Classic cardiovascular risk factors improve in very elderly hypopituitary patients treated on standard hormone replacement in long term follow-up

Background - Hypopituitarism in the elderly population is an underdiagnosed condition and may increase comorbidities related to glucose metabolism, dyslipidemia, and cardiovascular risk factors. Optimization of hormone replacement that considers alterations in clearance rates of hormones, interaction with other medications, and evaluation of the risk-benefit ratio of treatment is a big challenge for clinical practice. Objectives - This study aimed to evaluate classic cardiovascular risk factors in hypopituitary septuagenarians and octagenarians by diagnosis and after long-term hormone replacement. Methods - This is a retrospective observational study, with patients recruited and selected from a registry in a tertiary medical center. We included patients aged 70–99 years with hypopituitarism, evaluated hormonal and biochemical parameters, and cardiovascular risk scores were calculated by diagnosis and compared after long-term follow-up. All patients gave informed consent. Patient data were compared to a sex and age-matched control group, with long-term geriatric follow-up, without endocrine diseases. Results - Thirty-five patients were included, 16 patients aged 70–75 years (72.61), 12 patients 76–80 years (72.28), 7 patients 81–99 years (89.28). Pituitary macroadenomas were the main cause of hypopituitarism, mean maximal diameter 3.4 cm (2.9–4.3), and invasive craniopharyngiomas. At the moment of diagnosis, most patients were overweight, and abdominal adiposity was observed in 76.9% of women and 36.4% of men, primarily in octagenarians and nonagenarians. Comorbidities were frequent; 85.7% presented hypertension, 37.1% diabetes, 53.1% low HDL, 51.5% hypertriglyceridemia. Most patients presented more than two combined pituitary deficiencies; hypogonadism in 88.6%, central hypothyroidism in 82.9%, GH deficiency in 65.7%, and adrenal insufficiency in 25.7%. Analysis of cardiovascular risk prediction in the total cohort showed that 57.1% of patients presented a reduction in the General Cardiovascular Disease (CVD) Risk Prediction Score and 45.7% in atherosclerotic CVD risk estimated by ACC/AHA 2013 Pooled Cohort Equation, despite being submitted to conventional hormone replacement, during the mean follow-up of 14.5 years. This reduction was not observed in the control group. Discussion and conclusion - In this study, aged hypopituitary patients presented a reduction in estimated general CVD risk during long-term follow-up, despite replacement with corticosteroids, levothyroxine, or gonadal steroids. Early diagnosis and treatment of hypopituitarism in the elderly remain challenging. Larger studies should be performed to assess the risk-benefit ratio of hormone replacement on the metabolic profile in septuagenarian and octogenarian patients

Molecular and cellular biomarkers of COVID-19 prognosis : protocol for the prospective cohort TARGET study

Background: Since the beginning of the COVID-19 pandemic, the world’s attention has been focused on better understanding the relation between the human host and the SARS-CoV-2 virus, as its action has led to hundreds of thousands of deaths. Objective: In this context, we decided to study certain consequences of the abundant cytokine release over the innate and adaptive immune systems, inflammation, and hemostasis, comparing mild and severe forms of COVID-19. Methods: To accomplish these aims, we will analyze demographic characteristics, biochemical tests, immune biomarkers, leukocyte phenotyping, immunoglobulin profile, hormonal release (cortisol and prolactin), gene expression, thromboelastometry, neutralizing antibodies, metabolic profile, and neutrophil function (reactive oxygen species production, neutrophil extracellular trap production, phagocytosis, migration, gene expression, and proteomics). A total of 200 reverse transcription polymerase chain reaction–confirmed patients will be enrolled and divided into two groups: mild/moderate or severe/critical forms of COVID-19. Blood samples will be collected at different times: at inclusion and after 9 and 18 days, with an additional 3-day sample for severe patients. We believe that this information will provide more knowledge for future studies that will provide more robust and useful clinical information that may allow for better decisions at the front lines of health care. Results: The recruitment began in June 2020 and is still in progress. It is expected to continue until February 2021. Data analysis is scheduled to start after all data have been collected. The coagulation study branch is complete and is already in the analysis phase

Panoramic snapshot of serum soluble mediator interplay in pregnant women with convalescent COVID-19: an exploratory study

IntroductionSARS-CoV-2 infection during pregnancy can induce changes in the maternal immune response, with effects on pregnancy outcome and offspring. This is a cross-sectional observational study designed to characterize the immunological status of pregnant women with convalescent COVID-19 at distinct pregnancy trimesters. The study focused on providing a clear snapshot of the interplay among serum soluble mediators.MethodsA sample of 141 pregnant women from all prenatal periods (1st, 2nd and 3rd trimesters) comprised patients with convalescent SARS-CoV-2 infection at 3-20 weeks after symptoms onset (COVID, n=89) and a control group of pre-pandemic non-infected pregnant women (HC, n=52). Chemokine, pro-inflammatory/regulatory cytokine and growth factor levels were quantified by a high-throughput microbeads array.ResultsIn the HC group, most serum soluble mediators progressively decreased towards the 2nd and 3rd trimesters of pregnancy, while higher chemokine, cytokine and growth factor levels were observed in the COVID patient group. Serum soluble mediator signatures and heatmap analysis pointed out that the major increase observed in the COVID group related to pro-inflammatory cytokines (IL-6, TNF-α, IL-12, IFN-γ and IL-17). A larger set of biomarkers displayed an increased COVID/HC ratio towards the 2nd (3x increase) and the 3rd (3x to 15x increase) trimesters. Integrative network analysis demonstrated that HC pregnancy evolves with decreasing connectivity between pairs of serum soluble mediators towards the 3rd trimester. Although the COVID group exhibited a similar profile, the number of connections was remarkably lower throughout the pregnancy. Meanwhile, IL-1Ra, IL-10 and GM-CSF presented a preserved number of correlations (≥5 strong correlations in HC and COVID), IL-17, FGF-basic and VEGF lost connectivity throughout the pregnancy. IL-6 and CXCL8 were included in a set of acquired attributes, named COVID-selective (≥5 strong correlations in COVID and <5 in HC) observed at the 3rd pregnancy trimester.Discussion and conclusionFrom an overall perspective, a pronounced increase in serum levels of soluble mediators with decreased network interplay between them demonstrated an imbalanced immune response in convalescent COVID-19 infection during pregnancy that may contribute to the management of, or indeed recovery from, late complications in the post-symptomatic phase of the SARS-CoV-2 infection in pregnant women

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Functional and phenotypic characteristics modifications in high-density lipoprotein (HDL) during acute phase of myocardial infarction

Orientador: Andrei Carvalho SpositoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: INTRODUÇÃO: Apesar dos avanços terapêuticos, o infarto do miocárdio (IM) ainda é uma das maiores causas de mortalidade global. A injúria miocárdica após reperfusão é responsável por aproximadamente 50% da massa infartada. A lipoproteína de alta densidade (HDL) é candidata potencial para atenuar lesão de isquemia/reperfusão (I/R) por meio de diversas vias de sinalização. Entretanto, durante o IM, a captura de moléculas oxidadas e pró-inflamatórias gera mudanças fenotípicas e funcionais profundas na HDL. Múltiplos aspectos e implicações da relação recíproca entre HDL e IM necessitam de investigação. O primeiro capítulo da Tese objetivou investigar se na fase agudo do IM, a transferência de lípides para HDL de outras lipoproteínas e células é alterada. No segundo, a presença de interação entre HDL-C e massa infartada no IM com supradesnivelamento do segmento-ST (IMCSST), além da necessidade de reperfusão coronária para essa interação, foram investigas. Depois, verificou-se se o efeito cardioprotetor é diferente entre HDL de paciente infartados e voluntários saudáveis. MÉTODOS: Primeiro, as seguintes medidas relacionadas à HDL foram determinadas na admissão (D1) e no quinto dia (D5) em 41 pacientes pós-IMCSST: proteína C-reativa (PCR), atividade de CETP e PLTP, composição da HDL, efluxo de colesterol de macrófagos J774, e transferência de colesterol livre e esterificado, triglicérides e fosfolípides de nanoemulsão doadora para HDL. No segundo capítulo, HDL-C foi medido no D1 e a massa infartada foi quantificada por ressonância magnética cardíaca (n=94) e pelo pico de CKMB (n=393). Em modelo de coração de rato ex-vivo, comparou-se área infartada e a dP/dt máxima após reperfusão coronária com HDL de pacientes infartados e voluntários saudáveis. RESULTADOS: Do D1 para o D5, a atividade de CETP diminuiu em 25%, mas a atividade de PLTP não mudou. O conteúdo de colesterol éster (-23%) e fosfolípides (-9,5%) na HDL reduziu. A transferência de triglicérides (-36,5%) e colesterol éster (-14,7%) para HDL das nanoemulsões diminuiu, assim como o efluxo celular de colesterol (-8,5%) (p=0,04). A redução do efluxo foi mais pronunciada nos pacientes acima do p75 de PCR. Em geral, HDL-C acima da mediana (35 mg/dL) se associou com maiores níveis de CKMB [255(145-415) vs. 136(84-287)UI/L; p=0,02], maior massa infartada [17(9-21) vs. 10(6-14)g; p<0,01] e menor fração de ejeção [51(43-59)vs. 47(34-53);p=0,02] do que sua contraparte. Em restricted cubic spline e regressão linear multivariada, o HDL-C foi diretamente associado com o pico de CKMB (p<0,01) e massa infartada (p<0,01) apenas nos pacientes reperfundidos até 4 horas. Reperfusão com HDL saudável, mas não HDL de pacientes infartados, reduziu a massa infartada (p<0,01) e aumentou dP/dt máxima (p=0,02) em modelo animal. CONCLUSÕES: Após IM, uma redução simultânea da transferência de lípides e da capacidade da HDL em promover efluxo de colesterol de células ocorre. Nos pacientes infartados submetidos a reperfusão coronária precoce, níveis de HDL-C na admissão estão diretamente associados com tamanho do IM. Contrariamente à HDL saudável, a reperfusão com HDL de pacientes infartados não reduz área de IM em modelo animal ex-vivo. O sistema HDL gerado após IM é disfuncional impedindo suas potenciais ações benéficas na reperfusãoAbstract: INTRODUÇÃO: Apesar dos avanços terapêuticos, o infarto do miocárdio (IM) ainda é uma das maiores causas de mortalidade global. A injúria miocárdica após reperfusão é responsável por aproximadamente 50% da massa infartada. A lipoproteína de alta densidade (HDL) é candidata potencial para atenuar lesão de isquemia/reperfusão (I/R) por meio de diversas vias de sinalização. Entretanto, durante o IM, a captura de moléculas oxidadas e pró-inflamatórias gera mudanças fenotípicas e funcionais profundas na HDL. Múltiplos aspectos e implicações da relação recíproca entre HDL e IM necessitam de investigação. O primeiro capítulo da Tese objetivou investigar se na fase agudo do IM, a transferência de lípides para HDL de outras lipoproteínas e células é alterada. No segundo, a presença de interação entre HDL-C e massa infartada no IM com supradesnivelamento do segmento-ST (IMCSST), além da necessidade de reperfusão coronária para essa interação, foram investigas. Depois, verificou-se se o efeito cardioprotetor é diferente entre HDL de paciente infartados e voluntários saudáveis. MÉTODOS: Primeiro, as seguintes medidas relacionadas à HDL foram determinadas na admissão (D1) e no quinto dia (D5) em 41 pacientes pós-IMCSST: proteína C-reativa (PCR), atividade de CETP e PLTP, composição da HDL, efluxo de colesterol de macrófagos J774, e transferência de colesterol livre e esterificado, triglicérides e fosfolípides de nanoemulsão doadora para HDL. No segundo capítulo, HDL-C foi medido no D1 e a massa infartada foi quantificada por ressonância magnética cardíaca (n=94) e pelo pico de CKMB (n=393). Em modelo de coração de rato ex-vivo, comparou-se área infartada e a dP/dt máxima após reperfusão coronária com HDL de pacientes infartados e voluntários saudáveis. RESULTADOS: Do D1 para o D5, a atividade de CETP diminuiu em 25%, mas a atividade de PLTP não mudou. O conteúdo de colesterol éster (-23%) e fosfolípides (-9,5%) na HDL reduziu. A transferência de triglicérides (-36,5%) e colesterol éster (-14,7%) para HDL das nanoemulsões diminuiu, assim como o efluxo celular de colesterol (-8,5%) (p=0,04). A redução do efluxo foi mais pronunciada nos pacientes acima do p75 de PCR. Em geral, HDL-C acima da mediana (35 mg/dL) se associou com maiores níveis de CKMB [255(145-415) vs. 136(84-287)UI/L; p=0,02], maior massa infartada [17(9-21) vs. 10(6-14)g; p<0,01] e menor fração de ejeção [51(43-59)vs. 47(34-53);p=0,02] do que sua contraparte. Em restricted cubic spline e regressão linear multivariada, o HDL-C foi diretamente associado com o pico de CKMB (p<0,01) e massa infartada (p<0,01) apenas nos pacientes reperfundidos até 4 horas. Reperfusão com HDL saudável, mas não HDL de pacientes infartados, reduziu a massa infartada (p<0,01) e aumentou dP/dt máxima (p=0,02) em modelo animal. CONCLUSÕES: Após IM, uma redução simultânea da transferência de lípides e da capacidade da HDL em promover efluxo de colesterol de células ocorre. Nos pacientes infartados submetidos a reperfusão coronária precoce, níveis de HDL-C na admissão estão diretamente associados com tamanho do IM. Contrariamente à HDL saudável, a reperfusão com HDL de pacientes infartados não reduz área de IM em modelo animal ex-vivo. O sistema HDL gerado após IM é disfuncional impedindo suas potenciais ações benéficas na reperfusãoDoutoradoPesquisa ClínicaDoutor em Ciências Médicas01-P-1740772/201714/03742-0CAPESFAPES

Altered structural connectivity in olfactory disfunction after mild COVID-19 using probabilistic tractography

Abstract We aimed to investigate changes in olfactory bulb volume and brain network in the white matter (WM) in patients with persistent olfactory disfunction (OD) following COVID-19. A cross-sectional study evaluated 38 participants with OD after mild COVID-19 and 24 controls, including Sniffin' Sticks identification test (SS-16), MoCA, and brain magnetic resonance imaging. Network-Based Statistics (NBS) and graph theoretical analysis were used to explore the WM. The COVID-19 group had reduced olfactory bulb volume compared to controls. In NBS, COVID-19 patients showed increased structural connectivity in a subnetwork comprising parietal brain regions. Regarding global network topological properties, patients exhibited lower global and local efficiency and higher assortativity than controls. Concerning local network topological properties, patients had reduced local efficiency (left lateral orbital gyrus and pallidum), increased clustering (left lateral orbital gyrus), increased nodal strength (right anterior orbital gyrus), and reduced nodal strength (left amygdala). SS-16 test score was negatively correlated with clustering of whole-brain WM in the COVID-19 group. Thus, patients with OD after COVID-19 had relevant WM network dysfunction with increased connectivity in the parietal sensory cortex. Reduced integration and increased segregation are observed within olfactory-related brain areas might be due to compensatory plasticity mechanisms devoted to recovering olfactory function

Pregnancy outcomes and child development effects of SARS-CoV-2 Infection (PROUDEST Trial) : protocol for a multicenter, prospective cohort study

Background: A growing body of evidence suggests that SARS-COV-2 infection during pregnancy may affect maternal-fetal outcomes and possibly result in implications for the long-term development of SARSCoV-2–exposed children. Objective: The PROUDEST (Pregnancy Outcomes and Child Development Effects of SARS-CoV-2 Infection Study) is a multicenter, prospective cohort study designed to elucidate the repercussions of COVID19 for the global health of mothers and their children. Methods: The PROUDEST trial comprises 2 prospective, sequential substudies. The PREGNANT substudy will clinically assess the effects of SARS-CoV-2 infection on pregnancy, childbirth, and puerperium from a mechanistic standpoint to elucidate the pregnancy-related inflammatory and immunological phenomena underlying COVID-19. Pregnant women aged 18-40 years who have been exposed (proven with laboratory tests) to SARS-CoV-2 (group A; n=300) will be compared to control subjects with no laboratory evidence of in-pregnancy exposure to the virus (group B; n=300). Subjects exposed to other infections during pregnancy will be excluded. The BORN substudy is a long-term follow-up study that will assess the offspring of women who enrolled in the prior substudy. It will describe the effects of SARS-CoV-2 exposure during pregnancy on children’s growth, neurodevelopment, and metabolism from birth up to 5 years of age. It includes two comparison groups; group A (exposed; n=300) comprises children born from SARS-CoV-2– exposed pregnancies, and group B (controls; n=300) comprises children born from nonexposed mothers. Results: Recruitment began in July 2020, and as of January 2021, 260 pregnant women who were infected with SARS-CoV-2 during pregnancy and 160 newborns have been included in the study. Data analysis is scheduled to start after all data are collected. Conclusions: Upon completion of the study, we expect to have comprehensive data that will provide a better understanding of the effects of SARS-CoV-2 infection and related inflammatory and immunological processes on pregnancy, puerperium, and infancy. Our findings will inform clinical decisions regarding the care of SARS-CoV-2–exposed mothers and children and support the development of evidence-based public health policies.Faculdade de Medicina (FMD)Faculdade UnB Ceilândia (FCE

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially