Lung Cavities in Chronic Thromboembolic Pulmonary Hypertension

OBJECTIVES: Chronic thromboembolic pulmonary hypertension (CTEPH) is a unique form of pulmonary hypertension (PH) that arises from obstruction of the pulmonary vessels by recanalized thromboembolic material. CTEPH has a wide range of radiologic presentations. Commonly, it presents as main pulmonary artery enlargement, peripheral vascular obstructions, bronchial artery dilations, and mosaic attenuation patterns. Nevertheless, other uncommon presentations have been described, such as lung cavities. These lesions may be solely related to chronic lung parenchyma ischemia but may also be a consequence of concomitant chronic infectious conditions. The objective of this study was to evaluate the different etiologies that cause lung cavities in CTEPH patients. METHODS: A retrospective data analysis of the medical records of CTEPH patients in a single reference PH center that contained or mentioned lung cavities was conducted between 2013 and 2016. RESULTS: Seven CTEPH patients with lung cavities were identified. The cavities had different sizes, locations, and wall thicknesses. In two patients, the cavities were attributed to pulmonary infarction; in 5 patients, an infectious etiology was identified. CONCLUSION: Despite the possibility of being solely associated with chronic lung parenchyma ischemia, most cases of lung cavities in CTEPH patients were associated with chronic granulomatous diseases, reinforcing the need for active investigation of infectious agents in this setting

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: Analysis by the Pharmachild Safety Adjudication Committee

Background: To derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC). Methods: The SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI. Results: A total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI. Conclusions: We found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies. Trial registration: Clinicaltrials.gov NCT 01399281; ENCePP seal: awarded on 25 November 2011

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Pulmonary scintigraphy inhalation and perfusion study in patients with granulomatosis with poliangiitis in remission phase

Embora a literatura médica relate eventos tromboembólicos em pacientes com Granulomatose com Poliangeíte (GPA), as diversas alterações parenquimatosas pulmonares e vasculares da doença ainda são pouco conhecidas. Este estudo consistiu em uma análise prospectiva de pacientes com diagnóstico de Granulomatose com Poliangeíte acompanhados no ambulatório de vasculites da Disciplina de Pneumologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, em fase de remissão da doença. Os pacientes realizaram exame de cintilografia de inalação e perfusão pulmonar e tomografia computadorizada de tórax de alta resolução, para verificação de possíveis alterações de ventilação e perfusão pulmonar nos lobos e segmentos e a correlação com alterações parenquimatosas da tomografia torácica. Dezessete de 38 pacientes (44%) apresentaram alterações perfusionais demonstrado pelo exame de cintilografia de perfusão. Entre os dezessete pacientes com alteração de perfusão, seis (35.3%) não possuíam alteração em cintilografia de inalação (grupo mismatch) caracterizando uma alteração vascular isolada, neste grupo o segmento mais acometido foi o segmento apico-posterior do lobo superior esquerdo (X2 [2] = 3.996; p= 0.046). Onze dos dezessete pacientes com alteração de perfusão pulmonar (64.7%) possuíam concomitantemente alteração na fase de inalação pulmonar (grupo match). Este grupo apresentou maior número de alterações parenquimatosas pulmonares em relação ao grupo mismatch (U = 82,000; p = 0.046), e as alterações do grupo match foram detectadas principalmente no lobo superior direito (X2 [2] =4.898; p = 0.027)Athough the medical literature reports thromboembolic events in Granulomatous with polyangiitis (GPA) patients, pulmonary parenchymal and vascular alterations of the disease are still poorly understand. This study consisted of a prospective analysis of patients diagnosed with Granulomatosis with Polyangiitis, in the remission phase of the Disease, followed at the vasculitis outpatient clinic of the Pulmonology Department of the Hospital das Clínicas of the Medical School of the University of São Paulo. Patients underwent pulmonary inhalation and perfusion scintigraphy and high-resolution chest tomography to identify possible alterations in ventilation and pulmonary perfusion in the pulmonary lobes and segments, as well as the correlation with parenchymal changes in the chest tomography. Seventeen out of 38 patients (44%) presented perfusion alterations demonstrated by the perfusion scintigraphy exam. Among the seventeen patients with perfusion alteration, six (35.3%) had no alteration in inhalation scintigraphy (mismatch group) characterizing an isolated vascular alteration. In this group, the most affected segment was the apico-posterior segment of the left upper lobe (X2 [2] = 3,996; p = 0.046). Eleven of the seventeen patients with altered pulmonary perfusion (64.7%) had concomitant alterations in the pulmonary inhalation phase (match group). This group had a higher number of pulmonary parenchymal sequelae comparing to the mismatch group (U = 82,000; p = 0.046), and the findings in the match group were detected mainly in the right upper lobe (X2 [2] = 4,898; p = 0.027

A rodent model of NASH with cirrhosis, oval cell proliferation and hepatocellular carcinoma

Background/Aims: Hepatocellular carcinoma (HCC) is a well recognized complication of advanced NASH (non-alcoholic steatohepatitis). We sought to produce a rat model of NASH, cirrhosis and HCC. Methods: Adult Sprague-Dawley rats, weighing 250-300 g, were fed a choline-deficient, high trans-fat diet and exposed to DEN in drinking water. After 16 weeks, the animals underwent liver ultrasound (US), sacrifice and assessment by microscopy, immunohistochemistry and transmission electron microscopy (TEM). Results: US revealed steatosis and focal lesions in 6 of 7. All had steatohepatitis defined as inflammation, advanced fibrosis and ballooning with Mallory-Denk bodies (MDB) with frank cirrhosis in 6. Areas of more severe injury were associated with anti-CK19 positive ductular reaction. HCC, present in all, were macro-trabecullar or solid with polyhedral cells with foci of steatosis and ballooned cells. CK19 was positive in single or solid nests of oval cells and in neoplastic hepatocytes. TEM showed ballooning with small droplet fat, dilated endoplasmic reticulum and MDB in non-neoplastic hepatocytes and small droplet steatosis in some cancer cells. Conclusions: This model replicated many features of NASH including steatohepatitis with ballooning, fibrosis, cirrhosis and hepatocellular carcinoma. Oval cell proliferation was evident and the presence anti-CK 19 positivity in the cancer suggests oval cell origin of the malignancy. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Alves Queiroz Family Fund for Research in Sao PauloThe University of Virginia Cancer Center, Commonwealth Cancer FoundationMr. Jack P Chamber