiquantitative seizure intensity scores. However, visual inspection is time-consuming, low-throughput, and partially subjective, and there is a need for rigorously quantitative approaches that are scalable. In this study, we used supervised machine learning approaches to develop automated classifiers to predict seizure severity directly from noninvasive video data. Using the PTZ-induced seizure model in mice, we trained video-only classifiers to predict ictal events, combined these events to predict an univariate seizure intensity for a recording session, as well as time-varying seizure intensity scores. Our results show, for the first time, that seizure events and overall intensity can be rigorously quantified directly from overhead video of mice in a standard open field using supervised approaches. These results enable high-throughput, noninvasive, and standardized seizure scoring for downstream applications such as neurogenetics and therapeutic discovery.

Feeding protocol with live feed and inert diet to determine the ideal age/size for weaning mullet Mugil liza (Valenciennes, 1836).

The Lebranche mullet Mugil liza is a marine fish of great importance for artisanal and industrial fishing, as well as aquaculture. The use of live feeds during the larviculture phase of marine fish is a significant component of production costs. The present study evaluated the effects of the feeding transition on different larval stages of M. liza, from the combined supply of live feed (Brachionus rotundiformis + Artemia franciscana) and live + inert feed (Artemia franciscana + inert diet) until the weaning phase to only the inert diet. A total of 3240 M. liza larvae (weight 0.0133 ± 0.0062 g and length 0.793 ± 0.160 cm) were distributed among the 12 experimental units (n = 270), resulting in four groups with three replicates each. Treatment groups consisted of feed transition with A. franciscana (enriched metanauplii) to commercial inert feed starting weaning at four different larval ages: 28, 31, 34, and 37 days post hatching. Zootechnical performance indexes and intestinal histomorphometry were evaluated. Mortality, condition factor, and length variation coefficient did not show significant differences between treatments. Final weight, final length, weight gain, and length gain were significantly greater in larvae that started weaning at 31, 34, and 37 days post hatching. Weight coefficient of variation was significantly higher in larvae that started weaning at 28 days (67.51 ± 11.70) compared to 37 days (34.40 ± 7.30). In intestinal histology, villi height (180.3 ± 4.4) was significantly higher in larvae that started weaning at 37 days post hatching. Considering the evidence found in the present study, it is recommended to start weaning M. liza on the 31st day post-hatching, using a 2-day co-feeding protocol (31st and 32nd days). From the 33rd day after hatching, M. liza larvae can receive only commercial feed.

Ultrasound-Guided Peripheral Venipuncture Decreases the Procedure's Pain and Positively Impacts Patient's Experience: The PRECISE Randomized Clinical Trial.

This study aimed to compare patients' experience of pain during ultrasound (US)-guided peripheral venipuncture versus conventional peripheral venipuncture. This randomized clinical trial was conducted at a public university hospital in 2021. Adult patients with indication for intravenous therapy compatible with peripheral intravenous catheters (PIVCs) were included: intervention group (IG), US peripheral venipuncture executed by specialist nurses; control group (CG), conventional peripheral venipuncture executed by clinical practice nurses. The primary outcome was patient experience of pain during the procedure and patient experience related to the PIVC placement method. Sixty-four patients were included, 32 for each group. The pain experienced was none-to-mild in the IG for 25 patients (78.1%) and moderate-to-severe in the CG for 21 patients (65.7%; P < .001). The overall pain rating was 2 (1-3) in the IG and 4 (3-6) in the CG (P < .001). The recommendation of the procedure in IG (net promoter score [NPS] + 90.6%) versus CG (NPS + 18.8%) was considered excellent and good, respectively (P < .001). Patients had less pain and significantly recommended the US-guided procedure. Patient experience with US-guided PIVC, performed by a specialist nurse, was superior to that of conventional peripheral venipuncture.

Predicting kidney allograft survival with explainable machine learning.

INTRODUCTION: Despite significant progress over the last decades in the survival of kidney allografts, several risk factors remain contributing to worsening kidney function or even loss of transplants. We aimed to evaluate a new machine learning method to identify these variables which may predict the early graft loss in kidney transplant patients and to assess their usefulness for improving clinical decisions. MATERIAL AND METHODS: A retrospective cohort study was carried out with 627 kidney transplant patients followed at least three months. All these data were pre-processed, and their selected features were used to develop an automatically working a machine learning algorithm; this algorithm was then applied for training and parameterization of the model; and finally, the tested model was then used for the analysis of patients' features that were the most impactful for the prediction of clinical outcomes. Our models were evaluated using the Area Under the Curve (AUC), and the SHapley Additive exPlanations (SHAP) algorithm was used to interpret its predictions. RESULTS: The final selected model achieved a precision of 0.81, a sensitivity of 0.61, a specificity of 0.89, and an AUC value of 0.84. In our model, serum creatinine levels of kidney transplant patients, evaluated at the hospital discharge, proved to be the most important factor in the decision-making for the allograft loss. Patients with a weight equivalent to a BMI closer to the normal range prior to a kidney transplant are less likely to experience graft loss compared to patients with a BMI below the normal range. The age of patients at transplantation and Polyomavirus (BKPyV) infection had significant impact on clinical outcomes in our model. CONCLUSIONS: Our algorithm suggests that the main characteristics that impacted early allograft loss were serum creatinine levels at the hospital discharge, as well as the pre-transplant values such as body weight, age of patients, and their BKPyV infection. We propose that machine learning tools can be developed to effectively assist medical decision-making in kidney transplantation.

17ß-estradiol and methylprednisolone association as a therapeutic option to modulate lung inflammation in brain-dead female rats.

Introduction: Brain death (BD) is known to compromise graft quality by causing hemodynamic, metabolic, and hormonal changes. The abrupt reduction of female sex hormones after BD was associated with increased lung inflammation. The use of both corticoids and estradiol independently has presented positive results in modulating BD-induced inflammatory response. However, studies have shown that for females the presence of both estrogen and corticoids is necessary to ensure adequate immune response. In that sense, this study aims to investigate how the association of methylprednisolone (MP) and estradiol (E2) could modulate the lung inflammation triggered by BD in female rats. Methods: Female Wistar rats (8 weeks) were divided into four groups: sham (animals submitted to the surgical process, without induction of BD), BD (animals submitted to BD), MP/E2 (animals submitted to BD that received MP and E2 treatment 3h after BD induction) and MP (animals submitted to BD that received MP treatment 3h after BD induction). Results: Hemodynamics, systemic and local quantification of IL-6, IL-1ß, VEGF, and TNF-α, leukocyte infiltration to the lung parenchyma and airways, and adhesion molecule expression were analyzed. After treatment, MP/E2 association was able to reinstate mean arterial pressure to levels close to Sham animals (p<0.05). BD increased leukocyte infiltration to the airways and MP/E2 was able to reduce the number of cells (p=0.0139). Also, the associated treatment modulated the vasculature by reducing the expression of VEGF (p=0.0616) and maintaining eNOS levels (p=0.004) in lung tissue. Discussion: Data presented in this study show that the association between corticoids and estradiol could represent a better treatment strategy for lung inflammation in the female BD donor by presenting a positive effect in the hemodynamic management of the donor, as well as by reducing infiltrated leukocyte to the airways and release of inflammatory markers in the short and long term.

Effectiveness of dose-intensified salvage regimens versus standard-dose chemotherapy for progression-free survival in early progressed follicular lymphoma before autologous stem cell transplantation: a systematic review protocol.

OBJECTIVE: This review will evaluate the effectiveness of dose-intensified versus standard-dose salvage regimens on progression-free survival in early progressed follicular lymphoma before high-dose chemotherapy and autologous stem cell transplantation. INTRODUCTION: Despite the substantial advances in the management of follicular lymphoma, approximately 20% of patients experience progression of the disease within 2 years of induction therapy. These patients have worse outcomes, and autologous stem cell transplantation has been shown to improve outcomes in this context. Little is known about the optimal salvage regimen. INCLUSION CRITERIA: Studies must include patients ≥18 years old with early progressed follicular lymphoma who were submitted to autologous stem cell transplantation in subsequent remission. Clinical trials and observational studies will be included. METHODS: The search strategy will be carried out in MEDLINE (PubMed), Embase (Periódicos CAPES), Scopus, Web of Science, LiLACS, and the Cochrane Library. No date or language restrictions will be imposed. The recommended JBI approach to critical appraisal, study selection, data extraction, and data synthesis will be used. Studies should score at least 50% in accordance with the critical appraisal tool. Data will be pooled whenever possible using the random effects model. Heterogeneity will be assessed using the standard χ 2 and I2 tests. A funnel plot will be generated to assess publication bias if there are 10 or more studies included in the meta-analysis. The GRADE approach will be used to rate certainty of evidence. REVIEW REGISTRATION: PROSPERO CRD42022373345.

COVID-19-Associated Cognitive Biases on Pneumonia Differential Diagnosis.

The coronavirus disease 2019 (COVID-19) pandemic favors cognitive biases such as anchoring and availability biases. The first refers to overvaluing some of the initial information and establishing a diagnosis too early, with resistance to future adjustments. The latter happens when diagnoses more frequently considered are regarded as more common in reality. This case, in which the correct diagnosis was delayed due to these biases, highlights the need to remain aware of them as a means toward timely diagnosis and therapeutic success of pneumonia cases. An 84-year-old woman presented with a mild non-productive cough for two months and fever. She had a history of breast carcinoma treated with radiotherapy in the previous year. Computerized tomography (CT) showed extensive bilateral consolidation foci with ground-glass-opacification areas and bilateral pleural effusion, CO-RADS 3. COVID-19 with bacterial superinfection was suspected and levofloxacin was initiated. Nasopharyngeal swab polymerase chain reaction (PCR) was carried out three times, always negative for SARS-CoV-2. As the patient remained with fever and cough, the antibiotic was escalated to piperacillin/tazobactam and then to meropenem/vancomycin. She underwent bronchofibroscopy and alveolar lavage, with negative SARS-CoV-2 PCR. The re-evaluation CT scan maintained bilateral consolidations, with an aerial bronchogram. The biopsy of pulmonary consolidation allowed the diagnosis of radiation-induced organizing pneumonia. Prednisolone was initiated and achieved clinical remission and radiological improvement. This case highlights the need to remain aware of cognitive biases both when COVID-19 is suspected or ruled out and to consider other diagnoses when there is a lack of therapeutic response.

Factors associated with older adults' cognitive decline 6 months after gamma-variant SARS-CoV-2 infection.

Background: Cognitive deficits are commonly reported after COVID-19 recovery, but little is known in the older population. This study aims to investigate possible cognitive damage in older adults 6 months after contracting COVID-19, as well as individual risk factors. Methods: This cross-sectional study involved 70 participants aged 60-78 with COVID-19 6 months prior and 153 healthy controls. Montreal Cognitive Assessment-Basic (MoCA-B) screened for cognitive impairment; Geriatric Depression Scale and Geriatric Anxiety Inventory screened for depression and anxiety. Data were collected on demographics and self-reports of comorbid conditions. Results: The mean age of participants was 66.97 ± 4.64 years. A higher proportion of individuals in the COVID group complained about cognitive deficits (χ2 = 3.574; p = 0.029) and presented with deficient MoCA-B scores (χ2 = 6.098, p = 0.014) compared to controls. After controlling for multiple variables, all the following factors resulted in greater odds of a deficient MoCA-B: COVID-19 6-months prior (OR, 2.44; p = 0.018), age (OR, 1.15; p < 0.001), lower income (OR, 0.36; p = 0.070), and overweight (OR, 2.83; p = 0.013). Further analysis pointed to individual characteristics in COVID-19-affected patients that could explain the severity of the cognitive decline: age (p = 0.015), lower income (p < 0.001), anxiety (p = 0.049), ageusia (p = 0.054), overweight (p < 0.001), and absence of cognitively stimulating activities (p = 0.062). Conclusion: Our study highlights a profile of cognitive risk aggravation over aging after COVID-19 infection, which is likely mitigated by wealth but worsened in the presence of overweight. Ageusia at the time of acute COVID-19, anxiety, being overweight, and absence of routine intellectual activities are risk factors for more prominent cognitive decline among those infected by COVID-19.

Eficácia da midostaurina na mastocitose sistêmica ­ um relato de caso / Efficacy of midostaurin in systemic mastocytosis: a case report

Paciente do sexo feminino, com 63 anos de idade, portadora de mastocitose sistêmica há cerca de 20 anos, sendo agressiva há 10 anos. Crises quase diárias com manifestações do trato gastrointestinal e vasomotoras. Após diversas tentativas de tratamento, iniciou uso de midostaurina, um inibidor multiquinase. Depois de 6 meses de uso, observou-se bom controle dos sintomas, diminuição em quase 50% da triptase sérica e desaparecimento completo das lesões cutâneas.

A 63-year-old female presented with an approximately 20-year history of systemic mastocytosis, which had become aggressive over the past 10 years. She experienced almost daily episodes of gastrointestinal and vasomotor manifestations. After multiple treatment attempts, she was started on midostaurin, a multikinase inhibitor. At 6 months of therapy, satisfactory control of symptoms was achieved, with a nearly 50% reduction in serum tryptase and complete resolution of cutaneous lesions.

Peripherally Inserted Central Catheter Versus Centrally Inserted Central Catheter for In-Hospital Infusion Therapy: A Cost-Effectiveness Analysis.

OBJECTIVES: To evaluate the comparative effectiveness and cost-effectiveness of peripherally inserted central catheters (PICCs) compared with centrally inserted central catheters (CICCs). METHODS: Prospective cohort study was followed by an economic analysis over a 30-day time horizon. Propensity score matching was used to select hospitalized adults with similar indications for PICC or CICC. The composite outcome was device removal or replacement because of complications before the end of treatment. The economic evaluation was based on a decision tree model for cost-effectiveness analysis, with calculation of the incremental cost-effectiveness ratio (ICER) per catheter removal avoided. All costs are presented in Brazilian reais (BRL) (1 BRL = 0.1870 US dollar). RESULTS: A total of 217 patients were followed in each group; 172 (79.3%) of those receiving a PICC and 135 (62.2%) of those receiving a CICC had no device-related complication, respectively. When comparing the events leading to device removal, the risk of composite endpoint was significantly higher in the CICC group (hazard ratio 0.20; 95% CI 0.11-0.35). The cost of PICC placement was BRL 1290.98 versus BRL 467.16 for a CICC. In the base case, the ICER for placing a PICC instead of a CICC was BRL 3349.91 per removal or replacement avoided. On univariate sensitivity analyses, the model proved to be robust within an ICER range of 2500.00 to 4800.00 BRL. CONCLUSIONS: PICC placement was associated with a lower risk of complications than CICC placement. Although the cost of a PICC is higher, its use avoided complications and need for catheter replacement before the end of treatment.

Assessment of myocardial strain patterns in patients with left bundle branch block using cardiac magnetic resonance.

Recently, a classification with four types of septal longitudinal strain patterns was described using echocardiography, suggesting a pathophysiological continuum of left bundle branch block (LBBB)-induced left ventricle (LV) remodeling. The aim of this study was to assess the feasibility of classifying these strain patterns using cardiovascular magnetic resonance (CMR), and to evaluate their association with LV remodeling and myocardial scar. Single center registry included LBBB patients with septal flash (SF) referred to CMR to assess the cause of LV systolic dysfunction. Semi-automated feature-tracking cardiac resonance (FT-CMR) was used to quantify myocardial strain and detect the four strain patterns. A total of 115 patients were studied (age 66 ± 11 years, 57% men, 28% with ischemic heart disease). In longitudinal strain analysis, 23 patients (20%) were classified in stage LBBB-1, 37 (32.1%) in LBBB-2, 25 (21.7%) in LBBB-3, and 30 (26%) in LBBB-4. Patients at higher stages had more prominent septal flash, higher LV volumes, lower LV ejection fraction, and lower absolute strain values (p < 0.05 for all). Late gadolinium enhancement (LGE) was found in 55% of the patients (n = 63). No differences were found between the strain patterns regarding the presence, distribution or location of LGE. Among patients with LBBB, there was a good association between strain patterns assessed by FT-CMR analysis and the degree of LV remodeling and LV dysfunction. This association seems to be independent from the presence and distribution of LGE.

Validation of the SCORE2 risk prediction algorithm in a Portuguese population: A new model to estimate 10-year cardiovascular disease incidence in Europe.

INTRODUCTION AND OBJECTIVES: Subjects without cardiovascular (CV) disease (CVD) may suffer from subclinical atherosclerosis, and are at increased risk for atherosclerotic CV events (ASCVE). The ESC/EAS risk SCORE was updated by SCORE2, which estimates 10-year risk of fatal and non-fatal CVD in European populations aged 40-69 years without established CVD or diabetes. Our aim was to compare the two ESC/EAS risk scores and to validate SCORE2 in our population. METHODS: A total of 1071 individuals (age 57.2±6.1 years; 75.2% male) without CVD or diabetes, from GENEMACOR study controls, were analyzed over 5.4±3.9 years. The population was stratified into risk categories according to the two scores, and the area under the ROC curve (AUC) and Harrell's C-index assessed the scores' performance. Calibration was performed using the goodness-of-fit test, and occurrence of the first event assessed by Cox regression. Kaplan-Meier analysis estimated SCORE2 survival. RESULTS: SCORE stratified subjects into four risk categories: low (7.4%), moderate (46.5%), high (25.3%) and very high (20.8%), and SCORE2 into three: low-to-moderate (24.7%), high (59.0%) and very high (16.2%). SCORE presented good discrimination for CV mortality (AUC=0.838; C-index=0.834, 95% CI: 0.728-0.940), as did SCORE2 for total CV events (AUC=0.744; C-index=0.728, 95% CI: 0.648-0.808). Calibration did not show a disparity between observed and expected ASCVE. The probability of ASCVE was eight times higher in very-high-risk SCORE2 (p=0.001), and three times in the high-risk group (p=0.049). Event-free survival was 99%, 90% and 72% in the low-to-moderate, high and very-high-risk categories, respectively (p<0.0001). CONCLUSIONS: SCORE2 improved population stratification by identifying higher-risk patients, enabling early preventive measures. It showed good discriminative ability for all ASCVE.

Fragment-based screening targeting an open form of the SARS-CoV-2 main protease binding pocket.

To identify starting points for therapeutics targeting SARS-CoV-2, the Paul Scherrer Institute and Idorsia decided to collaboratively perform an X-ray crystallographic fragment screen against its main protease. Fragment-based screening was carried out using crystals with a pronounced open conformation of the substrate-binding pocket. Of 631 soaked fragments, a total of 29 hits bound either in the active site (24 hits), a remote binding pocket (three hits) or at crystal-packing interfaces (two hits). Notably, two fragments with a pose that was sterically incompatible with a more occluded crystal form were identified. Two isatin-based electrophilic fragments bound covalently to the catalytic cysteine residue. The structures also revealed a surprisingly strong influence of the crystal form on the binding pose of three published fragments used as positive controls, with implications for fragment screening by crystallography.

Human health risk assessment of metals in soil samples of a Brazilian city with a historic contamination complex.

Rio Grande is a city located on a narrow industrialized and urbanized Brazilian peninsula, characterized by wetlands. Due to population growth, numerous urban backfilled regions were built to expand the territorial area of the city. Currently, more than 60% of the central area of the city comes from the grounding of wetlands. The material used for the expansion of the territory had a history of contamination from metals from the tannery and textile industries (mainly Hg) and urban solid waste. In addition to past sources, the city has an active industrial complex with fertilizer, petrochemical, and grain industries. This study evaluated the risks to human health caused by metals (Hg, Fe, Ni, Cr, Cu, Pb, and Zn) in original soils and backfills, considering the oral, inhalation, and dermal routes of exposure for children and adults using the tool human health risk assessment (HHRA) proposed methodology by USEPA. A total of 63.81% of the original soil samples and 57.14% of the backfill soil samples showed a non-carcinogenic risk (HInc>1) for at least one evaluated metal. Still, approximately 10% of the samples presented carcinogenic risk when the Cr was considered in the hexavalent form. The dermal (Hg, Ni, and Cr) and oral (Fe, Cu, and Zn) exposure routes had the greatest contribution to the total risk. The non-carcinogenic risk for Hg, Cr(VI), and Pb was heterogeneously distributed between the original soils and backfills and associated with the proximity to some pollution sources. Given the complexity of historical occupation in the municipality and the increasing industrialization, both the original areas and the backfills should be included in the risk management strategy to minimize risks.

Male versus female inflammatory response after brain death model followed by ex vivo lung perfusion.

BACKGROUND: Ex vivo lung perfusion (EVLP) is a useful tool for assessing lung grafts quality before transplantation. Studies indicate that donor sex is as an important factor for transplant outcome, as females present higher inflammatory response to brain death (BD) than males. Here, we investigated sex differences in the lungs of rats subjected to BD followed by EVLP. METHODS: Male and female Wistar rats were subjected to BD, and as controls sham animals. Arterial blood was sampled for gas analysis. Heart-lung blocks were kept in cold storage (1 h) and normothermic EVLP carried out (4 h), meanwhile ventilation parameters were recorded. Perfusate was sampled for gas analysis and IL-1ß levels. Leukocyte infiltration, myeloperoxidase presence, IL-1ß gene expression, and long-term release in lung culture (explant) were evaluated. RESULTS: Brain dead females presented a low lung function after BD, compared to BD-males; however, at the end of the EVLP period oxygenation capacity decreased in all BD groups. Overall, ventilation parameters were maintained in all groups. After EVLP lung infiltrate was higher in brain dead females, with higher neutrophil content, and accompanied by high IL-1ß levels, with increased gene expression and concentration in the culture medium (explant) 24 h after EVLP. Female rats presented higher lung inflammation after BD than male rats. Despite maintaining lung function and ventilation mechanics parameters for 4 h, EVLP was not able to alter this profile. CONCLUSION: In this context, further studies should focus on therapeutic measures to control inflammation in donor or during EVLP to increase lung quality.

As there is a shortage of viable lungs for transplantation, methods of lung preservation, such as ex vivo perfusion, are important. This method is a good alternative, as it will not only preserve the lungs, but also enable lung function assessment and treatment of the organs. Studies have showed that lungs from donors of the female sex have greater risk of being rejected, when transplanted to male receptors. However, it's not certain if sex differences in anatomy, physiology and specially in immune response could interfere with the transplant result. Females do present a greater and more efficient immune response to any hazard, however after brain death this control is lost, producing a great inflammatory response as a result. Therefore, in this study we have investigated in more detail the influence of sex on the effects of brain death followed by the preservation method. Thus, we performed a brain death model in males and females rats and placed their lungs in an ex vivo lung perfusion machine. At the end of the experiment, we analyzed lung ventilation, gas exchange, and inflammatory parameters. The obtained data indicated that overall the lung ventilation and gas exchange is maintained by the ex vivo perfusion machine. Also, that lung inflammation is influenced by the sex of the donor; where the lungs from females present greater inflammation compared to the lungs from males.