Serum Thyrotropin and Triiodothyronine Levels in Levothyroxine-treated Patients.

CONTEXT: Small adjustments in levothyroxine (LT4) dose do not appear to provide clinical benefit despite changes in thyrotropin (TSH) levels within the reference range. We hypothesize that the accompanying changes in serum total triiodothyronine (T3) levels do not reflect the magnitude of the changes in serum TSH. OBJECTIVE: This work aims to characterize the relationships of serum free thyroxine (FT4) vs T3, FT4 vs TSH, and FT4 vs the T3/FT4 ratio. METHODS: This cross-sectional, observational study comprised 9850 participants aged 18 years and older treated with LT4 from a large clinical database from January 1, 2009, to December 31, 2019. Patients had been treated with LT4, subdivided by serum FT4 level. Main outcome measures included model fitting of the relationships between serum FT4 vs TSH, FT4 vs T3, and FT4 vs T3/FT4. Mean and median values of TSH, T3, and T3/FT4 were calculated. RESULTS: The relationships T3 vs FT4 and TSH vs FT4 were both complex and best represented by distinct, segmented regression models. Increasing FT4 levels were linearly associated with T3 levels until an inflection point at an FT4 level of 0.7 ng/dL, after which a flattening of the slope was observed following a convex quadratic curve. In contrast, increasing FT4 levels were associated with steep declines in TSH following 2 negative sigmoid curves. The FT4 vs T3/FT4 relationship was fit to an asymptotic regression curve supporting less T4 to T3 activation at higher FT4 levels. CONCLUSION: In LT4-treated patients, the relationships between serum FT4 vs TSH and FT4 vs T3 across a range of FT4 levels are disproportionate. As a result, dose changes in LT4 that robustly modify serum FT4 and TSH values may only minimally affect serum T3 levels and result in no significant clinical benefit.

Non-invasive liver fibrosis assessment: is transient elastography mandatory?

Real-time elastography (RTE) is a conventional ultrasonography-based liver stiffness assessment technique developed in chronic viral hepatitis. Evidence of its applicability in other aetiologies is lacking. This study aims to determine RTE diagnostic accuracy for advanced fibrosis in compensated chronic liver disease (cCLD) and to compare it with the biochemical scores FIB-4 and APRI, using transient elastography (TE) as the gold standard. A single center cross-sectional study including cCLD patients was conducted. RTE with assessment of Liver Fibrosis Index and TE were performed in the same day by different operators blind to the other technique result. The scores FIB-4 and APRI were calculated. Fibrosis cut-off values were inferred from previous evidence.

Proteomic Analysis of Decellularized Extracellular Matrix: Achieving a Competent Biomaterial for Osteogenesis.

Decellularized ECMs have been used as biological scaffolds for tissue repair due to their tissue-specific biochemical and mechanical composition, poorly simulated by other materials. It is used as patches and powders, and it could be further processed via enzymatic digestion under acidic conditions using pepsin. However, part of the bioactivity is lost during the digestion process due to protein denaturation. Here, stepwise digestion was developed to prepare a competent biomaterial for osteogenesis from three different ECM sources. In addition, three different proteases were compared to evaluate the most effective digestion protocol for specific cellular processes. GAGs and peptide quantification showed that the stepwise method yielded a higher concentration of bioactive residues. Circular dichroism analysis also showed that the stepwise approach preserved the secondary structures better. The protein profiles of the digested ECMs were analyzed, and it was found to be highly diverse and tissue-specific. The digestion of ECM from pericardium produced peptides originated from 94 different proteins, followed by 48 proteins in ECM from tendon and 35 proteins in ECM from bone. In addition, digested products from pericardium ECM yielded increased proliferation and differentiation of bone marrow mesenchymal stem cells to mature osteoblasts.

Use of Statins Among Patients Taking Levothyroxine: an Observational Drug Utilization Study Across Sites.

CONTEXT: Treatment with levothyroxine (LT4) that normalize serum thyrotropin (TSH) is expected to restore lipid metabolism. OBJECTIVE: To assess statin utilization in LT4-treated patients through an observational drug utilization study. METHODS: Three sites were involved: (1) 10 723 outpatients placed on LT4 during 2006-2019 identified from the Clinical Research Data Warehouse of the University of Chicago; (2) ~1.4 million LT4 prescriptions prepared by primary care physicians during January-December 2018, identified from the IQVIA™ database of medical prescriptions in Brazil; (30 ~5.4 million patient interviews during 2009-2019, including ~0.32 million patients on LT4, identified from the Fleury Group database in Brazil. RESULTS: On site 1, initiation of therapy with LT4 increased the frequency of statin utilization (19.1% vs 24.6%), which occurred ~1.5 years later (median 76 weeks) and, among those patients that were on statins, increased intensity of treatment by 33%, despite normalization of serum TSH levels; on site 2, after matching for sex and age, the frequency of statins prescription was higher for those patients using LT4: females, 2.1 vs 3.4% (odds ratio [OR] 1.656 [1.639-1.673]); males, 3.1 vs 4.4% (OR 1.435 [1.409-1.462]); and, on site 3, after matching for sex and age, the frequency of statin utilization was higher in those patients using LT4: females, 10 vs 18% (OR 2.02 [2.00-2.04]); males, 15 vs 25% (OR 1.92 [1.88-1.96]); all P values were <.0001. CONCLUSION: Prescription and utilization of statins were higher in patients taking LT4. The reasons for this association should be addressed in future studies.

No association between vitamin D status and COVID-19 infection in São Paulo, Brazil

ABSTRACT In recent years the immunomodulatory actions of vitamin D, a steroid hormone, have been extensively studied. In 2020, due to the COVID-19 pandemic, the question arose as to 25(OH)D status would be related to susceptibility to SARS-CoV-2 infection, since several studies pointed out a higher prevalence and severity of the disease in populations with low levels of 25(OH)D. Thus, we investigated the 25(OH)D levels in adults "Detected" positive for SARS CoV-2 by RT-PCR (reverse transcriptase polymerase chain reaction) test, and in negative controls, "not Detected", using the Fleury Group's examination database, in Sao Paulo, Brazil. Of a total of 14.692 people with recent assessments of 25(OH)D and RT-PCR tests for COVID-19, 2.345 were positive and 11.585 were negative for the infection. The groups did not differ in the percentage of men and women, or in the age distribution. There were no differences in the distribution of 25(OH)D between the two groups (p = 0.08); mean 25(OH)D of 28.8 ± 21.4 ng/mL and 29.6 ± 18.1 ng/mL, respectively. In the specific population studied, clinical, environmental, socioeconomic and cultural factors should have greater relevance than 25(OH)D in determining the susceptibility to COVID-19.

No association between vitamin D status and COVID-19 infection in São Paulo, Brazil.

In recent years the immunomodulatory actions of vitamin D, a steroid hormone, have been extensively studied. In 2020, due to the COVID-19 pandemic, the question arose as to 25(OH)D status would be related to susceptibility to SARS-CoV-2 infection, since several studies pointed out a higher prevalence and severity of the disease in populations with low levels of 25(OH)D. Thus, we investigated the 25(OH)D levels in adults "Detected" positive for SARS CoV-2 by RT-PCR (reverse transcriptase polymerase chain reaction) test, and in negative controls, "not Detected", using the Fleury Group's examination database, in Sao Paulo, Brazil. Of a total of 14.692 people with recent assessments of 25(OH)D and RT-PCR tests for COVID-19, 2.345 were positive and 11.585 were negative for the infection. The groups did not differ in the percentage of men and women, or in the age distribution. There were no differences in the distribution of 25(OH)D between the two groups (p = 0.08); mean 25(OH)D of 28.8 ± 21.4 ng/mL and 29.6 ± 18.1 ng/mL, respectively. In the specific population studied, clinical, environmental, socioeconomic and cultural factors should have greater relevance than 25(OH)D in determining the susceptibility to COVID-19.

Correction: Public communication by research institutes compared across countries and sciences: Building capacity for engagement or competing for visibility?

[This corrects the article DOI: 10.1371/journal.pone.0235191.].

Public communication by research institutes compared across countries and sciences: Building capacity for engagement or competing for visibility?

Leading academic institutions, governments, and funders of research across the world have spent the last few decades fretting publicly about the need for scientists and research organisations to engage more widely with the public and be open about their research. While a global literature asserts that public communication has changed from a virtue to a duty for scientists in many countries and disciplines, our knowledge about what research institutions are doing and what factors drive their 'going public' is very limited. Here we present the first cross-national study of N = 2,030 research institutes within universities and large scientific organisations in Brazil, Germany, Italy, Japan, the Netherlands, Portugal, the United Kingdom, and the United States of America. We find that institutes embrace communication with non-peers and do so through a variety of public events and traditional news media-less so through new media channels-and we find variation across countries and sciences, yet these are less evident than we expected. Country and disciplinary cultures contribute to the level of this communication, as do the resources that institutes make available for the effort; institutes with professionalised staff show higher activity online. Future research should examine whether a real change in the organisational culture is happening or whether this activity and resource allocation is merely a means to increase institutional visibility.

Mechanism of action of the erector spinae plane block: distribution of dye in a porcine model.

This study aimed to describe the anatomical distribution of dye injected in the erector spinae plane (ESP) in a porcine living model, which could aid to reveal factors potentially relevant to the unexplained clinical effects of the ESP block. Six pigs received 0.6 mL/kg of 0.25% new methylene blue at the level of the sixth thoracic vertebra through either a cranial-to-caudal or a caudal-to-cranial in-plane ultrasound-guided bilateral ESP injection 20 min before euthanasia.Spread of dye evaluated through transverse cryosections (four injections) extended from T5 to T10 and from T5 to T8 when a cranial-to-caudal direction of injection was used, and from T5 to T9 and from T5 to T8 when the opposite direction of injection was used. A median of 4.5 medial and lateral branches of the dorsal rami was observed stained through anatomical dissection (eight injections), regardless of the direction of injection. No evidence of dye was found in the thoracic paravertebral or epidural spaces, where the dorsal root ganglia, ventral rami and rami communicantes are located. In all the cases, dye solution was found in the prevertebral thoracic lymph nodes.In this study, ESP injection resulted in a median spread over five spinal segments (12 injections), staining the lateral and medial branches of the dorsal rami of the spinal nerves, regardless of the direction of the needle used.

Assessing the Impact of Sample Heterogeneity on Transcriptome Analysis of Human Diseases Using MDP Webtool.

Transcriptome analyses have increased our understanding of the molecular mechanisms underlying human diseases. Most approaches aim to identify significant genes by comparing their expression values between healthy subjects and a group of patients with a certain disease. Given that studies normally contain few samples, the heterogeneity among individuals caused by environmental factors or undetected illnesses can impact gene expression analyses. We present a systematic analysis of sample heterogeneity in a variety of gene expression studies relating to inflammatory and infectious diseases and show that novel immunological insights may arise once heterogeneity is addressed. The perturbation score of samples is quantified using nonperturbed subjects (i.e., healthy subjects) as a reference group. Such a score allows us to detect outlying samples and subgroups of diseased patients and even assess the molecular perturbation of single cells infected with viruses. We also show how removal of outlying samples can improve the "signal" of the disease and impact detection of differentially expressed genes. The method is made available via the mdp Bioconductor R package and as a user-friendly webtool, webMDP, available at http://mdp.sysbio.tools.

webCEMiTool: Co-expression Modular Analysis Made Easy.

Co-expression analysis has been widely used to elucidate the functional architecture of genes under different biological processes. Such analysis, however, requires substantial knowledge about programming languages and/or bioinformatics skills. We present webCEMiTool, a unique online tool that performs comprehensive modular analyses in a fully automated manner. The webCEMiTool not only identifies co-expression gene modules but also performs several functional analyses on them. In addition, webCEMiTool integrates transcriptomic data with interactome information (i.e., protein-protein interactions) and identifies potential hubs on each network. The tool generates user-friendly html reports that allow users to search for specific genes in each module, as well as check if a module contains genes overrepresented in specific pathways or altered in a specific sample phenotype. We used webCEMiTool to perform a modular analysis of single-cell RNA-seq data of human cells infected with either Zika virus or dengue virus.

Management of colorectal laterally spreading tumors: a systematic review and meta-analysis.

Objective and study aims To evaluate the efficacy and safety of different endoscopic resection techniques for laterally spreading colorectal tumors (LST). Methods Relevant studies were identified in three electronic databases (PubMed, ISI and Cochrane Central Register). We considered all clinical studies in which colorectal LST were treated with endoscopic resection (endoscopic mucosal resection [EMR] and/or endoscopic submucosal dissection [ESD]) and/or transanal minimally invasive surgery (TEMS). Rates of en-bloc/piecemeal resection, complete endoscopic resection, R0 resection, curative resection, adverse events (AEs) or recurrence, were extracted. Study quality was assessed with the Newcastle-Ottawa Scale and a meta-analysis was performed using a random-effects model. Results Forty-nine studies were included. Complete resection was similar between techniques (EMR 99.5 % [95 % CI 98.6 %-100 %] vs. ESD 97.9 % [95 % CI 96.1 - 99.2 %]), being curative in 1685/1895 (13 studies, pooled curative resection 90 %, 95 % CI 86.6 - 92.9 %, I 2  = 79 %) with non-significantly higher curative resection rates with ESD (93.6 %, 95 % CI 91.3 - 95.5 %, vs. 84 % 95 % CI 78.1 - 89.3 % with EMR). ESD was also associated with a significantly higher perforation risk (pooled incidence 5.9 %, 95 % CI 4.3 - 7.9 %, vs. EMR 1.2 %, 95 % CI 0.5 - 2.3 %) while bleeding was significantly more frequent with EMR (9.6 %, 95 % CI 6.5 - 13.2 %; vs. ESD 2.8 %, 95 % CI 1.9 - 4.0 %). Procedure-related mortality was 0.1 %. Recurrence occurred in 5.5 %, more often with EMR (12.6 %, 95 % CI 9.1 - 16.6 % vs. ESD 1.1 %, 95 % CI 0.3 - 2.5 %), with most amenable to successful endoscopic treatment (87.7 %, 95 % CI 81.1 - 93.1 %). Surgery was limited to 2.7 % of the lesions, 0.5 % due to AEs. No data of TEMS were available for LST. Conclusions EMR and ESD are both effective and safe and are associated with a very low risk of procedure related mortality.

Lymphoproliferative Disorders in Inflammatory Bowel Disease Patients: Is It the Drugs or the Disease.

INTRODUCTION: Systemic inflammatory diseases are related to an increased risk of lymphoproliferative disorders. Although inflammatory bowel disease (IBD) was also associated with these conditions, population-based studies failed to demonstrate this relationship, and most studies only identified a very small number of cases. In the last few years, concerns arose regarding the role of thiopurines and tumour necrosis factor-alpha (TNF-α)-blocking agents in the development of lymphoma, influencing therapeutic decisions in IBD patients. The aim of this study was to describe a case series of IBD patients who developed a lymphoproliferative disorder in our tertiary referral centre. MATERIAL AND METHODS: The clinical records of all IBD patients who were observed in our unit between January 2007 and December 2016 were retrospectively reviewed, and IBD subjects who were diagnosed with a lymphoproliferative disorder were selected. Clinical and demographic data regarding both conditions were collected. RESULTS: Six IBD patients were diagnosed with a lymphoma - 4 Hodgkin lymphomas and 2 B-cell non-Hodgkin lymphomas - of which 3 corresponded to primary colonic lymphomas. Immunohistochemical analysis detected the presence of Epstein-Barr virus in the tumour cells of 2 patients, both of them with Hodgkin lymphomas. Only 2 patients were previously treated with thiopurines or anti-TNF-α drugs; none of the remaining had any history of immunosuppressive treatment. DISCUSSION AND CONCLUSIONS: Despite major attention being currently focused on the effect of treatment, which may play the main role in the increased susceptibility to lymphoma in IBD patients, and although it may be difficult to demonstrate, IBD itself may contribute to the development of lymphoproliferative disorders, particularly primary intestinal lymphomas.

INTRODUÇÃO: Doenças inflamatórias crónicas estão relacionadas com um aumento de risco de doenças linfoproliferativas. Apesar da doença inflamatória intestinal (DII) também ter sido associada a estas complicações, estudos de base populacional falharam em demonstrar esta relação, e a maioria dos estudos apenas identificou um baixo número de casos. Nos últimos anos, preocupações foram levantadas no que diz respeito ao papel das tiopurinas e dos bloqueadores do factor de necrose tumoral alpha (TNF-α) no desenvolvimento de linfomas, influenciando decisões terapêuticas em doentes com DII. O objectivo deste estudo foi o de descrever uma série de casos de doentes com DII que desenvolveram doenças linfoproliferativas num centro de referência. MATERIAL E MÉTODOS: Os registos clínicos dos doentes que foram observados na nossa unidade entre Janeiro de 2007 e Dezembro de 2016 foram retrospectivamente analisados, tendo sido seleccionados os doentes diagnosticados com uma doença linfoproliferativa. Os dados clínicos e demográficos respeitantes a ambas as condições foram colectados. RESULTADOS: Seis doentes com DII foram diagnosticados com linfoma - 4 linfomas de Hodgkin e 2 linfomas não-Hodgkin de células B -, dos quais 3 corresponderam a linfomas primários do cólon. Análise imunohistoquímica detectou a presença do vírus Epstein-Barr nas células tumorais de 2 doentes, ambos com linfoma de Hodgkin. Apenas 2 doentes tinham recebido tratamento prévio com tiopurinas ou agentes anti-TNF-α; nenhum dos restantes tinha qualquer história de terapêutica imunossupressora. DISCUSSÃO E CONCLUSÃO: Apesar da maioria das atenções estar focada no efeito do tratamento, o qual será o principal responsável pela maior susceptibilidade para linfomas em doentes com DII, e apesar da dificuldade em demonstrá-lo, a própria DII poderá contribuir para o desenvolvimento de doenças linfoproliferativas, particular de linfomas intestinais primários.

CEMiTool: a Bioconductor package for performing comprehensive modular co-expression analyses.

BACKGROUND: The analysis of modular gene co-expression networks is a well-established method commonly used for discovering the systems-level functionality of genes. In addition, these studies provide a basis for the discovery of clinically relevant molecular pathways underlying different diseases and conditions. RESULTS: In this paper, we present a fast and easy-to-use Bioconductor package named CEMiTool that unifies the discovery and the analysis of co-expression modules. Using the same real datasets, we demonstrate that CEMiTool outperforms existing tools, and provides unique results in a user-friendly html report with high quality graphs. Among its features, our tool evaluates whether modules contain genes that are over-represented by specific pathways or that are altered in a specific sample group, as well as it integrates transcriptomic data with interactome information, identifying the potential hubs on each network. We successfully applied CEMiTool to over 1000 transcriptome datasets, and to a new RNA-seq dataset of patients infected with Leishmania, revealing novel insights of the disease's physiopathology. CONCLUSION: The CEMiTool R package provides users with an easy-to-use method to automatically implement gene co-expression network analyses, obtain key information about the discovered gene modules using additional downstream analyses and retrieve publication-ready results via a high-quality interactive report.

Safe use of infliximab for the treatment of severe perianal Crohn's disease after diagnosis and treatment of lymphoma.

Inflammatory bowel disease is associated with an increased likelihood of developing lymphoma. However, it is still controversial if this risk may be attributed to the disease itself or rather represents an effect of immunosuppressive treatment. Although tumor necrosis factor alpha (TNFα) is a key cytokine for cancer immunosurveillance, the potential relationship between anti-TNFα agents and the pathogenesis of lymphoproliferative disorders remains unclear. Here, we describe the case of a patient with severe perianal Crohn's disease, treated with infliximab monotherapy, whose unusual presentation with acute groin pain required surgical intervention and led to the diagnosis of diffuse large B-cell lymphoma. However, 10 months after this episode, treatment with infliximab was restarted because the patient continued with refractory and disabling perianal disease. Currently, with a follow-up of 36 months, under infliximab 10 mg/kg every 4 weeks, he maintains mild perianal Crohn's disease and persists in sustained clinical and imaging remission of the lymphoproliferative disorder.

Outcomes of Different Methods for Analysis of Biliary Brush Cytology and of Factors Associated with Positive Diagnosis in an Age-Dependent Retrospective Review.

BACKGROUND AND AIMS: Brush cytology during endoscopic retrograde cholangiopancreatography (ERCP) is the most frequently used strategy for obtaining a tissue sample from an indeterminate biliary stricture. A recent study reported that age is a factor associated with positive yields, but further analysis of how age influences the results was lacking. We aimed to evaluate clinical effectiveness of biliary cytology and prognostic factors for a positive outcome, especially age. METHODS: This study was a single-center, retrospective, clinical study of 77 consecutive patients who underwent brush cytology during ERCP to obtain a diagnosis of an indeterminate biliary stricture. We compared 2 routine cytology techniques: A (smear); B (centrifugation of the cytological material collected and the cut-off brush + cell block when sufficient amount of material was available). The data were collected aiming to compare the accuracy of the different techniques used and the prognostic factors affecting the outcome, with a particular focus on age. The yield for brush cytology was compared with the gold standard defined as either definitive histology or the long-term clinical course. RESULTS: The overall accuracy of the 2 used methods was 75.3%. Sensitivity was 52.5%, specificity was 100%, positive predictive value was 100%, and negative predictive value was 66.1%. Although not statistically significant, there was a trend toward accuracy for method B compared with method A (80.4 vs. 65.4%; p = 0.153). Multiple logistic regression analysis showed that younger age was the only independent prognostic factor associated with a positive diagnosis (OR 0.95; 95% CI 0.90-0.99; p = 0.039). Receiver operating characteristic curves for age yielded an area under the curve value of 68.2%. On the basis of the Youden index, 69 years was found to be the optimal cutoff for age. CONCLUSIONS: In this series, the accuracy of routine biliary brush cytology was not equal for all methods and ages; in particular, younger patients (below 69 years) tended to have a higher probability of a correct diagnosis.

INTRODUÇÃO: a citologia biliar é a técnica mais utilizada durante a CPRE para o diagnóstico de uma estenose indeterminada. Um artigo recente refere a importância da idade como fator preditivo de um resultado positivo, embora sem analisar este dado. Pretendemos avaliar a acuidade da citologia biliar e dos factores associados para a obtenção de um resultado positivo com especial interesse na idade. MÉTODOS: análise retrospectiva de um único centro de 77 doentes consecutivos submetidos, durante CPRE a citologia biliar para esclarecer a etiologia de uma estenose biliar. A análise comparou 2 técnicas de rotina: A (esfregaço); B (centrifugação do material colectado e da escova+cell block quando existia material suficiente). Pretendeu-se comparar a acuidade diagnóstica dos 2 diferentes métodos e dos factores de prognóstico associados ao resultado em especial a idade. A acuidade da citologia foi comparada com o "gold standard" definido como a histologia definitiva ou o curso clínico a longo prazo. RESULTADOS: a acuidade global dos diferentes métodos foi 75.3%. A sensibilidade foi 52.5%, a especificidade foi 100%, VPP foi 100% e o VPN foi 66.1%. Apesar de não ser estatisticamente definitivo existiu maior acuidade do método B, em comparação com o A (80.4 vs. 65.4%; p = 0.153). A análise multivariada por regressão logística mostrou que a menor idade é o único fator de prognóstico independente associado a um resultado positivo (OR: 0.95; 95% CI: 0.90­0.99; p = 0.039). As curvas ROC para a idade apresentaram um valor para a AUC de 68.2%. O índice de Youden, determinou que os 69 anos seriam o "cutoff" ideal para a idade. CONCLUSÕES: nesta população a acuidade de citologia biliar não foi idêntica para todos os métodos e idades; em particular doentes com idade inferior a 69 anos apresentam maior probabilidade de obter um diagnóstico correto.