Autoimmune Hepatitis Induced by Hepatitis Delta Virus: A Conundrum.

Introduction: The association of hepatitis delta virus (HDV) infection with positive autoantibodies and autoimmune features has been known for decades. However, to date, very few cases of clinical autoimmune hepatitis (AIH) have been reported in association with HDV infection, most of them being in the context of treatment with peginterferon. Case Report: This case refers to a 46-year-old woman born in Guinea-Bissau who moved to Portugal in 2018 to investigate complaints of diffuse abdominal discomfort and nausea. Her initial work-up, including laboratory and liver histology, was consistent with type 1 AIH. She had HBe antigen-negative chronic hepatitis B virus infection with negative DNA and also a positive total anti-HDV antibody, with negative IgM and undetectable RNA. Therefore, after initiating prophylactic tenofovir difumarate, she was started on prednisolone followed by azathioprine, which was later stopped due to presumed hepatotoxicity. Repeated histology showed signs of viral superinfection, and she was treated with acyclovir due to a positive herpes simplex IgM, with HDV RNA remaining negative. A third flare in transaminases prompted the introduction of mycophenolate mofetil (MMF) after a thorough exclusion of additional causes of liver disease. About 6 months later, during another bout of hepatitis, HDV RNA was finally positive and classified as genotype 5. MMF was stopped, and, considering a contraindication to interferon, the patient was offered therapy with bulevirtide, which she refused for personal reasons as she is currently living in her home country. Discussion: This is a challenging case of autoimmune or "autoimmune-like" hepatitis, probably induced by chronic HDV infection. High suspicion of HDV was essential because, had the case been interpreted as refractory AIH, with escalation of immunosuppression, a more severe course of the viral infection might have ensued. Recently, HDV suppression with bulevirtide was shown to reverse autoimmune liver disease. We hypothesize that the same could have happened to our patient, had she accepted this treatment.

Introdução: A associação da infeção pelo vírus da hepatite delta (VHD) com a presença de autoanticorpos e outros aspetos de autoimunidade é conhecida desde há várias décadas. Contudo, até à data, muito poucos casos de hepatite autoimune (HAI) clínica foram reportados em relação com a infeção VHD, sendo a maioria destes no contexto de terapêutica com interferão peguilado. Caso clínico: O caso refere-se a uma mulher de 46 anos natural da Guiné-Bissau, que se mudou para Portugal em 2018 para investigação de queixas de desconforto abdominal difuso e náuseas. A avaliação laboratorial inicial e a histologia hepática foram compatíveis com HAI tipo 1. A doente apresentava também infeção crónica a VHB (vírus da hepatite B) antigénio HBe negativa, com DNA negativo, e anti-VHD (vírus da hepatite delta) total positivo, com IgM negativo e RNA indetetável. Assim, após início de tenofovir difumarato profilático, foi iniciada terapêutica com prednisolona seguida de azatioprina, que posteriormente se interrompeu por presumível hepatotoxicidade. Uma segunda biópsia mostrou aspetos de superinfeção viral e como tal a doente foi tratada com aciclovir, tendo em conta IgM positivo para Herpes Simplex, mantendo-se o RNA VHD negativo. Um terceiro flare de transaminases motivou o início de micofenolato de mofetil, após extensa investigação e exclusão de outras causas de doença hepática. Cerca de 6 meses mais tarde, durante novo episódio de hepatite, o RNA VHD revelou-se finalmente positivo e este foi classificado como genotipo 5. O MMF foi suspenso e, considerando a contra-indicação para interferão, foi proposto à doente tratamento com bulevirtide, que esta recusou, alegando motivos pessoais, visto estar atualmente a residir no seu país de origem. Discussão: Este é um caso desafiante de hepatite autoimune, ou autoimune-like, provavelmente induzida pela infeção crónica pelo VHD. Um elevado índice de suspeição para VHD foi essencial porque, se o caso tivesse sido interpretado como HAI refratária, com incremento de imunossupressão, poderia ter-se verificado um agravamento da hepatite viral. Recentemente, foi reportado que a supressão do VHD pelo bulevirtide pode reverter a doença hepática autoimune. Questionamo-nos se o mesmo poderia ter sucedido com a nossa doente, caso esta tivesse aceite este tratamento.

Anti-tumor necrosis factor therapy is associated with attenuated humoral response to SARS-COV-2 vaccines in patients with inflammatory bowel disease.

BACKGROUND: Immunosuppressive therapy used in the treatment of inflammatory bowel disease (IBD) is known to reduce vaccine immunogenicity. AIMS: This study aimed to 1) predict the humoral response elicited by SARS-CoV-2 vaccination in IBD patients based on their ongoing treatment and other relevant patient and vaccine characteristics and 2) assess the humoral response to a booster dose of mRNA vaccine. METHODS: We conducted a prospective study in adult IBD patients. Anti-spike (S) IgG antibodies were measured after initial vaccination and again after one booster dose. A multiple linear regression model was created to predict anti-S antibody titer following initial complete vaccination in different therapeutic groups (no immunosuppression, anti-TNF, immunomodulators and combination therapy). A two-tailed Wilcoxon test for two dependent groups was performed to compare anti-S values before and after the booster dose. RESULTS: Our study included 198 IBD patients. The multiple linear regression identified anti-TNF and combination therapy (versus no immunosuppression), current smoking, viral vector (versus mRNA) vaccine and interval between vaccination and anti-S measurement as statistically significant predictors of the log anti-S antibody levels (p < 0.001). No statistically significant differences were found between no immunosuppression and immunomodulators (p = 0.349) and between anti-TNF and combination therapy (p = 0.997). Statistically significant differences for anti-S antibody titer before and after the booster dose of mRNA SARS-CoV-2 vaccine were found, both for non-anti-TNF and anti-TNF groups. CONCLUSIONS: Anti-TNF treatment (either alone or in combination therapy) is associated with lower anti-S antibody levels. Booster mRNA doses seem to increase anti-S both in non-anti-TNF and anti-TNF treated patients. Special attention should be paid to this group of patients when planning vaccination schemes.

The Role of Benralizumab in Eosinophilic Immune Dysfunctions: A Case Report-Based Literature Review.

In the past years, the knowledge of eosinophils playing a primary pathophysiologic role in several associated conditions has led to the development of biologics targeting therapies aiming at normalizing the immune response, reducing chronic inflammation, and preventing tissue damage. To better illustrate the potential relationship between different eosinophilic immune dysfunctions and the effects of biological therapies in this scenario, here, we present a case of a 63-year-old male first referred to our department in 2018 with a diagnosis of asthma, polyposis, and rhinosinusitis and presenting a suspicion of nonsteroidal anti-inflammatory drugs' allergy. He also had a past medical history of eosinophilic gastroenteritis/duodenitis (eosinophilia counts >50 cells/high-power field HPF). The use of multiple courses of corticosteroid therapy failed to completely control these conditions. In October 2019, after starting benralizumab (an antibody directed against the alpha chain of the IL-5 cytokine receptor) as add-on treatment for severe eosinophilic asthma, important clinical improvements were reported both on the respiratory (no asthma exacerbations) and gastrointestinal systems (eosinophilia count 0 cells/HPF). Patients' quality of life also increased. Since June 2020, systemic corticosteroid therapy was reduced without worsening of gastrointestinal symptoms or eosinophilic inflammation. This case warns of the importance of early recognition and appropriate individualized treatment of eosinophilic immune dysfunctions and suggests the conduction of further larger studies on the use of benralizumab in gastrointestinal syndromes aiming at better understanding its relying mechanisms of action in the intestinal mucosa.

Prevalence and Predictive Factors of Exclusive Breastfeeding in the First Six Months of Life.

INTRODUCTION: Exclusive breastfeeding (EBF) is currently recommended until six months of age. The Baby-friendly Hospital (BFH) initiative an international program to promote breastfeeding, was launched in Portugal in 1994. The aim of this study was to identify the prevalence and factors influencing breastfeeding in the first six months of life and to compare the results with a study carried out in 1999 including population from the same geographic area. MATERIAL AND METHODS: A prospective, longitudinal and observational study was carried out in two hospitals in the Lisbon metropolitan area, one BFH and another non-BFH. It consisted of different questionnaires answered by mothers at three distinct moments (zero, three and six months). The first questionnaire was applied between February and June 2019. RESULTS: A total of 423 infants were included, 324 from the BFH and 99 from the non-BFH. The breastfeeding rate was 94.3% at discharge, 78.2% at three months and 64.4% at six months, whereas EBF rate was 74.2%, 51.8% and 25.6% respectively. All women on EBF at six months, except one, were breastfeeding on demand. The discontinuation of EBF was associated with delayed skin-to-skin contact, Neonatal Intensive Care Unit admission, pacifier and artificial teats use, mother's return to work earlier and lower education levels. Conversely, factors that promote EBF were older gestational age, adequate birthweight, breastfeeding initiation in the first hour of life, rooming-in practice, shorter hospital stay and absence of infant's illnesses. Compared with 1999, although there was a significant improvement of breastfeeding rates at three and six months, the EBF rate was similar at six months (23%). Both studies identified the mother's lower education level and mother's return to work as contributing factors to breastfeeding discontinuation. CONCLUSION: Our results are in agreement with previously reported causes of breastfeeding discontinuation and emphasize the importance of sociocultural factors. Compared with 1999, the breastfeeding rates in this Portuguese population increased significantly at three and six months. However, it is still necessary to improve in order to achieve the World Health Organization global target.

Candida parapsilosis Virulence and Antifungal Resistance Mechanisms: A Comprehensive Review of Key Determinants.

Candida parapsilosis is the second most common Candida species isolated in Asia, Southern Europe, and Latin America and is often involved in invasive infections that seriously impact human health. This pathogen is part of the psilosis complex, which also includes Candida orthopsilosis and Candida metapsilosis. C. parapsilosis infections are particularly prevalent among neonates with low birth weights, individuals who are immunocompromised, and patients who require prolonged use of a central venous catheter or other indwelling devices, whose surfaces C. parapsilosis exhibits an enhanced capacity to adhere to and form biofilms. Despite this well-acknowledged prevalence, the biology of C. parapsilosis has not been as extensively explored as that of Candida albicans. In this paper, we describe the molecular mechanistic pathways of virulence in C. parapsilosis and show how they differ from those of C. albicans. We also describe the mode of action of antifungal drugs used for the treatment of Candida infections, namely, polyenes, echinocandins, and azoles, as well as the resistance mechanisms developed by C. parapsilosis to overcome them. Finally, we stress the importance of the ongoing search for species-specific features that may aid the development of effective control strategies and thus reduce the burden on patients and healthcare costs.

Genomic evolution towards azole resistance in Candida glabrata clinical isolates unveils the importance of CgHxt4/6/7 in azole accumulation.

The increasing prevalence of candidosis caused by Candida glabrata is related to its ability to acquire azole resistance. Although azole resistance mechanisms are well known, the mechanisms for azole import into fungal cells have remained obscure. In this work, we have characterized two hexose transporters in C. glabrata and further investigate their role as potential azole importers. Three azole susceptible C. glabrata clinical isolates were evolved towards azole resistance and the acquired resistance phenotype was found to be independent of CgPDR1 or CgERG11 mutations. Through whole-genome sequencing, CgHXT4/6/7 was found to be mutated in the three evolved strains, when compared to their susceptible parents. CgHxt4/6/7 and the 96% identical CgHxt6/7 were found to confer azole susceptibility and increase azole accumulation in C. glabrata cells, strikingly rescuing the susceptibility phenotype imposed by CgPDR1 deletion, while the identified loss-of-function mutation in CgHXT4/6/7, leads to increased azole resistance. In silico docking analysis shows that azoles display a strong predicted affinity for the glucose binding site of CgHxt4/6/7. Altogether, we hypothesize that hexose transporters, such as CgHxt4/6/7 and CgHxt6/7, may constitute a family of azole importers, involved in clinical drug resistance in fungal pathogens, and constituting promising targets for improved antifungal therapy.

Clinical azole cross-resistance in Candida parapsilosis is related to a novel MRR1 gain-of-function mutation.

OBJECTIVES: Hereby, we describe the molecular mechanisms underlying the acquisition of azole resistance by a Candida parapsilosis isolate following fluconazole treatment due to candiduria. METHODS: A set of three consecutive C. parapsilosis isolates were recovered from the urine samples of a patient with candiduria. Whole-genome sequencing and antifungal susceptibility assays were performed. The expression of MRR1, MDR1, ERG11 and CDR1B (CPAR2_304370) was quantified by RT-qPCR. RESULTS: The initial isolate CPS-A was susceptible to all three azoles tested (fluconazole, voriconazole and posaconazole); isolate CPS-B, collected after the second cycle of treatment, exhibited a susceptible-dose-dependent phenotype to fluconazole and isolate CPS-C, recovered after the third cycle, exhibited a cross-resistance profile to fluconazole and voriconazole. Whole-genome sequencing revealed a putative resistance mechanism in isolate CPS-C, associated with a G1810A nucleotide substitution, leading to a G604R change in the Mrr1p transcription factor. Introducing this mutation into the susceptible CPS-A isolate (MRR1RI) resulted in resistance to fluconazole and voriconazole, as well as up-regulation of MRR1 and MDR1. Interestingly, the susceptible-dose-dependent phenotype exhibited by isolate CPS-B was associated with an increased copy number of the CDR1B gene. The expression of CDR1B was increased in both isolates CPS-B and CPS-C and in the MRR1RI strain, harbouring the gain-of-function mutation. CONCLUSIONS: Our results describe clinical azole cross-resistance acquisition in C. parapsilosis due to a G1810A (G604R) gain-of-function mutation, resulting in MRR1 hyperactivation and consequently, MDR1 efflux pump overexpression. We also associated amplification of the CDR1B gene with decreased fluconazole susceptibility and showed that it is a putative target of the MRR1 gain-of-function mutation.

Osteoarticular infections in infants under 3 months of age.

BACKGROUND: Acute osteoarticular infections (OAI) in infants under 3 months of age (≤3M) are rare and remain a diagnostic challenge. Orthopedic complications and functional sequelae have been less well described in this age group. Our aims were to evaluate trends in aetiology, management, and outcomes of OAI ≤ 3M, and to compare these younger children who have OAI with older children. METHODS: A longitudinal observational study was conducted of OAI cases admitted to tertiary care pediatric hospital from 2008 to 2018. OAI ≤ 3M was compared with children above 3 months. Clinical, microbiological, imaging, and outcome data were analyzed. RESULTS: We identified 24 (9.1%) of the 263 OAI in children under 3 months. Analyzing OAI ≤ 3M there was a twofold increase since 2014; 54% were males with a median age of 28 days (IQR: 13.5-60.0), 10 (41.7%) were premature and nine (37.5%) had healthcare-associated infections. Microbiological causes were identified in 87.5%, mostly Staphylococcus aureus (57.1%) and Group B Streptococcus (23.8%), and 25% were multidrug-resistant (5 methicillin-resistant S. aureus and 1 Enterobacter cloacae). Bacteremia (100% vs 36.8%, P = 0.037), multidrug resistant bacteria (75% vs 16, P = 0.04), and healthcare-associated infections (100% vs 26.3%, P = 0.014) were associated with sequelae. Comparing OAI ≤ 3M with older children, OAI ≤ 3M were treated with longer antibiotic courses, had more complications and sequelae (17.4% vs 3.2%, P = 0.002). CONCLUSIONS: S. aureus is still the most common cause of OAI ≤ 3M, and 25% of causative bacteria were multidrug-resistant bacteria. Complications and sequelae were more frequent in OAI ≤ 3M when compared with older children.

A novel variant of DeSanto-Shinawi Syndrome with joint manifestations.

The clinical features associated with WAC haploinsufficiency include recognizable dysmorphic facial features, variable degrees of developmental delay and intellectual disability that were recently delineated as DeSanto-Shinawi syndrome (OMIM 616708). We describe a patient with DeSanto-Shinawi syndrome caused by a novel frameshift variant in WAC gene (NM_016628.4(WAC):c.1689del (p.Phe563Leufs*6)). As noted in cases previously reported, our patient phenotype included facial dysmorphism, intellectual disability, behavioral problems, feeding difficulties, hirsutism, constipation and astigmatism. She also had limited range of motion of joints since birth and Juvenile Idiopathic Arthritis diagnosed at eleven years old. Although in the last years some additional features were reported in DeSanto-Shinawi syndrome, joint manifestations have not been previously described. As limited range of motion of joints was reported since birth with no correlation with arthritis onset, it could be a new clinical feature. Polyarthritis in this patient can be only a coincidence, since there is a first degree relative with psoriasis, or might be related to WAC mutation. Indeed, WAC encodes a protein that plays a vital role in autophagy. It has already been demonstrated that WAC haploinsufficiency leads to increased autophagy and, according to different authors, increased autophagy may display a pathogenic role in several autoimmune disorders such as Rheumatoid Arthritis and Juvenile Idiopathic Arthritis. Thus, WAC haploinsufficiency may have contributed to autoimmune disorder in this patient.

Acute haematogenous osteomyelitis in Lisbon: an unexpectedly high association with myositis and arthritis.

INTRODUCTION: Despite the current trend toward less aggressive therapeutic approaches, acute haematogenous osteomyelitis (AHO) continues to be a challenge and is associated with significant morbidity worldwide. Our aim was to assess whether compliance with the current protocol was achieved in 80% of cases, to identify complications and the associated risk factors, and to analyse trends in the aetiology and management of AHO in the paediatric population. METHODS: We conducted a longitudinal, observational, single-centre study in patients with AHO aged less than 18 years admitted to a paediatric hospital between 2008 and 2018 divided in 2 cohorts (before and after 2014). We analysed data concerning demographic and clinical characteristics and outcomes. RESULTS: The study included 71 children with AHO, 56% male, with a median age of 3 years (interquartile range, 1-11). We found a 1.8-fold increase of cases in the last 5 years. The causative agent was identified in 37% of cases: MSSA (54%), MRSA (4%), S. pyogenes (19%), K. kingae (12%), S. pneumoniae (8%), and N. meningitidis (4%). Complications were identified in 45% of patients and sequelae in 3.6%. In recent years, there was an increase in myositis (30% vs 7%; P=.02), septic arthritis (68 vs 37.2%; p=0.012) and in the proportion of patients treated for less than 4 weeks (37 vs 3.5%; p=0.012), with a similar sequelae rates. The risk factors associated with complications were age 3 or more years, C-reactive protein levels of 20mg/L or higher, time elapsed between onset and admission of 5 or more days and positive culture, although the only factor that continued to be significantly associated in the multivariate analysis was positive culture. The presence of complications was a risk factor for sequelae at 6 months. CONCLUSIONS: Our study confirms that AHO can be aggressive. The identification of risk factors for complications is essential for management.

Risk factors for the emergence of multidrug-resistant organisms in liver cirrhosis / Factores de riesgo para la aparición de organismos multirresistentes en la cirrosis hepática

Background: Multidrug-resistant organisms (MDROs) are a reality that can alter the paradigm of treatment and prevention of infection in patients with liver cirrhosis (LC).ObjectiveIdentify risk factors for the occurrence of MDROs in patients with LC.Patients and methods: Prospective study from October 2017 to March 2018 in consecutively hospitalized patients with decompensated LC with infection. Blood, urine and ascitic fluid cultures were analyzed. A p-value ≤0.05 was considered statistically significant. Results: MDROs isolated in 18 of 52 episodes of infection. MDROs were associated with the use of proton pump inhibitors (PPIs) (p=0.0312), antibiotic therapy in the last 90 days (p=0.0033) and discharge within preceding 30 days or current hospitalization above 48h (p=0.0082). There was higher 90-day mortality in patients with MDROs infection (71.4% versus 35.7%, p=0.0316).Conclusion: MDROs infections were prevalent in this cohort and associated with 90-day mortality. Use of PPIs and antibiotics increased the risk of MDROs infections, suggesting that its prescription should be restricted to formal indication. Hospitalization was associated with the onset of MDROs, so LC patients should stay at the hospital the least possible. It is relevant to investigate other factors predisposing to the emergence of these microorganisms, in order to prevent it. (AU)

Antecedentes: Los organismos multirresistentes (MDROs, por sus siglas en inglés) son una realidad que puede alterar el paradigma del tratamiento y la prevención de la infección en los pacientes con cirrosis hepática (LC, por sus siglas en inglés).Objetivo: Identificar los factores de riesgo para la aparición de MDROs en pacientes con LC.Pacientes y métodos: Estudio prospectivo de octubre de 2017 a marzo de 2018 en pacientes hospitalizados consecutivamente con LC descompensada con infección. Se analizaron los cultivos de sangre, orina y líquido ascítico. Se consideró estadísticamente significativo un valor de p≤0,05.Resultados: Se aislaron MDROs en 18 de los 52 episodios de infección. Los MDROs se asociaron con el uso de inhibidores de la bomba de protones (IBP) (p=0,0312), la terapia antibiótica en los últimos 90 días (p=0,0033) y el alta en los 30 días anteriores o la hospitalización actual superior a 48h (p=0,0082). Hubo una mayor mortalidad a los 90 días en los pacientes con infección por MDROs (71,4 frente al 35,7%; p=0,0316).Conclusión: Las infecciones por MDROs fueron prevalentes en esta cohorte, y se asociaron con la mortalidad a los 90 días. El uso de IBP y antibióticos aumentó el riesgo de infecciones por MDROs, lo que sugiere que su prescripción debe restringirse a la indicación formal. La hospitalización se asoció a la aparición de MDROs, por lo que los pacientes con LC deberían permanecer en el hospital el menor tiempo posible. Es relevante investigar otros factores que predisponen a la aparición de estos microorganismos para prevenirla. (AU)

Osteomielitis hematógena aguda en Lisboa: asociación con miositis y artritis inesperadamente alta / Acute haematogenous osteomyelitis in Lisbon: An unexpectedly high association with myositis and arthritis

Introducción: Aunque actualmente se tiende a un abordaje terapéutico menos agresivo, la osteomielitis hematógena aguda (OHA) sigue suponiendo un reto, con una morbilidad significativa a nivel mundial. El objetivo del estudio fue evaluar si se alcanzó una adherencia del 80% con el protocolo vigente, identificar las complicaciones y riesgos asociados y analizar las tendencias en la etiología y el manejo de la OHA en la población pediátrica. Métodos: Estudio observacional longitudinal unicéntrico en pacientes menores de 18 años con OHA ingresados en un hospital pediátrico entre 2008 y 2018 divididos en 2 cohortes (antes y después de 2014). Se analizaron datos demográficos, clínicos y concernientes a la evolución de la enfermedad. Resultados: El estudio incluyó a 71 niños con OHA, 56% varones, con una edad mediana de 3 años (rango intercuartílico, 1-11). Se observó una incidencia 1,8 veces mayor en los últimos 5 años. El agente causal se identificó en el 37% de los casos: SASM (54%), SARM (4%), Streptococcus pyogenes (19%), Kingella kingae (12%), Streptococcus pneumoniae (8%) y Neisseria meningitidis (4%). Se identificaron complicaciones en el 45% y secuelas en 3,6% de los pacientes. En los últimos años aumentó la incidencia de miositis (30% vs. 7%; p=0,02) y de artritis séptica (después de 2015, 68% vs. 37,2%, p=0,012), así como la proporción de pacientes con tratamiento inferior a 4 semanas (37% vs. 3,5%; p=0,012), con tasas de secuelas similares. Los factores de riesgo de complicaciones fueron la edad ≥3 años, nivel de PCR≥20mg/l, duración de los síntomas al ingreso de 5 o más días y cultivo positivo, aunque en el análisis multivariado solo se validó el cultivo positivo. La presencia de complicaciones se identificó como factor de riesgo de secuelas a los 6 meses. Conclusiones: El presente estudio confirma que la OHA puede ser agresiva. La identificación de los factores de riesgo es fundamental para su abordaje. (AU)

Introduction: Despite the current trend towards less aggressive therapeutic approaches, acute haematogenous osteomyelitis (AHO) continues to be a challenge and is associated with significant morbidity worldwide. Our aim was to determine if 80% compliance with current protocol was achieved, identify complications and associated risk factors and analyse trends in aetiology and management of AHO in children. Methods: We conducted a longitudinal, observational, single-centre study in patients with AHO aged less than 18 years admitted to a paediatric hospital, between 2008 and 2018, divided into 2 cohorts (before and after 2014). Demographic, clinical data and disease progression were analysed. Results: The study included 71 children with AHO, 56% male, with a median age of 3 years (interquartile range, 1–11). We found a 1.8-fold increase of cases in the last 5 years. The causative agent was identified in 37% of cases: MSSA (54%), MRSA (4%), Streptococcus pyogenes (19%), Kingella kingae (12%), Streptococcus pneumoniae (8%), and Neisseria meningitidis (4%). Complications were identified in 45% of patients and sequelae in 3.6%. In recent years, there was an increase in myositis (30% vs. 7%; p=0.02), septic arthritis (68% vs. 37.2%; p=0.012) and in the proportion of patients treated for less than 4 weeks (37% vs. 3.5%; p=0.012), with a similar sequelae rates. The risk factors for complications were age 3 or more years, CRP levels of 20mg/l or higher, time elapsed between onset and admission of 5 or more days and positive culture, although on multivariate analysis only positive culture was significant. The presence of complications was a risk factor for sequelae at 6 months. Conclusions: Our study confirms that AHO can be aggressive. The identification of risk factors for complications may be fundamental for management. (AU)

Histological Inflammation in the Endoscopically Uninflamed Mucosa is Associated With Worse Outcomes in Limited Ulcerative Colitis.

BACKGROUND: The Montreal classification categorizes patients with ulcerative colitis (UC) based on their macroscopic disease extent. Independent of endoscopic extent, biopsies through all colonic segments should be retrieved during index colonoscopy. However, the prognostic value of histological inflammation at diagnosis in the inflamed and uninflamed regions of the colon has never been assessed. METHODS: This was a multicenter retrospective cohort study of newly diagnosed patients with treatment-naïve proctitis and left-sided UC. Biopsies from at least 2 colonic segments (endoscopically inflamed and uninflamed mucosa) were retrieved and reviewed by 2 pathologists. Histological features in the endoscopically inflamed and uninflamed mucosa were scored using the Nancy score. The primary outcomes were disease complications (proximal disease extension, need for hospitalization or colectomy) and higher therapeutic requirements (need for steroids or for therapy escalation). RESULTS: Overall, 93 treatment-naïve patients were included, with a median follow-up of 44 months (range, 2-329). The prevalence of any histological inflammation above the endoscopic margin was 71%. Proximal disease extension was more frequent in patients with histological inflammation in the endoscopically uninflamed mucosa at diagnosis (21.5% vs 3.4%, P = 0.04). Histological involvement above the endoscopic margin was the only predictor associated with an earlier need for therapy escalation (adjusted hazard ratio, 3.69; 95% confidence interval, 1.05-13.0); P = 0.04) and disease complications (adjusted hazard ratio, 4.79; 95% confidence interval, 1.10-20.9; P = 0.04). CONCLUSIONS: The presence of histological inflammation in the endoscopically uninflamed mucosa at the time of diagnosis was associated with worse outcomes in limited UC.

Risk factors for the emergence of multidrug-resistant organisms in liver cirrhosis.

BACKGROUND: Multidrug-resistant organisms (MDROs) are a reality that can alter the paradigm of treatment and prevention of infection in patients with liver cirrhosis (LC). OBJECTIVE: Identify risk factors for the occurrence of MDROs in patients with LC. PATIENTS AND METHODS: Prospective study from October 2017 to March 2018 in consecutively hospitalized patients with decompensated LC with infection. Blood, urine and ascitic fluid cultures were analyzed. A p-value ≤0.05 was considered statistically significant. RESULTS: MDROs isolated in 18 of 52 episodes of infection. MDROs were associated with the use of proton pump inhibitors (PPIs) (p=0.0312), antibiotic therapy in the last 90 days (p=0.0033) and discharge within preceding 30 days or current hospitalization above 48h (p=0.0082). There was higher 90-day mortality in patients with MDROs infection (71.4% versus 35.7%, p=0.0316). CONCLUSION: MDROs infections were prevalent in this cohort and associated with 90-day mortality. Use of PPIs and antibiotics increased the risk of MDROs infections, suggesting that its prescription should be restricted to formal indication. Hospitalization was associated with the onset of MDROs, so LC patients should stay at the hospital the least possible. It is relevant to investigate other factors predisposing to the emergence of these microorganisms, in order to prevent it.

Determinants of the Use of Health and Fitness Mobile Apps by Patients With Asthma: Secondary Analysis of Observational Studies.

BACKGROUND: Health and fitness apps have potential benefits to improve self-management and disease control among patients with asthma. However, inconsistent use rates have been reported across studies, regions, and health systems. A better understanding of the characteristics of users and nonusers is critical to design solutions that are effectively integrated in patients' daily lives, and to ensure that these equitably reach out to different groups of patients, thus improving rather than entrenching health inequities. OBJECTIVE: This study aimed to evaluate the use of general health and fitness apps by patients with asthma and to identify determinants of usage. METHODS: A secondary analysis of the INSPIRERS observational studies was conducted using data from face-to-face visits. Patients with a diagnosis of asthma were included between November 2017 and August 2020. Individual-level data were collected, including age, gender, marital status, educational level, health status, presence of anxiety and depression, postcode, socioeconomic level, digital literacy, use of health services, and use of health and fitness apps. Multivariate logistic regression was used to model the probability of being a health and fitness app user. Statistical analysis was performed in R. RESULTS: A total of 526 patients attended a face-to-face visit in the 49 recruiting centers and 514 had complete data. Most participants were ≤40 years old (66.4%), had at least 10 years of education (57.4%), and were in the 3 higher quintiles of the socioeconomic deprivation index (70.1%). The majority reported an overall good health status (visual analogue scale [VAS] score>70 in 93.1%) and the prevalence of anxiety and depression was 34.3% and 11.9%, respectively. The proportion of participants who reported using health and fitness mobile apps was 41.1% (n=211). Multivariate models revealed that single individuals and those with more than 10 years of education are more likely to use health and fitness mobile apps (adjusted odds ratio [aOR] 2.22, 95%CI 1.05-4.75 and aOR 1.95, 95%CI 1.12-3.45, respectively). Higher digital literacy scores were also associated with higher odds of being a user of health and fitness apps, with participants in the second, third, and fourth quartiles reporting aORs of 6.74 (95%CI 2.90-17.40), 10.30 (95%CI 4.28-27.56), and 11.52 (95%CI 4.78-30.87), respectively. Participants with depression symptoms had lower odds of using health and fitness apps (aOR 0.32, 95%CI 0.12-0.83). CONCLUSIONS: A better understanding of the barriers and enhancers of app use among patients with lower education, lower digital literacy, or depressive symptoms is key to design tailored interventions to ensure a sustained and equitable use of these technologies. Future studies should also assess users' general health-seeking behavior and their interest and concerns specifically about digital tools. These factors may impact both initial engagement and sustained use.

[Acute haematogenous osteomyelitis in Lisbon: An unexpectedly high association with myositis and arthritis]. / Osteomielitis hematógena aguda en Lisboa: asociación con miositis y artritis inesperadamente alta.

INTRODUCTION: Despite the current trend towards less aggressive therapeutic approaches, acute haematogenous osteomyelitis (AHO) continues to be a challenge and is associated with significant morbidity worldwide. Our aim was to determine if 80% compliance with current protocol was achieved, identify complications and associated risk factors and analyse trends in aetiology and management of AHO in children. METHODS: We conducted a longitudinal, observational, single-centre study in patients with AHO aged less than 18 years admitted to a paediatric hospital, between 2008 and 2018, divided into 2 cohorts (before and after 2014). Demographic, clinical data and disease progression were analysed. RESULTS: The study included 71 children with AHO, 56% male, with a median age of 3 years (interquartile range, 1-11). We found a 1.8-fold increase of cases in the last 5 years. The causative agent was identified in 37% of cases: MSSA (54%), MRSA (4%), Streptococcus pyogenes (19%), Kingella kingae (12%), Streptococcus pneumoniae (8%), and Neisseria meningitidis (4%). Complications were identified in 45% of patients and sequelae in 3.6%. In recent years, there was an increase in myositis (30% vs. 7%; p=0.02), septic arthritis (68% vs. 37.2%; p=0.012) and in the proportion of patients treated for less than 4 weeks (37% vs. 3.5%; p=0.012), with a similar sequelae rates. The risk factors for complications were age 3 or more years, CRP levels of 20mg/l or higher, time elapsed between onset and admission of 5 or more days and positive culture, although on multivariate analysis only positive culture was significant. The presence of complications was a risk factor for sequelae at 6 months. CONCLUSIONS: Our study confirms that AHO can be aggressive. The identification of risk factors for complications may be fundamental for management.

The transcription factor Ndt80 is a repressor of Candida parapsilosis virulence attributes.

Candida parapsilosis is an emergent opportunistic yeast among hospital settings that affects mainly neonates and immunocompromised patients. Its most remarkable virulence traits are the ability to adhere to prosthetic materials, as well as the formation of biofilm on abiotic surfaces. The Ndt80 transcription factor was identified as one of the regulators of biofilm formation by C. parapsilosis; however, its function in this process was not yet clarified. By knocking out NDT80 (CPAR2-213640) gene, or even just one single copy of the gene, we observed substantial alterations of virulence attributes, including morphogenetic changes, adhesion and biofilm growth profiles. Both ndt80Δ and ndt80ΔΔ mutants changed colony and cell morphologies from smooth, yeast-shaped to crepe and pseudohyphal elongated forms, exhibiting promoted adherence to polystyrene microspheres and notably, forming a higher amount of biofilm compared to wild-type strain. Interestingly, we identified transcription factors Ume6, Cph2, Cwh41, Ace2, Bcr1, protein kinase Mkc1 and adhesin Als7 to be under Ndt80 negative regulation, partially explaining the phenotypes displayed by the ndt80ΔΔ mutant. Furthermore, ndt80ΔΔ pseudohyphae adhered more rapidly and were more resistant to murine macrophage attack, becoming deleterious to such cells after phagocytosis. Unexpectedly, our findings provide the first evidence for a direct role of Ndt80 as a repressor of C. parapsilosis virulence attributes. This finding shows that C. parapsilosis Ndt80 functionally diverges from its homolog in the close related fungal pathogen C. albicans.

The role of gastroduodenal stents in palliation of malignant gastroduodenal outlet obstruction, regarding the article by Alcalá-González et al.

We read with great interest the article of Luis Alcalá-González et al. This study reinforces the scientific evidence regarding safety and effectiveness of self-expandable metal stent placement for the palliation of malignant gastric outlet obstruction (GOO). Our special interest in this topic makes us want to share the experience of our center and to strengthen some of the key points.

MAJOR PULMONARY SURGERY IN PATIENTS WITH COMPROMISED LUNG FUNCTION.

INTRODUCTION: The risk stratification of lung resection is fundamentally based on the results of pulmonary function tests. In patients considered to be at risk, major surgery is generally denied, opting for potentially less curative therapies. OBJECTIVE: To evaluate the postoperative outcomes of major lung surgery in a group of patients deemed high risk. METHODS: We performed a retrospective review of clinical records of all patients submitted to lobectomy, bilobectomy or pneumonectomy in a 3-year period in a reference Thoracic Surgery Unit. The patients were then divided in two groups: group A composed of patients with normal preoperative pulmonary function and group B which included patients with impaired lung function, defined as FEV1 and/or DLCO ≤60%. RESULTS: A total of 234 patients were included, 181 (77.4%) in group A and 53 (22.6%) in group B. In group B, patients had more smoking habits, were more often associated with chronic obstructive pulmonary disease and were also more frequently submitted to thoracotomy. When surgery was motivated by primary lung cancer this group had a more advanced clinical stage of the disease. In the postoperative period, these patients had longer hospital stay, longer chest drainage time and greater need for oxygen therapy at home, however, no statistically significant difference was noted in morbidity or mortality. CONCLUSIONS: Major thoracic surgery can be safely performed in selected patients considered to be high risk for resection by pulmonary function tests. A potentially curative surgery should not be denied based on respiratory function tests alone.