Use of homeopathic products in pigs feed improves the percentage, quality and marbling of meat.

Studies and innovations on alternative feed additives, especially on homeopathic remedies have been highlighted in order to replace or reduce the use of antibiotics in pig production. This paper aimed to assess the addition of homeopathic products in pig diet and their effects on the growth performance, serum metabolites, nutrient and energy digestibility, carcass traits and meat quality. A total of 60 immunocastrated male pigs, weighing on average 30.91 ± 0.95 kg, were distributed in two treatments, 10 replicates and three animals/experimental unit. There was no effect (P≥0.05) of treatment on the growth performance and serum metabolites. The percentage of acid-insoluble ash recovered in the diet was greater (P≤0.01) in diets containing homeopathic products. The apparent digestible energy of diets containing homeopathic products was reduced (P≤0.01) in the growing phase and reduced (P≤0.01) the apparent digestibility coefficients of dry matter, crude protein, soluble neutral and acid detergent fibers, and gross energy in the growing and finishing phases. Pig that received diets with homeopathic products had higher (P≤0.05) amount of meat, percentage of meat and marbling. The use of homeopathic products in diets improves the percentage and quality of meat, as well as the marbling of the pig carcass, maintaining the performance.

Unveiling the role of osteosarcoma-derived secretome in premetastatic lung remodelling.

BACKGROUND: Lung metastasis is the most adverse clinical factor and remains the leading cause of osteosarcoma-related death. Deciphering the mechanisms driving metastatic spread is crucial for finding open therapeutic windows for successful organ-specific interventions that may halt or prevent lung metastasis. METHODS: We employed a mouse premetastatic lung-based multi-omics integrative approach combined with clinical features to uncover the specific changes that precede lung metastasis formation and identify novel molecular targets and biomarker of clinical utility that enable the design of novel therapeutic strategies. RESULTS: We found that osteosarcoma-bearing mice or those preconditioned with the osteosarcoma cell secretome harbour profound lung structural alterations with airway damage, inflammation, neutrophil infiltration, and extracellular matrix remodelling with increased deposition of fibronectin and collagens by resident stromal activated fibroblasts, favouring the adhesion of disseminated tumour cells. Systemic-induced microenvironmental changes, supported by transcriptomic and histological data, promoted and accelerated lung metastasis formation. Comparative proteome profiling of the cell secretome and mouse plasma identified a large number of proteins involved in extracellular-matrix organization, cell-matrix adhesion, neutrophil degranulation, and cytokine-mediated signalling, consistent with the observed lung microenvironmental changes. Moreover, we identified EFEMP1, an extracellular matrix glycoprotein exclusively secreted by metastatic cells, in the plasma of mice bearing a primary tumour and in biopsy specimens from osteosarcoma patients with poorer overall survival. Depletion of EFEMP1 from the secretome prevents the formation of lung metastasis. CONCLUSIONS: Integration of our data uncovers neutrophil infiltration and the functional contribution of stromal-activated fibroblasts in ECM remodelling for tumour cell attachment as early pro-metastatic events, which may hold therapeutic potential in preventing or slowing the metastatic spread. Moreover, we identified EFEMP1, a secreted glycoprotein, as a metastatic driver and a potential candidate prognostic biomarker for lung metastasis in osteosarcoma patients. Osteosarcoma-derived secreted factors systemically reprogrammed the lung microenvironment and fostered a growth-permissive niche for incoming disseminated cells to survive and outgrow into overt metastasis. Daily administration of osteosarcoma cell secretome mimics the systemic release of tumour-secreted factors of a growing tumour in mice during PMN formation; Transcriptomic and histological analysis of premetastatic lungs revealed inflammatory-induced stromal fibroblast activation, neutrophil infiltration, and ECM remodelling as early onset pro-metastatic events; Proteome profiling identified EFEMP1, an extracellular secreted glycoprotein, as a potential predictive biomarker for lung metastasis and poor prognosis in osteosarcoma patients. Osteosarcoma patients with EFEMP1 expressing biopsies have a poorer overall survival.

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.

Identification of biomarkers to stratify response to B-cell-targeted therapies in systemic lupus erythematosus: an exploratory analysis of a randomised controlled trial.

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disease associated with widespread immune dysregulation and diverse clinical features. Immune abnormalities might be differentially associated with specific organ involvement or response to targeted therapies. We aimed to identify biomarkers of response to belimumab after rituximab to facilitate a personalised approach to therapy. Methods: In this exploratory analysis of a randomised controlled trial (BEAT-LUPUS), we investigated immune profiles of patients with SLE recruited to the 52-week clinical trial, which tested the combination of rituximab plus belimumab versus rituximab plus placebo. We used machine learning and conventional statistics to investigate relevant laboratory and clinical biomarkers associated with major clinical response. BEAT LUPUS is registered at ISRCTN, 47873003, and is now complete. Findings: Between Feb 2, 2017, and March 28, 2019, 52 patients were recruited to BEAT-LUPUS, of whom 44 provided clinical data at week 52 and were included in this analysis. 21 (48%) of 44 participants were in the belimumab group (mean age 39·5 years [SD 12·1]; 17 [81%] were female, four [19%] were male, 13 [62%] were White) and 23 (52%) were in the placebo group (mean age 42·1 years [SD 10·5]; 21 [91%] were female, two [9%] were male, 16 [70%] were White). Ten (48%) of 21 participants who received belimumab after rituximab and eight (35%) of 23 who received placebo after rituximab had a major clinical response at 52 weeks (between-group difference of 13% [95% CI -15 to 38]). We found a predictive association between baseline serum IgA2 anti-double stranded DNA (dsDNA) antibody concentrations and clinical response to belimumab after rituximab, with a between-group difference in major clinical response of 48% (95% CI 10 to 70) in patients with elevated baseline serum IgA2 anti-dsDNA antibody concentrations. Moreover, among those who had a major clinical response, serum IgA2 anti-dsDNA antibody concentrations significantly decreased from baseline only in the belimumab group. Increased circulating IgA2 (but not total) plasmablast numbers, and T follicular helper cell numbers predicted clinical response and were both reduced only in patients who responded to belimumab after rituximab. Serum IgA2 anti-dsDNA antibody concentrations were also associated with active renal disease, whereas serum IgA1 anti-dsDNA antibody and IFN-α concentrations were associated with mucocutaneous disease activity but did not predict response to B-cell targeted therapy. Patients with a high baseline serum interleukin-6 concentration were less likely to have a major clinical response, irrespective of therapy. Interpretation: This exploratory study revealed the presence of distinct molecular networks associated with renal and mucocutaneous involvement, and response to B-cell-targeted therapies, which, if confirmed, could guide precision targeting of advanced therapies for this heterogenous disease. Funding: Versus Arthritis, UCLH Biomedical Research Centre, LUPUS UK, and GSK.

A novel isolation method for spontaneously released extracellular vesicles from brain tissue and its implications for stress-driven brain pathology.

BACKGROUND: Extracellular vesicles (EVs), including small EVs (sEVs) such as exosomes, exhibit great potential for the diagnosis and treatment of brain disorders, representing a valuable tool for precision medicine. The latter demands high-quality human biospecimens, especially in complex disorders in which pathological and specimen heterogeneity, as well as diverse individual clinical profile, often complicate the development of precision therapeutic schemes and patient-tailored treatments. Thus, the collection and characterization of physiologically relevant sEVs are of the utmost importance. However, standard brain EV isolation approaches rely on tissue dissociation, which can contaminate EV fractions with intracellular vesicles. METHODS: Based on multiscale analytical platforms such as cryo-EM, label-free proteomics, advanced flow cytometry, and ExoView analyses, we compared and characterized the EV fraction isolated with this novel method with a classical digestion-based EV isolation procedure. Moreover, EV biogenesis was pharmacologically manipulated with either GW4869 or picrotoxin to assess the validity of the spontaneous-release method, while the injection of labelled-EVs into the mouse brain further supported the integrity of the isolated vesicles. RESULTS: We hereby present an efficient purification method that captures a sEV-enriched population spontaneously released by mouse and human brain tissue. In addition, we tested the significance of the release method under conditions where biogenesis/secretion of sEVs was pharmacologically manipulated, as well as under animals' exposure to chronic stress, a clinically relevant precipitant of brain pathologies, such as depression and Alzheimer's disease. Our findings show that the released method monitors the drug-evoked inhibition or enhancement of sEVs secretion while chronic stress induces the secretion of brain exosomes accompanied by memory loss and mood deficits suggesting a potential role of sEVs in the brain response to stress and related stress-driven brain pathology. CONCLUSIONS: Overall, the spontaneous release method of sEV yield may contribute to the characterization and biomarker profile of physiologically relevant brain-derived sEVs in brain function and pathology. Video Abstract.

Survey on selenium clinical supplementation in autoimmune thyroid disease.

Objective: Previous trials show that selenium could be a very useful tool in the control and treatment of autoimmune thyroid diseases. In this cross-sectional study, through a survey, we aim to evaluate Portuguese endocrinologists' perception and pattern of prescription of selenium supplements in these diseases and verify its agreement with current guidelines. Methods: The endocrinologists registered in the Portuguese Medical Association were sent an email with a web-based questionnaire, regarding their knowledge and use of selenium supplements in thyroid autoimmune pathology. Results: A total of 105 physicians (33% of the total) submitted the survey. The selenium serum concentration in the general population was unknown to 80% of respondents. Over a third of respondents have never prescribed selenium for autoimmune thyroid disease. However, 89% are not afraid of recommending it, and 61% indicate Graves' orbitopathy as the pathology they would supplement. In Hashimoto's thyroiditis, 36% of respondents use selenium occasionally or frequently, and this percentage rises to 60% in Graves' disease. Conclusions: Although recommendations only encompass mild Graves' orbitopathy, selenium is prescribed across the spectrum of autoimmune thyroid diseases, probably due to recent studies that consistently show improvement of biochemical hallmarks in these patients. Further investigation is required on the impact of selenium supplements on primarily clinical outcomes and to identify disorders and/or patients who will benefit the most. Also, there is still insufficient knowledge of this field in the medical community, and evidence-based practice should continue to be promoted by endocrinology societies.

O uso de tecnologias digitais nas práticas de trabalhadores comunitários de saúde: uma revisão internacional de escopo / El uso de las tecnologías digitales en las prácticas de los trabajadores comunitarios de la salud: una revisión internacional del alcance / The use of digital technologies in the practices of community health workers: an international scoping review

RESUMO Este artigo objetiva mapear a literatura sobre as aplicações e percepções acerca do uso de tecnologias digitais nas práticas de trabalhadores comunitários de saúde. Trata-se de uma revisão de escopo realizada na PubMed, Bireme, SciELO, Web of Science, Embase e Scopus. Foram incluídos 63 artigos que relatam o uso de tecnologias digitais por esses trabalhadores em 24 países. Como resultados, identificou-se que o suporte à saúde materno-infantil é a condição com maior predomínio das práticas. Os benefícios identificados envolvem ampliação do acesso, melhoria da gestão do trabalho, qualificação, diversificação, ampliação da formação e ganho de legitimidade da categoria. Os desafios se traduzem nas limitações em relação ao vínculo com a comunidade, longitudinalidade do cuidado, acesso à internet, energia elétrica e alfabetização digital. Como conclusão, corrobora-se com análises acerca da irreversibilidade do uso de tecnologias de informação e comunicação no mundo do trabalho, destacando-se a necessidade do seu uso racional dessas com a garantia do acesso de forma integral, universal e equitativa.

RESUMEN Este artículo tiene por objeto mapear la literatura sobre las aplicaciones y percepciones acerca del uso de tecnologías digitales en las prácticas de los trabajadores comunitarios de la salud. Se trata de una revisión del alcance realizada en PubMed, Bireme, SciELO, Web of Science, Embase y Scopus. Se han incluido 63 artículos sobre el uso de tecnologías digitales por parte de estos trabajadores en 24 países. Como resultado, se ha identificado que el apoyo a la salud maternoinfantil es la condición con mayor predominio de las prácticas. Los beneficios identificados implican la ampliación del acceso, mejora de la gestión del trabajo, calificación, diversificación, ampliación de la formación y aumento de la legitimidad de la categoría. Los desafíos se traducen en limitaciones en relación con el vínculo con la comunidad, la longitudinalidad de la atención, el acceso a Internet, la energía eléctrica y la alfabetización digital. En conclusión, se corrobora con análisis sobre la irreversibilidad del uso de las tecnologías de la información y la comunicación en el mundo del trabajo, y se destaca la necesidad de su uso racional con la garantía del acceso de manera integral, universal y equitativa.

ABSTRACT This article aims to map the literature on the applications and perceptions regarding the use of digital technologies in the practices of community health workers. This is a scoping review conducted on PubMed, Bireme, SciELO, Web of Science, Embase, and Scopus. A total of 63 articles reporting the use of digital technologies by these workers in 24 countries were included. As a result, it was identified that support for maternal and child health is the most prevalent condition in these practices. The identified benefits involve increased access, improved work management, qualification, diversification, expanded training, and increased legitimacy of the profession. The challenges are reflected in limitations regarding community engagement, continuity of care, internet access, electricity, and digital literacy. In conclusion, it supports analyses regarding the irreversibility of the use of information and communication technologies in the world of work, emphasizing the need for their rational use while ensuring comprehensive, universal, and equitable access.

Detection of SARS-CoV-2 infection in thyroid follicular cells from a COVID-19 autopsy series.

Objective: To understand whether thyroid cells can be directly infected by the SARS-CoV-2 virus and to establish a putative correlation with the expression of the host entry machinery: ACE-2, TMPRSS2, and furin. Methods: We assessed the presence of SARS-CoV-2 virus at the gene level by RT-PCR, viral RNA transcripts localization by in situ hybridization, and by detecting viral proteins by immunohistochemistry for the nucleocapsid and the spike proteins. Furthermore, we also described the immunoexpression of key host factors for virus entry in the COVID-19 thyroid samples. Results: We performed RT-PCR for SARS-CoV-2 in all autopsy specimens and detected viral genome positivity in 13 of 15 thyroid tissues and in a lung specimen. In 9 of the 14 positive samples, we were also able to confirm SARS-CoV-2 signal by in situ hybridization. Immunohistochemistry for the viral nucleocapsid and spike protein was also positive for ten and nine of the RT-PCR-positive cases, respectively, but revealed a lower sensitivity. We also described, for the first time in a COVID-19 series, the immunohistochemical expression of ACE-2, TMPRSS2, and furin in the thyroid. Conclusions: Our results obtained in thyroid specimens from deceased COVID-19 patients indicate that thyrocytes can be directly infected by SARS-CoV-2 since we detected the presence of SARS-CoV-2 genome in follicular cells. Nevertheless, we did not find a clear correlation between the presence of viral genome and the expression of the host factors for virus entry, namely ACE-2, TMPRSS2, and furin.

Silage as a pre-treatment of orange bagasse waste to increase the potential for methane generation.

Among the various methods of pre-treatment of lignocellulosic waste with the objective of optimizing the production of methane, silage stands out as a promising alternative due to its operational simplicity, low cost and effective results. In this work, the silage of orange waste (Citrus cinensis) with 14 and 21 days and its influence on the potential of methane generation was evaluated, also evaluating the impacts of silage on the kinetics of the process. Among several configurations of substrate and inoculum studied, the best configuration observed was using the ensiled residue with 21 days and granular anaerobic sludge (ENS21 + GS), reaching a methane generation potential of about 171 N mL·g-1 VS, increasing by 119% in terms of methane generation potential without silage pre-treatment (WENS+GS), obtaining biogas with 70% in CH4. In relation to the kinetics, the silage process drastically interfered in the kinetic behavior of the methane production, being the Cone model the one that obtained the best adjustments, among those studied, for the orange bagasse residue in the evaluated experimental conditions. Silage is an attractive alternative to increase the production of methane for lignocellulosic waste, as a pre-treatment, without significantly increasing operating costs, and it can also be associated with other sequential processes to take advantage of the maximum energy potential of lignocellulosic waste.

Caveats of the internal transcribed spacer region as a barcode to resolve species boundaries in Diaporthe.

Species in Diaporthe are largely reported as important plant pathogens. Identification of species in this genus has been complemented by morphological and molecular features. However, one important factor delaying this process is the struggle to formulate robust species concepts to create adequate international phytosanitary measures. Regardless of the wide use of the internal transcribed spacer (ITS) rDNA region, established as the primary DNA barcode for fungi, the tendency for intraspecific variation has been reported, misleading interpretation of phylogenetic analyses. Therefore, the present study aimed to illustrate, using specific examples, how the ITS region may be problematic for species delimitation. We showed that the ITS region is highly variable, with strains of Diaporthe malorum and Diaporthe novem falling into more than one clade, which if analyzed on their own, would be likely recognized as distinct taxa. Divergent ITS paralogs were also proven to coexist within the genome of D. novem. We also suggest that ITS may have escaped from concerted evolution or has undergone a duplication event. Furthermore, this study reports for the first time the existence of a putative hybrid in the genus Diaporthe. Our findings offer new clues towards the intraspecific and intragenomic variation in the ITS region, raising questions about its value for barcoding, i.e., identifying species in the genus Diaporthe. Therefore, we recommend that the ITS region be analyzed cautiously and always compared for congruence prior to description of novel taxa.

Desastres com petróleo e ações governamentais ante os impactos socioambientais e na saúde: scoping review / Oil disasters and government actions in the face of social, environmental, and health-related impacts: A scoping review

RESUMO Este artigo teve por objetivo analisar as ações desenvolvidas pelos governos para o enfrentamento dos impactos socioambientais e na saúde em decorrência dos desastres envolvendo petróleo no mundo. Trata-se de uma revisão de escopo realizada na Bireme, Lilacs, SciELO, PubMed, Cochrane Library e Embase, considerando artigos publicados entre 1973 e 2021. As buscas efetuadas nas bases de dados resultaram em 22 artigos sobre 10 desastres de petróleo ao redor do mundo em três continentes (Ásia, América e Europa), cujas causas dos desastres foram encalhe (3), naufrágio (1), colisão (2), derrame (3) e explosão (1). As ações desenvolvidas foram caracterizadas como intersetoriais, econômicas, ambientais e na saúde, sendo que as mais frequentes foram ações ambientais e econômicas. Nas ações desenvolvidas, observaram-se críticas ao controle, mitigação ou prevenção dos danos instantâneos ou futuros decorrentes dos desastres por petróleo, sendo essa uma agenda ainda em aberto para os movimentos sociais na luta pela garantia de um ambiente saudável, promotor de saúde e com preservação de toda a sua biodiversidade. Conclui-se que as ações para o enfrentamento dos desastres por petróleo nos diferentes países parecem ter sido incipientes, revelando uma incapacidade governamental de orientar o enfrentamento dos impactos desse evento inusitado.

ABSTRACT This article aims to analyze the actions taken by governments to face the social, environmental, and health impacts of oil spill disasters worldwide. This scoping review was conducted in Bireme, Lilacs, SciELO, PubMed, Cochrane Library, and Embase databases, considering articles published between 1973 and 2021. The database search returned 22 articles on ten global oil disasters in three continents (Asia, the Americas, and Europe), whose causes were grounding (03), shipwreck (01), collision (02), spill (03), and explosion (01). The actions developed were characterized as intersectoral, economic, environmental, and health-related, and the most frequent were environmental and economic actions. In the actions developed, we observed criticisms of controlling, mitigating, or preventing instantaneous or future damages resulting from oil disasters, which is still an open agenda for social movements in the struggle to ensure a healthy, health-promoting environment that preserves all its biodiversity. The actions to face oil disasters in different countries seem incipient, revealing a governmental inability to guide the confrontation of the impacts of this unusual event.

Nanobody-Based Theranostic Agents for HER2-Positive Breast Cancer: Radiolabeling Strategies.

The overexpression of human epidermal growth factor 2 (HER2) in breast cancer (BC) has been associated with a more aggressive tumor subtype, poorer prognosis and shorter overall survival. In this context, the development of HER2-targeted radiotracers is crucial to provide a non-invasive assessment of HER2 expression to select patients for HER2-targeted therapies, monitor response and identify those who become resistant. Antibodies represent ideal candidates for this purpose, as they provide high contrast images for diagnosis and low toxicity in the therapeutic setting. Of those, nanobodies (Nb) are of particular interest considering their favorable kinetics, crossing of relevant biological membranes and intratumoral distribution. The purpose of this review is to highlight the unique characteristics and advantages of Nb-based radiotracers in BC imaging and therapy. Additionally, radiolabeling methods for Nb including direct labeling, indirect labeling via prosthetic group and indirect labeling via complexation will be discussed, reporting advantages and drawbacks. Furthermore, the preclinical to clinical translation of radiolabeled Nbs as promising theranostic agents will be reported.

Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus : A Randomized Controlled Trial.

BACKGROUND: B-cell depletion with rituximab is commonly used for patients with systemic lupus erythematosus (SLE) that is refractory to conventional therapy, but it yields variable responses. We hypothesized that high B-cell activating factor (BAFF) levels after rituximab can cause disease flares, thereby limiting its effectiveness. OBJECTIVE: To obtain preliminary evidence for efficacy of the anti-BAFF therapeutic belimumab after rituximab in SLE. DESIGN: Phase 2, randomized, double-blind (patients, assessors, researchers, care providers), placebo-controlled, parallel-group, superiority trial. (ISRCTN: 47873003). SETTING: England. PARTICIPANTS: Fifty-two patients who had SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy were recruited between 2 February 2017 and 28 March 2019. INTERVENTION: Participants were treated with rituximab and 4 to 8 weeks later were randomly assigned (1:1) to receive intravenous belimumab or placebo for 52 weeks. MEASUREMENTS: The prespecified primary end point was serum IgG anti-double-stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes included incidence of disease flares and adverse events. RESULTS: At 52 weeks, IgG anti-dsDNA antibody levels were lower in patients treated with belimumab compared with placebo (geometric mean, 47 [95% CI, 25 to 88] vs. 103 [CI, 49 to 213] IU/mL; 70% greater reduction from baseline [CI, 46% to 84%]; P < 0.001). Belimumab reduced risk for severe flare (BILAG-2004 grade A) compared with placebo (hazard ratio, 0.27 [CI, 0.07 to 0.98]; log-rank P = 0.033), with 10 severe flares in the placebo group and 3 in the belimumab group. Belimumab did not increase incidence of serious adverse events. Belimumab significantly suppressed B-cell repopulation compared with placebo (geometric mean, 0.012 [CI, 0.006 to 0.014] vs. 0.037 [CI, 0.021 to 0.081] × 109/L) at 52 weeks in a subset of patients (n = 25) with available data. LIMITATIONS: Small sample size; biomarker primary end point. CONCLUSION: Belimumab after rituximab significantly reduced serum IgG anti-dsDNA antibody levels and reduced risk for severe flare in patients with SLE that was refractory to conventional therapy. The results suggest that this combination could be developed as a therapeutic strategy. PRIMARY FUNDING SOURCE: Versus Arthritis.

Diaporthe amygdali, a species complex or a complex species?

Delimitation of species boundaries within the fungal genus Diaporthe has been challenging, but the analyses of combined multilocus DNA sequences has become an important tool to infer phylogenetic relationships and to circumscribe species. However, analyses of congruence between individual gene genealogies and the application of the genealogical concordance principle have been somehow overlooked. We noted that a group of species including D. amygdali, D. garethjonesii, D. sterilis, D. kadsurae, D. ternstroemia, D. ovoicicola, D. fusicola, D. chongqingensis and D. mediterranea, commonly known as D. amygdali complex, occupy a monophyletic clade in Diaporthe phylogenies but the limits of all species within the complex are not entirely clear. To assess the boundaries of species within this complex we employed the Genealogical Concordance Phylogenetic Species Recognition principle (GCPSR) and coalescence-based models: General Mixed Yule-Coalescent (GMYC) and Poisson Tree Processes (PTP). The incongruence detected between individual gene phylogenies, as well as the results of coalescent methods do not support the recognition of lineages within the complex as distinct species. Moreover, results support the absence of reproductive isolation and barriers to gene flow in this complex, thus providing further evidence that the D. amygdali species complex constitutes a single species. This study highlights the relevance of the application of the GCPSR principle, showing that concatenation analysis of multilocus DNA sequences, although being a powerful tool, might lead to an erroneous definition of species limits. Additionally, it further shows that coalescent methods are useful tools to assist in a more robust delimitation of species boundaries in the genus Diaporthe.

Bird Fancier's Lung diagnosis in times of COVID-19 / Diagnóstico de la neumonitis de los avicultores en tiempos de la covid-19

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Immunosuppression Therapy in Acquired Hemophilia A: Pursuing an Optimal Regimen.

Acquired hemophilia A (AHA) is a rare bleeding disorder occurring mostly in elderly persons, caused by inhibition of factor VIII (FVIII). It is generally detected prior to surgery by an isolated prolonged activated partial thromboplastin time (aPTT) not correcting on mixing studies, with subsequent identification of reduced FVIII levels and presence of FVIII inhibitor. It is treated with hemostatics and immunosuppressants, which may increase the risk for life-threatening opportunistic infections. A 79-year-old woman with idiopathic acquired FVIII inhibition and severe bleeding presented with anemia, isolated and prolonged aPTT, low FVIII activity (<1%), and elevated FVIII inhibitor titer (471 Bethesda units per milliliter [BU/mL]). Initially, she was treated with recombinant activated factor VII and steroids. However, several hematomas appeared, one of which caused airway compression that required orotracheal intubation. Cyclophosphamide, rituximab (RTX), and activated prothrombin complex concentrate were initiated, resulting in clinical and laboratory resolution after five weeks. Cyclophosphamide and RTX were maintained for six and four weeks more, respectively. After 12 weeks of oral immunosuppression, the patient was readmitted due to antibiotic-resistant Pseudomonas aeruginosa sepsis, which resulted in death. Infection secondary to immunosuppression is the leading cause of death of patients with AHA. In AHA, combination therapy was shown to be more effective than monotherapy, but it was also identified to increase the risk of infection. Age, FVIII activity <1%, and FVIII inhibitor titers >20 BU are predictors of adverse events and poor prognosis in AHA patients. Additional studies are needed to clarify the ideal drug regimens and the need for prophylactic antibiotics in this population.

Intranasal fosphenytoin: The promise of phosphate esters in nose-to-brain delivery of poorly soluble drugs.

Intranasal administration could increase both safety and efficacy of drugs acting on the central nervous system, but low solubility severely limits administration through this route. Phenytoin's prodrug, fosphenytoin, is hydrophilic and freely soluble in water, but less permeable since it is dianionic. We aimed to assess whether this phosphoester prodrug could be a suitable alternative to phenytoin in intranasal delivery. Secondly, we aimed to compare simple formulation strategies in fosphenytoin delivery. Fosphenytoin formulations containing thermosensitive and/or mucoadhesive (hydroxypropyl methylcellulose, HPMC) polymers were developed, guided by viscosity, gelling temperatures, osmolality, and in vitro drug release tests. Then, a pharmacokinetic study was performed, comparing an intravenous fosphenytoin solution, an intranasal fosphenytoin solution, and intranasal fosphenytoin mucoadhesive formulations with or without albumin. Formulations containing HPMC allowed high drug strengths, and had a relatively fast release profile, which was not changed by albumin. Intranasal administration of a formulation with HPMC and albumin prolonged drug concentration over time and led to complete or even increased absolute bioavailability. Moreover, phenytoin's blood levels did not reach the high peak obtained with intravenous administration. In conclusion, the use of phosphate ester prodrugs could be an efficient and safe strategy to increase the intranasal bioavailability of poorly soluble drugs.