Influence of Thyroglobulin (Tg) Autoantibodies on Tg levels Measured by Different Methodologies: (IMA, LC-MS/MS and RIA).

CONTEXT: Serum thyroglobulin (Tg) measured by Immunometric assays (IMA) is prone to underestimation due to Tg autoantibody (TgAb) interference, often prompting reflex Tg measurement by liquid chromatography/tandem mass spectrometry (MS) or radioimmunoassay (RIA). OBJECTIVE: IMA, MS and RIA methodologies were used to measure serum Tg in TgAb-negative (TgAb-) and TgAb-positive (TgAb+) patients with either distant metastatic thyroid cancer (DTC) or hyperthyroidism (HY) - patients in whom a detectable serum Tg would be expected. CONCLUSIONS: 1) Between-method Tg variability necessitates method continuity when monitoring the Tg trends of TgAb- DTC patients. 2) The presence and concentration of TgAb appeared to have a lowering effect on serum Tg measured by all methodologies (IMA, MS and RIA). 3) Since the reliability of Tg measured in the presence of TgAb is often uncertain, the TgAb trend (measured by the same method) may be a useful surrogate DTC tumor marker.

A New Advancement in Germination Biotechnology of Purple Creole Corn: Bioactive Compounds and In Situ Enzyme Activity for Water-Soluble Extract and Pan Bread.

Germination is a simple and cost-effective technology that enhances the technological, sensory, and nutritional potential of grains, making them more attractive for use in the food industry. Germinating indigenous seeds is an alternative to increase noticeability and add value to these grains, which hold social and economic significance in the regions where they are cultivated, such as creole purple pericarp corn (PPCC) from the Couto Magalhães de Minas region in Brazil. This study aimed to optimize the germination parameters of time (24-96 h) and temperature (18-32 °C) for PPCC to produce water-soluble extracts and bread. Endogenous enzymes resulting from the germination process significantly enhanced (p < 0.10) the technological (total reducing sugars, total soluble solids, and soluble proteins) and biological properties (γ-aminobutyric acid, total soluble phenolic compounds, and antioxidant capacity) of the water-soluble extracts. The optimum point for obtaining the extracts was found to be at 85.3 h at 30.46 °C (with desirability of 90.42%), and this was statistically validated. The incorporation of germinated PPCC flours into bread was also promising (p < 0.10) and had a positive impact on the dough property (dough volume increase) and the final product, especially in terms of instrumental texture (springiness, cohesiveness, gumminess, chewiness, and resilience), resulting in a softer texture (lower firmness and hardness). The addition of PPCC flours did not alter instrumental color parameters, which may lead to greater consumer acceptance due to imperceptible differences in color to untrained individuals, with the optimized point at 96 h at 29.34 °C, with a desirability of 92.60%. Therefore, germinated PPCC shows promise for use as a base for obtaining water-soluble extracts and in bread as a replacement for commercial flour improvers, while also adding value to a raw material that is part of the local culture and agrobiodiversity.

New Breakfast Cereal Developed with Sprouted Whole Ryegrass Flour: Evaluation of Technological and Nutritional Parameters.

Ryegrass is one such cereal that has been underutilized in human nutrition despite its high nutritional and functional value due to the presence of phytochemicals and dietary fibers. Exploiting ryegrass for human consumption is an exciting option, especially for countries that do not produce wheat, as it is easily adaptable and overgrows, making it economically viable. This study evaluated the nutritional content of γ-aminobutyric acid and bioactive compounds (total soluble phenolic compounds) and the physicochemical and technological properties of partially substituting maize flour (MF) with sprouted whole ryegrass flour (SR) in developing extrusion-cooked breakfast cereals. A completely randomized design with substitutions ranging from 0 to 20% of MF with SR was employed as the experimental strategy (p < 0.05). Partial incorporation of SR increased the content of γ-aminobutyric acid and total soluble phenolic compounds. Using sprouted grains can adversely affect the technological quality of extruded foods, mainly due to the activation of the amylolytic enzymes. Still, ryegrass, with its high dietary fiber and low lipid content, mitigates these negative effects. Consequently, breakfast cereals containing 4 and 8% SR exhibited better physicochemical properties when compared to SR12, SR16, SR20, and USR10, presenting reduced hardness and increased crispness, and were similar to SR0. These results are promising for ryegrass and suggest that combining the age-old sprouting process with extrusion can enhance the nutritional quality and bioactive compound content of cereal-based breakfast products while maintaining some technological parameters, especially crispiness, expansion index, water solubility index, and firmness, which are considered satisfactory.

Impact of Genomic Deletion RD16 on the Expression of the Mycobacterium bovis BCG Moreau VapBC47 Toxin-Antitoxin System.

Mycobacterium bovis BCG is the only vaccine against tuberculosis. The variable forms of cultivation throughout the years, before seed-lots were developed, allowed in vitro evolution of the original strain, generating a family of vaccines with different phenotypic and genotypic characteristics. Molecular studies revealed regions of difference (RDs) in the genomes of the various BCG strains. This work aims to characterize the gene pair rv3407-rv3408 (vapB47-vapC47), coding for a toxin-antitoxin system of the VapBC family, and to evaluate possible transcriptional effects due to the adjacent BCG Moreau-specific genomic deletion RD16. We show that these genes are co-transcribed in BCG strains Moreau and Pasteur, and that the inactivation of an upstream transcriptional repressor (Rv3405c) due to RD16 has a polar effect, leading to increased vapBC47 expression. Furthermore, we detect VapB47 DNA binding in vitro, dependent on a 5' vapB47 sequence that contributes to a palindrome, spanning the promoter and coding region. Our data shed light on the regulation of VapBC systems and on the impact of the BCG Moreau RD16 deletion in the expression of adjacent genes, contributing to a better understanding of BCG Moreau physiology.

Use of Thermography to Evaluate Alternative Crops for Off-Season in the Cerrado Region.

Future predictions due to climate change are of decreases in rainfall and longer drought periods. The search for new tolerant crops is an important strategy. The objective of this study was to evaluate the effect of water stress on the physiology and productivity of crops with potential for growing in the off-season period in the Cerrado, and evaluate correlations with the temperature of the canopy obtained by means of thermography. The experiment was conducted under field conditions, with experimental design in randomized blocks, in a split-plot scheme and four replications. The plots were: common bean (Phaseolus vulgaris); amaranth (Amaranthus cruentus); quinoa (Chenopodium quinoa); and buckwheat (Fagopyrum esculentum). The subplots were composed of four water regimes: maximum water regime (WR 535 mm), high-availability regime (WR 410 mm), off-season water regime (WR 304 mm) and severe water regime (WR 187 mm). Under WR 304 mm, the internal concentration of CO2 and photosynthesis were reduced by less than 10% in amaranth. Common bean and buckwheat reduced 85% in photosynthesis. The reduction in water availability increased the canopy temperature in the four crops and, in general, common bean was the most sensitive species, while quinoa had the lowest canopy temperatures. Furthermore, canopy temperature correlated negatively with grain yield, biomass yield and gas exchange across all plant species, thus thermal imaging of the canopy represents a promising tool for monitoring crop productivity for farmers, For the identification of crops with high water use management for research.

Synthetic hydrazones: In silico studies and in vitro evaluation of the antileishmania potential.

Bioprospecting and synthesis of strategically designed molecules have been used in the search for drugs that can be in leishmaniasis. Hydrazones (HDZ) are promising compounds with extensive biological activities. The objective of this work was to perform in silico studies of hydrazones 1-5 and to evaluate their antileishmanial, cytotoxic and macrophage immunomodulatory potential in vitro. Hydrazones were subjected to prediction and molecular docking studies. Antileishmanial protocols on promastigotes and amastigotes of Leishmania amazonensis, cytotoxicity and macrophage immunomodulatory activity were performed. Hydrazones showed a good pharmacokinetic profile and hydrazone 3 and hydrazone 5 were classified as non-carcinogenic. Hydrazone 5 obtained the best conformation with trypanothione reductase. Hydrazone 1 and hydrazone 3 obtained the best mean inhibitory concentration (IC50) values for promastigotes, 4.4-61.96 µM and 8.0-58.75 µM, respectively. It also showed good activity on intramacrophagic amastigotes, with hydrazone 1 being the most active (IC50 = 6.79 µM) with selectivity index of 56. In cytotoxicity to macrophages hydrazone 3 was the most cytotoxic (CC50 = 256.3 ± 0,04 µM), while hydrazone 4 the least (CC50 = 1055.9 ± 0.03 µM). It can be concluded that the hydrazones revealed important pharmacokinetic and toxicological properties, in addition to antileishmania potential in reducing infection and infectivity in parasitized macrophages.

After-effects of thixotropic conditionings on operational chest wall and compartmental volumes of patients with Parkinson's disease.

Individuals with Parkinson's disease (PD) present respiratory dysfunctions, mainly due to decreased chest wall expansion, which worsens with the course of the disease. These findings contribute to the restrictive respiratory pattern and the reduction in chest wall volume. According to literature, inspiratory muscle thixotropic conditioning maneuvers may improve lung volumes in these patients. The study aimed to determine the after-effects of respiratory muscle thixotropic maneuvers on breathing patterns and chest wall volumes of PD. A crossover study was performed with twelve patients with PD (8 males; mean age 63.9±8.8 years, FVC%pred 89.7±13.9, FEV1%pred 91.2±15, FEV1/FVC%pred 83.7±5.7). Chest wall volumes were assessed using OEP during thixotropic maneuvers. Increases in EIVCW (mean of 126mL, p = 0.01) and EEVCW (mean of 150mL, p = 0.005) were observed after DITLC (deep inspiration from total lung capacity) due to increases in pulmonary (RCp) and abdominal (RCa) ribcage compartments. Changes in ICoTLC (inspiratory contraction from TLC) led to significant EIVCW (mean of 224mL, p = 0.001) and EEVCW (mean of 229mL, p = 0.02) increases that were mainly observed in the RCp. No significant changes were found when performing DERV (deep expiration from residual volume) and ICoRV (Inspiratory contraction from RV). Positive correlations were also observed between the degree of inspiratory contraction during ICoTLC and EEVRCp (rho = 0.613, p = 0.03) and EIVRCp (rho = 0.697, p = 0.01) changes. Thixotropy conditioning of inspiratory muscles at an inflated chest wall volume increases EIVCW and EEVCW in the ten subsequent breaths in PD patients. These maneuvers are easy to perform, free of equipment, low-cost, and may help patients improve chest wall volumes during rehabilitation.

Pathophysiology of COVID-19: Critical Role of Hemostasis.

The COVID-19 pandemic, caused by SARS-CoV-2, had its first cases identified in late 2019 and was considered a clinical pandemic in March 2020. In March 2022, more than 500 million people were infected and 6,2 million died as a result of this disease, increasingly associated with changes in human hemostasis, such as hypercoagulation. Numerous factors contribute to the hypercoagulable state, and endothelial dysfunction is the main one, since the activation of these cells can strongly activate platelets and the coagulation system. In addition, there is a dysregulation of the renin-angiotensin system due to the SARS-CoV-2 takeover of the angiotensin converting enzyme 2, resulting in a strong immune response that could further damage the endothelium. Thrombus formation in the pulmonary microvasculature structure in patients with COVID-19 is an important factor to determine the severity of the clinical picture and the outcome of this disease. This review describes the hemostatic changes that occur in SARS-CoV-2 infection, to further improve our understanding of pathogenic mechanisms and the interaction between endothelium dysfunction, kallikrein-kinins, renin angiotensin, and the Coagulation/fibrinolysis systems as underlying COVID-19 effectors. This knowledge is crucial for the development of new effective therapeutic approaches, attenuating the severity of SARS-CoV-2's infection and to reduce the deaths.

Metastatic Differentiated Thyroid Cancer Survival Is Unaffected by Mode of Preparation for 131I Administration.

Context: Recombinant human thyrotropin (rhTSH) is currently not Food and Drug Administration approved for the treatment of high-risk patients with differentiated thyroid cancer (DTC). Objective: The goal of our study was to compare the outcomes in higher-risk patients with metastatic DTC prepared for radioiodine (RAI) therapy with rhTSH vs thyroid hormone withdrawal (THW). Methods: A retrospective chart review was performed of patients with metastatic DTC in follow-up at MedStar Washington Hospital Center and MedStar Georgetown University Hospital from 2009 to 2017. Patients were divided according to their preparation for RAI therapy, with assessment of progression-free survival (PFS) and overall survival (OS). Results: Fifty-five patients with distant metastases (16 men, 39 women) were prepared for RAI therapy exclusively either with rhTSH (n = 27) or with THW (n = 28). There were no statistically significant differences between the groups regarding clinicopathological features and history of RAI therapies. The median follow-up time for patients with rhTSH-aided therapies was 4.2 years (range, 3.3-5.5 years) and for patients with THW-aided therapies was 6.8 years (range, 4.2-11.6 years) (P = .002). Multivariate analysis showed that the method of thyrotropin stimulation was not associated with a difference in PFS or OS. Conclusion: As has been shown previously for low-risk DTC, this study indicates that the mode of preparation for RAI therapy does not appear to influence the outcomes of patients with metastatic DTC. PFS and OS were similar for patients with THW-aided or rhTSH-aided RAI therapies.

Segurança do paciente em hemodinâmica: trajetória de um serviço em busca da excelência / Patient safety in the cath lab: the trajectory of a service in search of excellence

Introdução: A segurança do paciente é considerada uma prioridade global pela Organização Mundial da Saúde, e o Brasil, como país-membro, lançou, em 2013, o Programa Nacional de Segurança do Paciente, recomendando práticas seguras para todos os serviços de saúde. Embora obrigatório, muitos estabelecimentos não possuem Núcleos de Segurança do Paciente estruturados para o gerenciamento de seus riscos e incidentes. Objetivo: Descrever a experiência na implantação de um programa de segurança para pacientes submetidos a procedimentos hemodinâmicos. Métodos: Estudo observacional, descritivo e retrospectivo da criação do Núcleo de Segurança do Paciente e do programa de gerenciamento de riscos. Resultados: O núcleo foi constituído em 2014, e o programa foi desenvolvido em quatro fases: criação do plano de segurança, mapeamento de riscos, criação de instruções de trabalho e gerenciamento de incidentes. Entre dezembro de 2014 e dezembro de 2019, foram monitorados 6.913 pacientes e identificado 146 incidentes, sendo 44,52% classificados como inconformidade a protocolos, 20,54% como circunstância notificável, 13,69% como quase-erro, 10,95% como incidente sem dano e 10,27% como evento adverso (incidente com dano). Entre 2017 e 2019, observaram-se redução no número de inconformidade de protocolo (0,66% versus 0,42%; p=0,01) e circunstância notificável (0,5% versus 0,32%; p=0,32), com incremento na comunicação de quase erro (0% versus 0,07%; p=0,018). Ao longo do estudo, observou-se aumento na adesão às metas dos indicadores relacionados à notificação de incidentes, ao tempo porta-balão e às horas- treinamento. Conclusão: A criação do Núcleos de Segurança do Paciente, somada à incorporação de um plano efetivo, é ferramenta efetiva, que contribui para a construção de uma cultura de excelência.

Background: Patient safety is considered a global priority by the World Health Organization, and Brazil, as a Member State, launched the National Patient Safety Program in 2013, recommending safe practices for all health services. Although mandatory, many facilities do not have structured Patient Safety Units to manage their risks and incidents. Objective: To describe the experience in implementing a safety program for patients undergoing invasive cardiology procedures. Methods: This was an observational, descriptive, and retrospective study on the creation of a patient safety unit and a risk management program. Results: The unit was established in 2014, and the program was developed in four phases: creation of the safety plan, risk mapping, creation of work instructions, and incident management. Between December 2014 and December 2019, a total of 6,913 patients were monitored and 146 incidents were identified, with 44.52% classified as non-compliance to protocol, 20.54% as reportable circumstances, 13.69% as near-misses, 10.95% as no harm incidents, and 10.27% as adverse events (harmful incidents). Between 2017 and 2019, there was a reduction in amount of non-compliance to protocol (0.66% versus 0.42%; p=0.01) and reportable circumstances (0.5% versus 0.32%; p=0.32), with an increase in near-miss reporting (0% versus 0.07%; p=0.018). Throughout the study, there was an increase in adherence to indicator targets related to incident reporting, door-to-balloon time, and training hours. Conclusion: The creation of Patient Safety Units, together with employing an effective plan, is an effective tool that contributes to the construction of a culture of excellence.

Pathophysiology of COVID-19: critical role of hemostasis

The COVID-19 pandemic, caused by SARS-CoV-2, had its first cases identified in late 2019 and was considered a clinical pandemic in March 2020. In March 2022, more than 500 million people were infected and 6,2 million died as a result of this disease, increasingly associated with changes in human hemostasis, such as hypercoagulation. Numerous factors contribute to the hypercoagulable state, and endothelial dysfunction is the main one, since the activation of these cells can strongly activate platelets and the coagulation system. In addition, there is a dysregulation of the renin-angiotensin system due to the SARS-CoV-2 takeover of the angiotensin converting enzyme 2, resulting in a strong immune response that could further damage the endothelium. Thrombus formation in the pulmonary microvasculature structure in patients with COVID-19 is an important factor to determine the severity of the clinical picture and the outcome of this disease. This review describes the hemostatic changes that occur in SARS-CoV-2 infection, to further improve our understanding of pathogenic mechanisms and the interaction between endothelium dysfunction, kallikrein-kinins, renin angiotensin, and the Coagulation/fibrinolysis systems as underlying COVID-19 effectors. This knowledge is crucial for the development of new effective therapeutic approaches, attenuating the severity of SARS-CoV-2’s infection and to reduce the deaths.

Protein provision and lower mortality in critically ill patients with COVID-19.

BACKGROUND AND AIMS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) severely impacted the management of critically ill patients, including nutritional therapy. This study aimed to verify an association between mortality and the energy and protein provided to critically ill patients affected by the SARS-CoV-2 and receiving enteral nutrition support. METHODS: Patients with confirmed COVID-19, with >7 days of stay in the ICU, on enteral nutrition were followed from the moment of hospitalization until discharge from the ICU or death. Data about age, gender, Simplified Acute Physiology Score III (SAPS3), intensive care unit (ICU) length of stay, days on mechanical ventilation (MV), clinical endpoint outcome (discharge or death), and daily energy and protein provision were collected from electronic medical records. Cox regression analyses and Kaplan-Meyer curves were used in statistical analysis. RESULTS: Fifty-two patients (66.2 ± 13.1 years; 53.8% women) were enrolled in the present study. The mean length of hospitalizations and SAPS3 score were 17.8 ± 9.8 days and 78.7 ± 14.7, respectively; all patients needed mechanical ventilation (mean of days was 16.42 ± 9.1). For most patients (73.1%) the endpoint was death. Twenty-five percent of patients had protein supply >0.8 g/IBW/day. Survival during COVID-19 hospitalization at ICU was significantly different among patients according to protein supply (p = 0.005). Hazard Ratios (HR) for protein supply showed that a protein intake >0.8 g/IBW/day was associated with significantly lower mortality (HR 0.322, p = 0.049). CONCLUSION: Our study suggests that a protein supply at least > 0.8 g/IBW/day could be related to reduced mortality in ICU patients with COVID-19.

COVID-19 induces proatherogenic alterations in moderate to severe non-comorbid patients: A single-center observational study.

Patients with COVID-19 can be asymptomatic or present mild to severe symptoms, leading to respiratory and cardiovascular complications and death. Type 2 diabetes mellitus (T2DM) and obesity are considered risk factors for COVID-19 poor prognosis. In parallel, COVID-19 severe patients exhibit dyslipidemia and alterations in neutrophil to lymphocyte ratio (NLR) associated with disease severity and mortality. To investigate whether such alterations are caused by the infection or results from preexisting comorbidities, this work analyzed dyslipidemia and the hemogram profile of COVID-19 patients according to the severity and compared with patients without T2DM or obesity comorbidities. Dyslipidemia, with a marked decrease in HDL levels, and increased NLR accompanied the disease severity, even in non-T2DM and non-obese patients, indicating that COVID-19 causes the observed alterations. Because decreased hemoglobin is involved in COVID-19 severity, and hemoglobin concentration is associated with metabolic diseases, the erythrogram of patients was also evaluated. We verified a drop in hemoglobin and erythrocyte number in severe patients, independently of T2DM and obesity, which may explain in part the need for artificial ventilation in severe cases. Thus, the control of such parameters (especially HDL levels, NLR, and hemoglobin concentration) could be a good strategy to prevent COVID-19 complications and death.

Quinoa for the Brazilian Cerrado: Agronomic Characteristics of Elite Genotypes under Different Water Regimes.

Quinoa stands out as an excellent crop in the Cerrado region for cultivation in the off-season or irrigated winter season. Here, we tested the effects of different water regimes on the agronomic characteristics, physiology, and grain quality of different elite quinoa genotypes under field conditions. The experiment was conducted under field conditions at Embrapa Cerrados (Planaltina, DF, Brazil). The experimental design was in randomized blocks, in a split-plot scheme, with four replications. The plots were composed of 18 quinoa genotypes and modified BRS Piabiru (the currently used genotype), and the split-plots were divided into 4 different water regimes. The following variables were evaluated: productivity and productivity per unit of applied water (PUAA), plant height, flavonoids, anthocyanins, gas exchange, chlorophyll, leaf proline, and relative water content. Our results showed that water regimes between 309 and 389 mm can be recommended for quinoa in the Cerrado region. CPAC6 and CPAC13 presented the highest yield and PUAA under high and intermediate WRs, and hence were the most suitable for winter growth under irrigation. CPAC17 is most suitable for off-season growth under rainfed conditions, as it presented the highest PUAA under the low WRs (247 and 150). CPAC9 stood out in terms of accumulation of flavonoids and anthocyanins in all WRs. Physiological analyses revealed different responses of the genotypes to water restriction, together with symptoms of stress under lower water regimes. Our study reinforces the importance of detailed analyses of the relationship between productivity, physiology, and water use when choosing genotypes for planting and harvest in different seasons.

Biotin Interference in Assays for Thyroid Hormones, Thyrotropin and Thyroglobulin.

Background: Biotin has been reported to interfere with several commonly used laboratory assays resulting in misleading values and possible erroneous diagnosis and treatment. This report describes a prospective study of possible biotin interference in thyroid-related laboratory assays, with a comparison of different commonly used assay platforms. Materials and Methods: Thirteen adult subjects (mean age 45 ± 13 years old) were administered biotin 10 mg/day for eight days. Blood specimens were collected at three time points on day 1 and on day 8 (baseline, two, and five hours after biotin ingestion). Thyrotropin (TSH), free triiodothyronine (fT3), free thyroxine (fT4), total triiodothyronine (TT3), total thyroxine (TT4), thyroxine binding globulin (TBG), and thyroglobulin (Tg) levels were analyzed with four different platforms: Abbott Architect, Roche Cobas 6000, Siemens IMMULITE 2000, and liquid chromatography with tandem mass spectrometry (LC-MS/MS). TSH, fT3, fT4, TT3, and TT4 were measured with Abbott Architect and Roche Cobas 6000. fT3, fT4, TT3, and TT4 were also measured by LC-MS/MS. Tg was measured by Siemens IMMULITE 2000. TBG was assessed with Siemens IMMULITE 2000. Results: Significant changes in TSH, fT4, and TT3 measurements were observed after biotin exposure when the Roche Cobas 6000 platform was used. Biotin intake resulted in a falsely lower Tg level when measurements were performed with Siemens IMMULITE 2000. At the time points examined, maximal biotin interference was observed two hours after biotin exposure both on day 1 and day 8. Conclusions: A daily dose of 10 mg was shown to interfere with specific assays for TSH, fT4, TT3, and Tg. Physicians must be aware of the potential risk of erroneous test results in subjects taking biotin supplements. Altered test results for TSH and Tg can be particularly problematic in patients requiring careful titration of levothyroxine therapy such as those with thyroid cancer.

Racial disparities in immune-related adverse events of immune checkpoint inhibitors and association with survival based on clinical and biochemical responses.

BACKGROUND: Immune checkpoint inhibitors (ICPi) cause various immune-related adverse events (irAE) with thyroid dysfunction as a commonly reported abnormality. There is increasing evidence showing positive association with development of irAE and survival. However, prior trials with ICPi had underrepresentation of minorities with < 5% African Americans. AIM: To evaluate the association between development of irAE and survival outcomes among a racially diverse patient population. METHODS: Data on patients with stage IV solid malignancies treated with programmed cell death-protein 1/programmed death ligand 1 blockers between January 2013 and December 2018 across MedStar Georgetown Cancer Institute facilities were retrospectively reviewed. Patients treated with cytotoxic T-lymphocyte-associated protein 4 inhibitors were excluded. Progression free survival (PFS) and overall survival (OS) were primary endpoints and were calculated using Kaplan-Meier methods and Wilcoxon rank sum test for comparison. RESULTS: Out of 293 patients who met eligibility criteria, 91 pts (31%) had any grade irAE; most common AE were endocrine (40.7%) specifically TSH elevation, dermatological (23.1%) and rheumatologic (18.7%). Proportion of irAE was significantly higher in Caucasians vs African Americans (60.4% vs 30.8%), in patients with low programmed death ligand 1, lower LDH, older age, and those who had more treatment cycles with ICPi. Rate of progression was lower in patients with irAE (30.8% vs 46.0%, P = 0.0140). Median PFS (5.8 vs 3.0 mo, P = 0.0204) and OS (17.1 vs 7.2 mo, P < 0.0001) were higher with irAE. Statistically significant difference in OS (17.1 vs 8.6 mo, P = 0.0002) but not in PFS (5.8 vs 3.3 mo, P = 0.0545) was noted with endocrine irAE. No differences in survival were observed among other commonly reported irAE. Differences in survival among subgroups of patients with irAE are described. CONCLUSION: Development of irAE positively correlated with improved PFS and OS as reported in previous studies. To our knowledge, this is the first study observing differences in OS favoring endocrine AE and Caucasian race. These factors may be potential surrogate markers of prognosis pending replication of these results in large-scale studies.

Do Molecular Profiles of Primary Versus Metastatic Radioiodine Refractory Differentiated Thyroid Cancer Differ?

Management of metastatic radioiodine refractory differentiated thyroid cancer (DTC) can be a therapeutic challenge. Generally, little is known about the paired molecular profile of the primary tumor and the metastases and whether they harbor the same genetic abnormalities. The present study compared the molecular profile of paired tumor specimens (primary tumor/metastatic sites) from patients with radioiodine refractory DTC in order to gain insight into a possible basis for resistance to radioiodine. Twelve patients with radioiodine refractory metastases were studied; median age at diagnosis of 61 years (range, 25-82). Nine patients had papillary TC (PTC), one had follicular TC (FTC), and two had Hürthle cell TC (HTC). Distant metastases were present in the lungs (n = 10), bones (n = 4), and liver (n = 1). The molecular profiling of paired tumors was performed with a panel of 592 genes for Next Generation Sequencing, RNA-sequencing, and immunohistochemistry. Digital microfluidic PCR was used to investigate TERT promoter mutations. The genetic landscape of all paired sites comprised BRAF, NRAS, HRAS, TP53, ATM, MUTYH, POLE, and NTRK genes, including BRAF and NTRK fusions. BRAF V600E was the most common point mutation in the paired specimens (5/12). TERT promoter mutation C228T was detected in one case. PD-L1 expression at metastatic sites was highly positive (95%) for one patient with HTC. All specimens were stable for microsatellite instability testing, and the tumor mutation burden was low to intermediate. Therefore, the molecular profile of DTC primary and metastatic lesions can show heterogeneity, which may help explain some altered responses to therapeutic intervention.

Synergistic effect of serine protease inhibitors and a bothropic antivenom in reducing local hemorrhage and coagulopathy caused by Bothrops jararaca venom

Snakebite accidents are a public health problem that affects the whole world, causing thousands of deaths and amputations each year. In Brazil, snakebite envenomations are caused mostly by snakes from the Bothrops genus. The local symptoms are characterized by pain, swelling, ecchymosis, and hemorrhages. Systemic disturbances can lead to necrosis and amputations. The present treatment consists of intravenous administration of bothropic antivenom, which is capable of reversing most of the systemic symptoms, while presenting limitations to treat the local effects, such as hemorrhage and to neutralize the snake venom serine protease (SVSP). In this context, we aimed to evaluate the activity of selective serine protease inhibitors (pepC and pepB) in combination with the bothropic antivenom in vivo. Further, we assessed their possible synergistic effect in the treatment of coagulopathy and hemorrhage induced by Bothrops jararaca venom. For this, we evaluated the in vivo activity in mouse models of local hemorrhage and a series of in vitro hemostasis assays. Our results showed that pepC and pepB, when combinated with the antivenom, increase its protective activity in vivo and decrease the hemostatic disturbances in vitro with high selectivity, possibly by inhibiting botropic proteases. These data suggest that the addition of serine protease inhibitor to the antivenom can improve its overall potential.