The impact of nintedanib and pirfenidone on lung function and survival in patients with idiopathic pulmonary fibrosis in real-life setting.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing interstitial pneumonia of unknown cause that is associated with radiological and/or histological features of usual interstitial pneumonia (UIP). A mean survival of 2-5 years was reported previously to the advent of antifibrotics. According to clinical trials, nintedanib and pirfenidone induce a significant delay in functional decline, with a favorable impact on survival. METHODS: A real-life retrospective and longitudinal study was conducted to assess the efficacy and tolerability of antifibrotics in IPF patients, between January 2014 and December 2020. Two groups (under nintedanib or pirfenidone) were analyzed at diagnosis through their clinical features and radiological patterns. Lung function was assessed at diagnosis (time 0) and after 6, 12 and 24 months of treatment. We also compared this antifibrotic cohort with an older naïve antifibrotic cohort, mainly treated with immunosuppressive drugs and/or N- acetylcysteine. Survival was analyzed and prognostic features were also studied. Statistical analysis was performed with IBM® SPSS®. RESULTS: A cohort of 108 patients under antifibrotics (nintedanib n = 54; pirfenidone n = 54) was assessed. Lung function analysis showed an overall stabilization in FVC and DLCO mean predicted percentages at 6, 12 and 24 months of treatment. The mean decline in FVC and DLCO, at 12 months, was -40.95 ± 438.26 mL and -0.626 ± 1.31 mL/min/mmHg, respectively. However, during this period, 34.2% of the patients died mostly due to acute exacerbation associated with a poorer lung function at diagnosis. Mean survival in the naïve antifibrotic cohort was significantly lower than in the antifibrotic cohort (39.9 months versus 58.2 months; p < 0.005). Regarding lung function evolution and survival, we found no differences between definitive or probable UIP radiological patterns, both on patients under nintedanib and pirfenidone (p = 0.656). CONCLUSIONS: In this real-life observational study, the positive impact of antifibrotic therapy on the IPF clinical course and on survival was corroborated. Regarding efficacy, there was no difference between patients taking nintedanib or pirfenidone. The need for an early treatment was also demonstrated, since a worse outcome is clearly associated with lower lung volumes and lower diffusing capacity at diagnosis.

The Role of Ultrasonography in the Diagnosis and Decision Algorithm for the Management of Pneumothorax after Transbronchial Lung Cryobiopsy.

BACKGROUND: Pneumothorax is one of the main complications of transbronchial lung cryobiopsy (TBLC). Chest ultrasound (CUS) is a radiation-free alternative method for pneumothorax detection. OBJECTIVE: We tested CUS diagnostic accuracy for pneumothorax and assessed its role in the decision algorithm for pneumothorax management. Secondary objectives were to evaluate the post-procedure pneumothorax occurrence and risk factors. METHODS: Eligible patients underwent TBLC, followed by chest X-ray (CXR) evaluation 2 h after the procedure, as our standard protocol. Bedside CUS was performed within 30 min and 2 h after TBLC. Pneumothorax by CUS was defined by the absence of lung sliding and comet-tail artefacts and confirmed with the stratosphere sign on M-mode. Pneumothorax size was determined through lung point projection on CUS and interpleural distance on CXR and properly managed according to clinical status. RESULTS: Sixty-seven patients were included. Nineteen pneumothoraces were detected at 2 h after the procedure, of which 8 (42.1%) were already present at the first CUS evaluation. All CXR-detected pneumothoraces had a positive CUS detection. There were 3 discordant cases (κ = 0.88, 95% CI: 0.76-1.00, p < 0.001), which were detected by CUS but not by inspiration CXR. We calculated a specificity of 97.5% (95% CI: 86.8-99.9) and a sensitivity of 100% (95% CI: 87.2-100) for CUS. Pneumothorax rate was higher when biopsies were taken in 2 lobes and if histology had pleural representation. Final diagnosis was achieved in 79.1% of patients, with the most frequent diagnosis being hypersensitivity pneumonitis. Regarding patients with large-volume pneumothorax needing drainage, the rate of detection was similar between CUS and CRX. CONCLUSION: CUS can replace CXR in detecting the presence of pneumothorax after TBLC, and the lung point site can reliably indicate its size. This useful method optimizes time spent at the bronchology unit and allows immediate response in symptomatic patients, helping to choose optimal treatment strategies, while preventing ionizing radiation exposure.

Impact of Azathioprine use in chronic hypersensitivity pneumonitis patients.

INTRODUCTION: Systemic corticosteroids are widely used in chronic hypersensitivity pneumonitis (CHP); however, there is not much evidence to support their use, besides being associated with significant side effects. Azathioprine (AZA) use is common in CHP, although not prospectively tested in randomized controlled trials. Our objective was to evaluate the lung function trajectory of CHP patients after AZA initiation, as well as to assess the safety profile of this drug. METHODS: Retrospective analysis of patients initiated on AZA following a multidisciplinary team diagnosis of CHP. The longitudinal trajectory of lung function in the first 2 years of treatment was assessed. RESULTS: Thirty-five out of 62 patients (56.5%) remained on treatment after 2 years. AZA treatment was associated with a significant improvement in forced vital capacity (FVC) at 12 and 24 months (p = 0.015 and p < 0.001, respectively). A slight increase in total lung capacity (TLC) and 6-min walking test (6MWT) were also reported, although it did not reach statistical differences at the end of 2 years. No changes in diffusion capacity for carbon monoxide (DLCO) were observed. CONCLUSIONS: This is the first study identifying an improvement in lung function (FVC) of CHP patients on AZA treatment for 2 years. Prospective studies are needed to confirm these results and to more adequately select CHP patients who may benefit from AZA.

Collagen I and collagen III polymorphisms in women with pelvic organ prolapse.

AIMS: Verify the presence of the single nucleotide polymorphisms rs1800012 of the collagen I (COL1A1) and rs1800255 of the collagen III (COL3A1) genes and their association with pelvic organ prolapse (POP) in Brazilian women and to determine risk factors for POP. METHODS: We assessed 826 postmenopausal women divided into POP (stages III and IV) and control groups (stages 0 and I) by examination and peripheral blood sample collection. DNA sequences of interest were analyzed by real-time reverse-transcriptase polymerase chain reaction. We used logistic regression analyses, recessive and codominance models of inheritance, and P < .05 for significance. RESULTS: Six-hundred and thirty-four postmenopausal women were included: 348 (54.8%) POP cases and 286 (45.1%) controls. The frequencies of GG, GA, and AA genotypes for COL1A1 were 69.12%, 20.24%, and 10.59% in POP group and 71.79%, 20%, and 8.21% in controls; GG, GT, and TT for COL3A1 were 37.54%, 59.53%, and 2.93% in POP group and 36.24%, 60.14%, and 3.62% in controls. There were no genotypic or allelic association with POP phenotype that link both SNPs rs1800012 and rs1800255 to increased risk of POP. Vaginal delivery (odds ratio [OR] = 13; 95% confidence interval [CI] [4.00-47.08]), POP family history (OR = 3.1; 95% CI [1.49-6.50]), diabetes mellitus (OR = 2.3; 95% CI [1.08-5.21]), number of pregnancies (OR = 1.2; 95% CI [1.05-1.36]), and age (OR = 1.1; 95% CI [1.09-1.19]), were variables of increased risk for POP (P < .05 for all). CONCLUSION: Our study suggests lack of association between DNA polymorphisms rs1800012 of COL1A1 and rs1800255 of COL3A1 with advanced POP. Vaginal delivery, POP family history, diabetes mellitus, number of pregnancies, and age are risk factors for POP.

Virulence-Related Genes and Coenteropathogens Associated with Clinical Outcomes of Enteropathogenic Escherichia coli Infections in Children from the Brazilian Semiarid Region: a Case-Control Study of Diarrhea.

Enteropathogenic Escherichia coli (EPEC) is a major cause of diarrhea in children from developing countries and presents high genetic variability. We aimed to characterize the EPEC virulence-related gene (VRG) distribution and copathogens associated with diarrhea and nutrition-related outcomes in children from the low-income Brazilian semiarid region. A cross-sectional case-control study of diarrhea was conducted in 1,191 children aged 2 to 36 months from the northeast region of Brazil. Stool samples were collected and clinical, epidemiological, and anthropometric data were identified from each child. A broad molecular evaluation of enteropathogens was performed, and EPEC-positive samples were further investigated for 18 VRGs using five multiplex PCRs. EPEC was detected in 28.2% of the study population, with similar proportions among cases and controls. Typical EPEC (tEPEC) infections were more often associated with diarrhea than atypical EPEC (aEPEC) infections, while aEPEC infections presented a higher prevalence. The VRG ler, a negative regulator of the locus of enterocyte effacement, was associated with the absence of diarrhea in aEPEC-positive children; espB, a major component of the type 3 secretion system, was associated with diarrhea in tEPEC-positive children; the presence of procolonization VRGs-the combination of cesT positivity, espP negativity, and the presence of the map gene-was associated with undernutrition; and Campylobacter spp., norovirus, and enteroaggregative E. coli (EAEC) coinfections were associated with increased clinical severity in EPEC-infected children. These data identified tEPEC strains associated with diarrhea and specific VRGs of EPEC (ler, espB, cesT, and map genes) and Campylobacter spp., norovirus, and EAEC to be major contributors to diarrhea and undernutrition in children from a low-income Brazilian region.

NK and NKT cells in the diagnosis of diffuse lung diseases presenting with a lymphocytic alveolitis.

BACKGROUND: Diffuse lung diseases (DLD) are characterized by different immunophenotypes in the bronchoalveolar lavage fluid (BALF). We aimed to evaluate the diagnostic value of BALF NK and NKT cell counts of patients with DLD and lymphocytic alveolitis. METHODS: We assessed 202 patients with DLD, who underwent BALF immunophenotyping. Samples were routinely processed by flow cytometry and lymphocyte subsets were compared between patients with sarcoidosis (n = 106), hypersensitivity pneumonitis (HP; n = 53), and other DLDs (n = 43). We compared absolute counts and percentages of NK and NKT cells between patients with HP versus the remaining DLD patients. To assess the accuracy of BALF lymphocyte subsets in the diagnosis of HP, we calculated the respective areas under the receiver operating characteristic curves (AUC-ROC). RESULTS: Patients with HP had significantly higher numbers of BALF NK cells, and its percentage was significantly associated with a higher odds of HP, even after adjustment for the NKT and CD8+ cells. For the absolute number of BALF NK cells, we found an AUC-ROC of 0.76 (95%CI = 0.68-0.84) when comparing patients with HP versus the remaining DLD. The cut-offs of 2000 NK cells/mL and of 2.4% NK cells in the BALF had a specificity and a negative predictive value over 80% for the diagnosis of HP. BALF NK cells absolute counts were significantly higher in HP patients with a restrictive pattern. No such differences were observed for NKT cells. CONCLUSIONS: BALF NK immunophenotyping may be a helpful adjunct to the diagnostic work-up of DLD, particularly in the differential diagnosis of HP.

Diagnostic Yield of Computed Tomography-Guided Transthoracic Lung Biopsy in Diffuse Lung Diseases.

BACKGROUND: Accurate diagnosis is essential for successful management of diffuse lung disease (DLD). Histopathology may sometimes be necessary. Surgical lung biopsy, the gold standard, carries a risk of morbidity and mortality. Computed tomography (CT) guided transthoracic lung biopsy (CT-TLB) is a minimally invasive method for obtaining lung tissue. However, its diagnostic yield is unknown in DLD. OBJECTIVE: To assess the diagnostic yield of CT-TLB in DLD according to the predominant high-resolution CT (HRCT) patterns. METHODS: Between January 2009 and December 2016, we enrolled all consecutive adult patients with suspicion of DLD who underwent CT-guided transthoracic lung biopsy during the diagnostic work-up. All biopsies were performed by a senior interventional radiologist using CT fluoroscopy. RESULTS: The study included 169 patients (50.3% men) with a mean (±SD) age of 58.3 ± 14 years. Consolidation was the predominant HRCT pattern. A definitive or probable diagnosis was made in 66.3%. The most frequent diagnosis was organizing pneumonia (36.2%). Diagnostic yield was higher when the predominant HRCT pattern was consolidation or nodular. The most common complication was pneumothorax (17.8%); other complications included mild hemoptysis (7.7%), hemothorax (1.2%), and death (0.59%). No acute exacerbation of the underlying condition was observed. CONCLUSIONS: CT-TLB proved to be accurate and safe for the diagnosis of DLD. The overall diagnostic yield of the procedure was 66.3%. Given its low complication rates, CT-TLB can be an option in patients whose respiratory function is seriously impaired and in those with substantial comorbidities, where more invasive procedures cannot be performed for reasons of safety.

Obstructive sleep apnoea in patients with fibrotic diffuse parenchymal lung disease-characterization and treatment compliance assessment.

INTRODUCTION: Recent studies have reported a high prevalence of obstructive sleep apnoea (OSA) among patients with diffuse parenchymal lung disease (DPLD), mainly idiopathic pulmonary fibrosis (IPF). Effective OSA treatment appears to have a positive impact on morbidity and mortality in these patients. However, poor compliance to positive airway pressure (PAP) treatment in fibrotic DPLD patients has been reported. The aims of our study were to characterize patients with fibrotic DPLD and OSA and to assess their compliance to PAP treatment. METHODS: Forty-nine patients with fibrotic DPLD underwent level III polysomnography. Auto-adjusting PAP (APAP) treatment was proposed for those patients with moderate-to-severe OSA and those with mild OSA with daytime sleepiness and/or cardiovascular disease. The APAP treatment compliance was assessed after 1 month of therapy. RESULTS: The distribution of the 49 fibrotic DPLD patients included was as follows: 21 with chronic hypersensitivity pneumonitis, 12 with IPF, 10 with connective-tissue associated DPLD, 4 with stage IV sarcoidosis, 1 with idiopathic pleuropulmonary fibroelastosis, and 1 with DPLD-associated vasculitis. Thirty-four (69.4%) of the patients presented with OSA; 22 had mild OSA, and 12 had moderate-to-severe OSA. APAP treatment was prescribed in 17 of the patients. After 1 month of therapy, all patients used APAP more than 70% of the nights for more than 4 h per night. CONCLUSION: We found a high prevalence of OSA among all of the patients with fibrotic DPLD (not only IPF). Despite certain difficulties, it was possible to achieve good APAP compliance in these patients.

Observation of interference effects via four-photon excitation of highly excited Rydberg states in thermal cesium vapor.

We report on the observation of electromagnetically induced transparency (EIT) and absorption (EIA) of highly excited Rydberg states in thermal Cs vapor using a four-step excitation scheme. The advantage of this four-step scheme is that the final transition to the Rydberg state has a large dipole moment and one can achieve similar Rabi frequencies to two- or three-step excitation schemes using two orders of magnitude less laser power. This scheme enables new applications such as dephasing free Rydberg excitation. The observed lineshapes are in good agreement with simulations based on multilevel optical Bloch equations.

Effects of a Bacillus-based direct-fed microbial on performance, blood parameters, fecal characteristics, rumen morphometrics, and intestinal gene expression in finishing beef bulls.

We evaluated the effects of supplementing direct fed microbials (DFM), containing Bacillus licheniformis and Bacillus subtilis, on performance, rumen morphometrics, intestinal gene expression, and blood and fecal parameters in finishing bulls. Nellore × Angus bulls (n = 144; initial BW = 401 ± 45.5 kg) were distributed at random in 36 pens (4 bulls/pen and 18 pens/treatment), following a completely randomized design. A ground corn-based finishing diet was offered for ad libitum intake twice a day for 84 days, containing the following treatments: (1) control (without DFM); (2) DFM (B. licheniformis and B. subtilis) at 6.4 × 109 CFU (2 g) per animal. The data were analyzed using the MIXED procedure of SAS, with a pen representing an experimental unit, the fixed effect of the treatment, and the random effect of pen nested within the treatment. For fecal parameters (two collections made), the collection effect and its interaction with the treatment was included in the model. Bulls that received the DFM had a decreased dry matter intake (P ≤ 0.01), did not differ in average daily gain (2.05 kg; P = 0.39), and had a 6% improvement in G:F (P = 0.05). The other performance variables, final BW, hot carcass weight, and hot carcass yield, did not differ (P > 0.10). Plasma urea-N concentration decreased by 6.2% (P = 0.02) in the bulls that received DFM. Glucose, haptoglobin, and lipopolysaccharides (LPS) were not different between treatments (P > 0.10). Ruminal morphometrics were not affected by the treatment (P > 0.10). The use of DFM tended to reduce fecal starch (P = 0.10). At slaughter, bulls fed DFM had an increased duodenal gene expression of tryptophan hydroxylase-1 (P = 0.02) and of superoxide dismutase-1 (P = 0.03). Overall, supplementation with DFM based on B. licheniformis and B. subtilis to Nellore × Angus bulls in the finishing phase decreased DMI, did not influence ADG, improved G:F, and increased the expression of genes important for duodenal function.

Using active learning strategies during a quality improvement collaborative: exploring educational games to enhance learning among healthcare professionals.

BACKGROUND: The Breakthrough Series model uses learning sessions (LS) to promote education, professional development and quality improvement (QI) in healthcare. Staff divergences regarding prior knowledge, previous experience, preferences and motivations make selecting which pedagogic strategies to use in LS a challenge. AIM: We aimed to assess new active-learning strategies: two educational games, a card game and an escape room-type game, for training in healthcare-associated infection prevention. METHODS: This descriptive case study evaluated the performance of educational strategies during a Collaborative to reduce healthcare-associated infections in Brazilian intensive care units (ICUs). A post-intervention survey was voluntarily offered to all participants in LS activities. RESULTS: Seven regional 2-day LS were held between October and December 2022 (six for adult ICUs and one for paediatric/neonatal ICUs). Of 194 institutions participating in a nationwide QI initiative, 193 (99.4%) participated in these activities, totalling 850 healthcare professionals. From these, 641 participants responded to the survey (75.4%). The post-intervention survey showed that the participants responded positively to the educational activities. CONCLUSION: The participants perceived the various pedagogical strategies positively, which shows the value of a broad and diverse educational approach, customised to local settings and including game-based activities, to enhance learning among healthcare professionals.

Safety of CoronaVac and ChAdOx1 vaccines against SARS-CoV-2 in patients with rheumatoid arthritis: data from the Brazilian multicentric study safer.

BACKGROUND: Patients with immune-mediated rheumatic diseases (IMRDs) have been prioritized for COVID-19 vaccination to mitigate the infection severity risks. Patients with rheumatoid arthritis (RA) are at a high risk of severe COVID-19 outcomes, especially those under immunosuppression or with associated comorbidities. However, few studies have assessed the safety of the COVID-19 vaccine in patients with RA. OBJECTIVE: To evaluate the safety of vaccines against SARS-CoV-2 in patients with RA. METHODS: This data are from the study "Safety and Efficacy on COVID-19 Vaccine in Rheumatic Diseases," a Brazilian multicentric prospective phase IV study to evaluate COVID-19 vaccine in IMRDs in Brazil. Adverse events (AEs) in patients with RA of all centers were assessed after two doses of ChAdOx1 (Oxford/AstraZeneca) or CoronaVac (Sinovac/Butantan). Stratification of postvaccination AEs was performed using a diary, filled out daily and returned at the end of 28 days for each dose. RESULTS: A total of 188 patients with RA were include, 90% female. CoronaVac was used in 109 patients and ChAdOx1 in 79. Only mild AEs were observed, mainly after the first dose. The most common AEs after the first dose were pain at the injection (46,7%), headache (39,4%), arthralgia (39,4%), myalgia (30,5%) and fatigue (26,6%), and ChAdOx1 had a higher frequency of pain at the injection (66% vs 32 %, p < 0.001) arthralgia (62% vs 22%, p < 0.001) and myalgia (45% vs 20%, p < 0.001) compared to CoronaVac. The more common AEs after the second dose were pain at the injection (37%), arthralgia (31%), myalgia (23%), headache (21%) and fatigue (18%). Arthralgia (41,4% vs 25%, p = 0.02) and pain at injection (51,4% vs 27%, p = 0.001) were more common with ChAdOx1. No serious AEs were related. With Regard to RA activity level, no significant difference was observed between the three time periods for both COVID-19 vaccines. CONCLUSION: In the comparison between the two immunizers in patients with RA, local reactions and musculoskeletal symptoms were more frequent with ChAdOx1 than with CoronaVac, especially after the first dose. In summary, the AE occurred mainly after the first dose, and were mild, like previous data from others immunizing agents in patients with rheumatoid arthritis. Vaccination did not worsen the degree of disease activity.

Prognostic Impact of AGR3 Protein Expression in Breast Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: To investigate the clinicopathological significance and prognosis of the expression of the anterior gradient 3 (AGR3) protein in women with breast cancer. DATA SOURCES: The PubMed, CINAHL, EMBASE, Scopus, and Web of Science databases were searched for studies published in English and without restrictions regarding the year of publication. The search terms were: breast cancer AND anterior gradient 3 OR AGR3 expression. STUDY SELECTION: We included observational or interventional studies, studies on AGR3 protein expression by immunohistochemistry, and studies on invasive breast cancer. Case reports, studies with animals, and reviews were excluded. In total, 4 studies were included, containing 713 cases of breast cancer. DATA COLLECTION: Data were extracted on clinicopathological characteristics and survival. A meta-analysis of the prevalence of AGR3 expression was performed according to the clinicopathological characteristics, hazard ratios (HRs), and overall survival and disease-free survival. DATA SYNTHESIS: The expression of AGR3 was found in 62% of the cases, and it was associated with histological grade II, positivity of estrogen and progesterone receptors, low expression of ki67, recurrence or distant metastasis, and lumen subtypes. In patients with low and intermediate histological grades, AGR3 expression was associated with worse overall survival (HR: 2.39; 95% confidence interval [95%CI]: 0.628-4.159; p = 0.008) and worse disease-free survival (HR: 3.856; 95%CI: 1.026-6.686; p = 0.008). CONCLUSION: The AGR3 protein may be a biomarker for the early detection of breast cancer and predict prognosis in luminal subtypes. In addition, in patients with low and intermediate histological grades, AGR3 protein expression may indicate an unfavorable prognosis in relation to survival.

OBJETIVO: Investigar o significado clinicopatológico e prognóstico da expressão da proteína anterior gradient 3 (AGR3) em mulheres com câncer de mama. FONTES DE DADOS: Utilizamos as bases de dados PubMed, CINAHL, EMBASE, Scopus e Web of Science para pesquisar estudos em inglês, sem restrições quanto ao ano de publicação. Os termos buscados foram: breast cancer AND anterior gradient 3 OR AGR3 expression. SELEçãO DOS ESTUDOS: Foram incluídos estudos observacionais ou intervencionais, estudos sobre a expressão da proteína AGR3 por imuno-histoquímica, e estudos sobre câncer de mama invasivo. Excluíram-se relatos de casos, estudos com animais e revisões. Quatro estudos foram selecionados, que continham 713 casos de câncer de mama. COLETA DE DADOS: Foram extraídos dados relativos a características clinicopatológicas e sobrevida. A metanálise da prevalência da expressão de AGR3 foi realizada conforme as características clinicopatológicas, razões de risco (RRs) e sobrevida global (SG) e sobrevida livre de doença (SLD). SíNTESE DOS DADOS: Encontrou-se expressão de AGR3 em 62% dos casos, que se associou com grau histológico II, positividade de receptores de estrogênio e progesterona, baixa expressão de ki67, recorrência ou metástase à distância e subtipos luminais. Em pacientes com graus histológicos baixo e intermediário, a expressão de AGR3 conferiu pior SG (RR: 2,39; intervalo de confiança de 95% [IC95%]: 0,628­4,159; p = 0,008) e pior SLD (RR: 3,856; IC95%: 1,026­6,686; p = 0,008). CONCLUSãO: A AGR3 pode ser um biomarcador para a detecção precoce do câncer de mama e predizer o prognóstico em subtipos luminais. Em graus histológicos baixo e intermediário, a expressão da proteína AGR3 pode indicar um prognóstico desfavorável em relação à sobrevida.

Microcephaly and Associated Risk Factors in Newborns: A Systematic Review and Meta-Analysis Study.

Congenital microcephaly is caused by a multitude of drivers affecting maternal−fetal health during pregnancy. It is a rare outcome in high-income industrial countries where microcephaly rates are in the range of 0.3−0.9 per 1000 newborns. Prevalence of microcephaly varies considerably across developing countries and can go as high as 58 cases per 1000 live births in pregnancies exposed to infection by Zika virus (ZIKV). Not only ZIKV-infected pregnancies, but other drivers can modulate the occurrence and severity of this outcome. Here, we sought to test the ZIKV−microcephaly association vs. competing hypotheses using a meta-analysis with 8341 microcephaly cases pooled from 10,250,994 newborns in the Americas, Africa, and Asia. Analysis of risk ratios (RR) showed teratogens the most likely microcephaly-associated risk factor (RR = 3.43; 95%-CI 2.69−4.38; p-value < 0.0001), while the statistical significance of the ZIKV−microcephaly association was marginal (RR = 2.12; 95%-CI 1.01−4.48; p-value = 0.048). Other congenital infections showed strong but variable associations with microcephaly (RR = 15.24; 95%-CI 1.74−133.70; p-value = 0.014). Microcephaly cases were associated with impoverished socioeconomic settings, but this association was statistically non-significant (RR = 2.75; 95%-CI 0.55−13.78; p-value = 0.22). The marginal ZIKV−microcephaly association and statistical significance of the competing hypotheses suggest maternal ZIKV infection might not be a cause of microcephaly alone.

AGR2 and AGR3 play an important role in the clinical characterization and prognosis of basal like breast cancer.

INTRODUCTION: Basal-like Breast Cancer (BLBC) represents an important molecular subtype of breast cancer characterized by an aggressive behavior, molecular pathology poorly understood and a limited treatment. OBJECTIVE: We aim to search for molecular differences between non-BLBC and BLBC tumors in order to propose possible diagnostic and prognostic biomarkers using databases. Metodology: Microarray processed data were downloaded from GEO database considering non-BLBC and BLBC. Enrichment analysis was evaluated using GO consortium and Ingenuity, protein-protein interaction, gene Ontology and co-expression analysis using STRING. Gene expression data was extracted using TCGA, METABRIC and Breast Cancer Gene-Expression Miner v4.2 databases. The Survival was evaluated using The Kaplan-Meier plotter. RESULTS: Were identified 58 upregulated and 58 downregulated genes enriched in signaling pathways like PDGF, Angiogenesis, Integrin and WNT. AGR2 and AGR3 expression were reduced in BLBC in relation to non-BLBC tumors, patients aged ≤51 years, and with negativity of ER, PR and HER-2 and nodal status. Low expression of AGR2 and AGR3 were associated with worse OS and RFS for all breast cancer cases. But according to the molecular stratification, low AGR2 conferred worst OS in luminal A, worst RFS in BLBC and good OS and RFS in luminal B. High AGR3 conferred worse OS and RFS in BLBC, but low AGR3 attributed worse OS in luminal A. CONCLUSION: AGR2 and AGR3 expression were able to differentiate non-BLBC from BLBC. Downregulation of AGR2 and AGR3 was associated with BLBC clinical phenotype. Furthermore, both genes behave different when considering prognosis and molecular stratification.

Common variable immunodeficiency and its inflammatory neurological manifestations: A case report and literature review.

BACKGROUND: Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies characterized by impaired immunoglobulin production and dysregulated immune response. Neurological manifestations have been described in a few patients, and little is known about its clinic and therapeutic approach. Thus, this work aimed to review the literature on it and to help differentiate CVID from its mimics, especially sarcoidosis. METHODS: We described a case report and included a literature review of inflammatory neurological involvement in CVID. RESULTS: A 32-year-old female patient with a medical history of recurrent bacterial infections, temporal focal epilepsy and granulomatous lung disease under study, and cervix squamous cell carcinoma, was initially admitted to the emergency department due to intracranial hypertension. After excluding infectious and neoplastic etiologies, the most likely hypothesis was that granulomatous pulmonary, cerebral, and leptomeningeal inflammatory involvement were associated with sarcoidosis. Two years later, a diagnosis of CVID was made, and the patient was secondarily diagnosed with Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD) and related inflammatory brain disease - both complications of CVID. After starting targeted treatment with immunoglobulin replacement and pulse glucocorticoids followed by a chronic taper, the patient became stable. However, three consecutive failures in immunoglobulin intake during the COVID-19 pandemic led to disease recurrence with relapse of neurological manifestations. CONCLUSION: This case illustrates the complex multiple organ manifestations of CVID. When granulomatous conditions arise in these patients, a rare lung disease arising in the context of CVID, the GLILD disease with multisystem involvement, should be taken into consideration. Early treatment with combined steroids and immunotherapy seems to be effective in controlling CVID's neurological manifestations.

Pleuroparenchymal fibroelastosis as a complication of chemotherapy: A case report.

Pleuroparenchymal fibroelastosis (PPFE) is a rare and recently described distinct pattern of lung apical fibrosis involving the upper lobe parenchyma and pleural dome. PPFE has definable and reproducible clinical, radiological and histopathological criteria, which allowed its classification as an independent interstitial lung disease. Several factors have been associated with PPFE, such as chemotherapy, especially with alkylating agents. The authors present a case of a 34-year-old female with previous history of Hodgkin lymphoma treated with first line chemotherapy (doxorubicin, bleomycin, vinblastine and dacarbazine). The patient had no other known comorbidities or relevant exposure to lung irritants. A total of 2 years after completing cancer treatment, the patient developed clinical and radiological features of PPFE. Given their previous history of malignancy, a biopsy of the lesion was obtained, which confirmed the diagnosis of PPFE. The authors present this case to raise awareness of this disease and to demonstrate that PPFE can develop months to years following chemotherapy treatment. Moreover, to date, none of these chemotherapy agents have been associated with the development of PPFE.

Mortality risk prediction with ILD-GAP index in a fibrotic hypersensitivity pneumonitis cohort.

BACKGROUND: Fibrotic hypersensitivity pneumonitis (fHP) is associated with significant morbidity and mortality. Interstitial lung disease-gender-age-physiology (ILD-GAP) performance in fHP outside the initial cohort was never performed. AIM: To assess the ILD-GAP index's ability to predict mortality in a Portuguese cohort of patients with fHP and analyse whether other clinical variables add value. METHODS: Retrospective analysis of fHP cohort in two Portuguese ILD centres. The baseline ILD-GAP index was calculated. Survival was analysed in months; mortality was the primary outcome. Univariate and multivariate analyses to identify mortality risk factors were performed. RESULTS: A total of 141 patients were included. Fifty-three patients (37.6%) died during the follow-up. The usual interstitial pneumonia (UIP) pattern was found in 49.6%, and their survival was inferior to non-UIP [32 months (interquartile range, IQR = 19, 60) versus 52 months (IQR = 28, 98), p = 0.048]. Patients with an ILD-GAP index higher than three double their risk of mortality [hazard ratio (HR) = 6.48, 95% confidence interval (CI) = (3.03-13.96)] when compared with the patients with an index between 2 and 3 [HR = 3.04, 95% CI = (1.62-5.71)] adjusting for acute exacerbation history. Even though UIP patients had worse survival, it did not reach statistical significance when UIP pattern was added to this model. Acute exacerbation history was an independent risk factor for mortality; however, ILD-GAP still predicted mortality after adjusting for this factor. PaO2 and 6-minute walk test desaturation were not significant risk factors. CONCLUSION: ILD-GAP index is a good predictor for mortality in fHP, even after adjusting for other mortality risk factors.

Predictive value of common genetic variants in idiopathic pulmonary fibrosis survival.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown etiology. The role of genetic risk factors has been the focus of numerous studies probing for associations of genetic variants with IPF. We aimed to determine whether single-nucleotide polymorphisms (SNPs) of four candidate genes are associated with IPF susceptibility and survival in a Portuguese population. A retrospective case-control study was performed with 64 IPF patients and 74 healthy controls. Ten single-nucleotide variants residing in the MUC5B, TOLLIP, SERPINB1, and PLAU genes were analyzed. Single- and multi-locus analyses were performed to investigate the predictive potential of specific variants in IPF susceptibility and survival. Multifactor dimensionality reduction (MDR) was employed to uncover predictive multi-locus interactions underlying IPF susceptibility. The MUC5B rs35705950 SNP was significantly associated with IPF: T allele carriers were significantly more frequent among IPF patients (75.0% vs 20.3%, P < 1.0 × 10-6). Genotypic and allelic distributions of TOLLIP, PLAU, and SERPINB1 SNPs did not differ significantly between groups. However, the MUC5B-TOLLIP T-C-T-C haplotype, defined by the rs35705950-rs111521887-rs5743894-rs5743854 block, emerged as an independent protective factor in IPF survival (HR = 0.37, 95% CI 0.17-0.78, P = 0.009, after adjustment for FVC). No significant multi-locus interactions correlating with disease susceptibility were detected. MUC5B rs35705950 was linked to an increased risk for IPF, as reported for other populations, but not to disease survival. A haplotype incorporating SNPs of the MUC5B-TOLLIP locus at 11p15.5 seems to predict better survival and could prove useful for prognostic purposes and IPF patient stratification. KEY MESSAGES : The MUC5B rs35705950 minor allele is associated with IPF risk in the Portuguese. No predictive multi-locus interactions of IPF susceptibility were identified by MDR. A haplotype defined by MUC5B and TOLLIP SNPs is a protective factor in IPF survival. The haplotype may be used as a prognostic tool for IPF patient stratification.