Conversion to Autologous Breast Reconstruction with Latissimus Dorsi and Immediate Fat Grafting in Patients with Previous Implant Failure: An Efficient, Reproducible, and Safe Technique.

Introduction Implant-based breast reconstructions (IBBRs) increased last years despite the growing indications for radiotherapy in the treatment of breast cancer. As a result, complications and reconstructive failures associated to IBBR have increased. Autologous breast reconstruction (ABR) using fat-augmented latissimus dorsi (FALD) has become popular in recent years. Methods We aimed to evaluate conversion to ABR using latissimus dorsi and immediate fat grafting in 61 cases with IBBR failure. Results Immediate reconstruction was found significatively related with an increased number of surgeries resulting from IBBR complications ( p < 0.001). Note that 41% of the cases presented a grade III/IV Baker and Palmer capsular contracture, 29% implant extrusion, and 21% implant infection. Mean survival of the first implant was 16.95 months. ABR process was completed in 47% of cases with a single surgery. Statistically significant differences were observed between this fact and previous IBBR failure due to infection ( p = 0.03) or extrusion ( p = 0.01). Mean volume of fat graft was 429.61 mL, mean length of the surgical procedure was 3.17 hours, and the average length of hospital stay after surgery was 2.67 days. Only 3.3% of the cases developed some major complication. None of the cases presented reconstructive failure. Conclusion FALD is a very safe total ABR technique, an important fact in patients with previous reconstructive failures. The large volume of fat that can be grafted in a single surgery allows the reconstruction of breast in a reasonable size. The reduced length of surgery and hospital stay make the FALD technique an option to consider when an autologous but efficient and safe reconstruction is desired.

Application of the iPLUS non-coding sequence in improving biopharmaceuticals production.

The biotechnological landscape has witnessed significant growth in biological therapeutics particularly in the field of recombinant protein production. Here we investigate the function of 3'UTR cis-regulatory elements in increasing mRNA and protein levels in different biological therapeutics and model systems, spanning from monoclonal antibodies to mRNA vaccines. We explore the regulatory function of iPLUS - a universal sequence capable of consistently augmenting recombinant protein levels. By incorporating iPLUS in a vector to express a monoclonal antibody used in immunotherapy, in a mammalian cell line used by the industry (ExpiCHO), trastuzumab production increases by 2-fold. As yeast Pichia pastoris is widely used in the manufacture of industrial enzymes and pharmaceuticals, we then used iPLUS in tandem (3x) and iPLUSv2 (a variant of iPLUS) to provide proof-of-concept data that it increases the production of a reporter protein more than 100-fold. As iPLUS functions by also increasing mRNA levels, we hypothesize that these sequences could be used as an asset in the mRNA vaccine industry. In fact, by including iPLUSv2 downstream of Spike we were able to double its production. Moreover, the same effect was observed when we introduced iPLUSv2 downstream of MAGEC2, a tumor-specific antigen tested for cancer mRNA vaccines. Taken together, our study provides data (TLR4) showing that iPLUS may be used as a valuable asset in a variety of systems used by the biotech and biopharmaceutical industry. Our results underscore the critical role of non-coding sequences in controlling gene expression, offering a promising avenue to accelerate, enhance, and cost-effectively optimize biopharmaceutical production processes.

Twenty-first-century demographic and social inequalities of heat-related deaths in Brazilian urban areas.

Population exposure to heat waves (HWs) is increasing worldwide due to climate change, significantly affecting society, including public health. Despite its significant vulnerabilities and limited adaptation resources to rising temperatures, South America, particularly Brazil, lacks research on the health impacts of temperature extremes, especially on the role played by socioeconomic factors in the risk of heat-related illness. Here, we present a comprehensive analysis of the effects of HWs on mortality rates in the 14 most populous urban areas, comprising approximately 35% of the country's population. Excess mortality during HWs was estimated through the observed-to-expected ratio (O/E) for total deaths during the events identified. Moreover, the interplay of intersectionality and vulnerability to heat considering demographics and socioeconomic heterogeneities, using gender, age, race, and educational level as proxies, as well as the leading causes of heat-related excess death, were assessed. A significant increase in the frequency was observed from the 1970s (0-3 HWs year-1) to the 2010s (3-11 HWs year-1), with higher tendencies in the northern, northeastern, and central-western regions. Over the 2000-2018 period, 48,075 (40,448-55,279) excessive deaths were attributed to the growing number of HWs (>20 times the number of landslides-related deaths for the same period). Nevertheless, our event-based surveillance analysis did not detect the HW-mortality nexus, reinforcing that extreme heat events are a neglected disaster in Brazil. Among the leading causes of death, diseases of the circulatory and respiratory systems and neoplasms were the most frequent. Critical regional differences were observed, which can be linked to the sharp North-South inequalities in terms of socioeconomic and health indicators, such as life expectancy. Higher heat-related excess mortality was observed for low-educational level people, blacks and browns, older adults, and females. Such findings highlight that the strengthening of primary health care combined with reducing socioeconomic, racial, and gender inequalities represents a crucial step to reducing heat-related deaths.

Implementation of esophageal endoscopic submucosal dissection in Spain: Results from the nationwide registry. / Implementación de la disección endoscópica submucosa esofágica en España: resultados del registro nacional.

INTRODUCTION AND AIMS: The outcomes of endoscopic submucosal dissection (ESD) in the esophagus have not been assessed in our country. Our primary aim was to analyze the effectiveness and safety of the technique. MATERIAL AND METHODS: Analysis of the prospectively maintained national registry of ESD. We included all superficial esophageal lesions removed by ESD in 17 hospitals (20 endoscopists) between January 2016 and December 2021. Subepithelial lesions were excluded. The primary outcome was curative resection. We conducted a survival analysis and used logistic regression analysis to assess predictors of non-curative resection. RESULTS: A total of 102 ESD were performed on 96 patients. The technical success rate was 100% and the percentage of en-bloc resection was 98%. The percentage of R0 and curative resection was 77.5% (n=79; 95%CI: 68%-84%) and 63.7% (n=65; 95%CI: 54%-72%), respectively. The most frequent histology was Barrett-related neoplasia (n=55 [53.9%]). The main reason for non-curative resection was deep submucosal invasion (n=25). The centers with a lower volume of ESD obtained worse results in terms of curative resection. The rate of perforation, delayed bleeding and post-procedural stenosis were 5%, 5% and 15.7%, respectively. No patient died or required surgery due to an adverse effect. After a median follow-up of 14months, 20patients (20.8%) underwent surgery and/or chemoradiotherapy, and 9 patients died (mortality 9.4%). CONCLUSIONS: In Spain, esophageal ESD is curative in approximately two out of three patients, with an acceptable risk of adverse events.

Computer-aided drug repurposing to tackle antibiotic resistance based on topological data analysis.

The progressive emergence of antimicrobial resistance has become a global health problem in need of rapid solution. Research into new antimicrobial drugs is imperative. Drug repositioning, together with computational mathematical prediction models, could be a fast and efficient method of searching for new antibiotics. The aim of this study was to identify compounds with potential antimicrobial capacity against Escherichia coli from US Food and Drug Administration-approved drugs, and the similarity between known drug targets and E. coli proteins using a topological structure-activity data analysis model. This model has been shown to identify molecules with known antibiotic capacity, such as carbapenems and cephalosporins, as well as new molecules that could act as antimicrobials. Topological similarities were also found between E. coli proteins and proteins from different bacterial species such as Mycobacterium tuberculosis, Pseudomonas aeruginosa and Salmonella Typhimurium, which could imply that the selected molecules have a broader spectrum than expected. These molecules include antitumor drugs, antihistamines, lipid-lowering agents, hypoglycemic agents, antidepressants, nucleotides, and nucleosides, among others. The results presented in this study prove the ability of computational mathematical prediction models to predict molecules with potential antimicrobial capacity and/or possible new pharmacological targets of interest in the design of new antibiotics and in the better understanding of antimicrobial resistance.

Localized Colonic Small-Cell Carcinoma with Pathological Complete Response after Neoadjuvant Cisplatin and Etoposide: A Case Report.

Extrapulmonary small-cell carcinoma (SCC) is a rare neoplasm that shares certain features with its pulmonary counterpart and occurs predominantly in the gastrointestinal tract (GIT). It is a high-grade and poorly differentiated neuroendocrine tumor, usually diagnosed in advanced stages, with a poor prognosis and few therapeutic options in that setting. This is a case report of a 77-year-old Spanish male patient with localized SCC of the colon, who presented a pathological complete response in the surgical specimen after neoadjuvant chemotherapy with cisplatin and etoposide. To date, 5 years after surgery, the patient remains without evidence of tumor recurrence. As clinical guidelines for the management of this entity are lacking, and therefore its management has not been standardized, an attempt to summarize the current evidence in the literature was made.

Patterns and outcome of unplanned care in lung cancer patients: an observational study in a medical oncology department.

Background: There is increasing interest in unplanned care utilization among lung cancer patients and its evaluation should allow the identification of areas for quality improvement. Being a major priority for transformation in oncology, we aim to measure the risk and burden of unplanned care in a medical oncology department and identify factors that determine acute care. Methods: This was an observational retrospective cohort study that included all lung cancer patients treated at Puerta de Hierro-Majadahonda University Hospital between January 1st 2016 and December 31st 2020. Data cut off: June 30th, 2021. The main objective was to assess the incidence of unplanned care, emergency department (ED) visits and unplanned hospital admissions, from the first visit to the medical oncology service and its potential conditioning variables, considering patient death as a competitive event. As secondary objectives, a description and a quality of unplanned care evaluation was carried out. Results: A total of 821 lung cancer patients, all histologies and stages, were included (median follow-up: 32.8 months). Six hundred and eighty-one patients required consultation in the ED (82.9%), and 558 required an unplanned admission (68%). Eighty-six percent of ED consultations and 80.9% of unplanned hospital admissions were related to cancer or its treatment. The 1-year cumulative incidence for ED consultation and for unplanned hospital admission was 71.3% (95% CI: 67.8-74.5%) and 56.7% (95% CI: 53-60%), respectively. In the multivariable analysis, a higher tumor stage increased the risk of consultation in the ED, while a higher stage, Eastern Cooperative Oncology Group performance status (ECOG PS) 2 compared to ECOG PS 0, male sex, opioid or steroid use at first consultation increased the risk of unplanned admission. Conclusions: Our study shows that lung cancer patients have an extremely high demand for unplanned care. It is an early need and related to cancer in the majority of consultations and admissions and therefore a key issue for the management of oncology departments. We must optimize the follow-up of patients with a higher risk of unplanned care, advanced lung cancer or symptomatic patients, incorporating remote monitoring strategies and early interventions, as developing specific urgent care pathways for a better comprehensive cancer care.

Silicone Shell Breast Implants in Patients Undergoing Risk-Reducing Mastectomy With a History of Breast-Conserving Surgery and Adjuvant Radiotherapy: A Long-term Study.

BACKGROUND: Indications for breast-conserving surgery and adjuvant radiotherapy (BCSAR) in patients with breast carcinoma are increasing, as are indications for risk-reducing mastectomy (RRM) in healthy subjects. Most of these cases are reconstructed with silicone shell breast implants (SSBIs). OBJECTIVES: The aim of this work was to study complications of SSBIs in breast reconstruction in patients undergoing RRM with previous BCSAR. METHODS: A prospective cohort study was designed. The study group included cases of RRM reconstructed with SSBI in patients who had previously undergone BCSAR in the same breast. The control group consisted of patients with high-risk breast cancer who had undergone RRM and immediate SSBI reconstruction without previous BCSAR. RESULTS: There was a history of BCSAR in 15.8% of cases. The first SSBI used in immediate reconstruction after RRM was replaced in 51.5% of cases with a mean [standard deviation] survival of 24.04 [28.48] months. BCSAR was significantly associated with pathological capsular contracture (P = .00) with this first SSBI (37.5% vs 5.9%). Of the cases requiring the replacement of the first SSBI, 44.23% suffered failure of the second SSBI, with a mean survival of 27.95 [26.53] months. No significant association was found between the consecutive development of capsular contracture in the second SSBI and a previous history of BCSAR (P = .10). CONCLUSIONS: BCSAR prior to RRM reconstructed with an SSBI is associated with a significant increase in pathological capsular contracture. Patients should be warned of the high rate of SSBI complications and reconstruction failure. Polyurethane-coated implants may provide an alternative in cases in which alloplastic reconstruction is considered in patients with previous BCSAR.

The Mechanism of Resistance of EUROPEAN Plum to Plum pox virus Mediated by Hypersensitive Response Is Linked to VIRAL NIa and Its Protease Activity.

Plum pox virus (PPV) infects Prunus trees across the globe, causing the serious Sharka disease. Breeding programs in the past 20 years have been successful, generating plum varieties hypersensitive to PPV that show resistance in the field. Recently, a single tree displaying typical PPV symptoms was detected in an orchard of resistant plums. The tree was eradicated, and infected material was propagated under controlled conditions to study the new PPV isolate. Performing overlapping PCR analysis, the viral sequence was reconstructed, cloned and tested for infectivity in different 'Jojo'-based resistant plums. The results confirmed that the isolate, named PPV-D 'Herrenberg' (PPVD-H), was able to infect all these varieties. Analyses of chimeras between PPVD-H and a PPV-D standard isolate (PPVD) revealed that the NIa region of PPD-H, carrying three amino acid changes, was enough to break the resistance of these plums. Experiments with single and double mutants showed that all changes were essential to preserve the escaping phenotype. Additionally, one of the changes at the VPg-NIapro junction suggested the involvement of controlled endopeptidase cleavage in the viral response. Transient expression experiments in Nicotiana benthamiana confirmed that NIa cleavage in PPVD-H was reduced, compared to PPVD, linking the observed behavior to an NIa cleavage modulation.

Urinary cystatin C and N-acetyl-beta-D-glucosaminidase (NAG) as early biomarkers for renal disease in dogs with leishmaniosis.

Canine leishmaniasis (CanL) is a disease caused by Leishmania infantum that can vary from a subclinical infection to a severe disease. Dogs affected with CanL present varying degrees of renal dysfunction. Unfortunately, traditional biomarkers such as urea and creatinine detect renal damage in advanced stages of the disease, so more accurate biomarkers are needed. Hence, we aimed to study how urinary cystatin C (CysC) and N-acetyl-beta-D-glucosaminidase (NAG), behave in dogs with CanL at different stages of the disease. Eighty-six CanL infected dogs were classified according to LeishVet stages: LI (16 dogs), LIIa (12 dogs), LIIb (12 dogs), LIII (16 dogs) and LIV (30 dogs); as a control, 17 healthy dogs were studied. Blood samples were collected for complete haematological and biochemistry analysis including plasma cystatin C. Urine analysis included urine specific gravity (USG), urine protein to creatinine ratio (UPC), CysC and NAG expressed as a ratio with creatinine uCysCc (µg/g) and uNAGc (IU/g). The haematological, biochemical and urinary analysis coincided with the LeishVet guidelines. The statistical study of the uCysCc ratio and the uNAGc, showed significant increase when compared against control starting from group LI (p < 0.05). Interestingly, when the cut-off values were calculated using the ROC curve, uCysCc (258.85 µg/g) and uNAGc (2.25 IU/g) 75 % of the dogs included in LI groups surpassed the threshold. Hence our study indicates that uCysCc and uNAGc, could help to detect early renal damage in CanL affected dogs.

Long-term outcomes in Hodgkin lymphoma survivors. Temporary trends and comparison with general population.

The high cure rates of Hodgkin lymphoma (HL) make this oncological disease among those with the greatest number of long-term survivors. This single-institution study including 383 HL patients with up to 45 years of follow-up, analyses the morbidity and mortality of this population after treatments in comparison with the overall Spanish population, and investigates whether it has changed over time stratifying by periods of time, as a consequence of therapeutic optimization. The median age was 34.8 years (range 15-87) with median overall survival of 30 years, significantly higher in women (HR 0.58, 95% CI 0.42-0.79) (p = 0.0002). 185 late-stage diseases were noted (35% patients), cardiovascular disease (CVD) being the most frequent (23.2%). 30% of patients developed at least one second malignant neoplasm (SMN) to give a total of 174 SMNs. 20.9% of the patients died from HL and 67.0% died from non-HL causes (32.2% from SMN, 17% from CVD). The overall standardized mortality ratio (SMR) was 3.57 (95% CI: 3.0-4.2), with striking values of 7.73 (95% CI: 5.02-8.69) and of 14.75 (95% CI: 11.38-19.12) for women and patients <30 years at diagnosis, respectively. Excluding HL as the cause of death, the SMRs of those diagnosed before 2000 and from 2000 were proved to be similar (3.88 vs 2.73), maintaining in this last period an unacceptable excess of mortality due to secondary toxicity in patients cured of HL. Our study confirm that HL treatment substantially reduces the life expectancy of patients cured of HL. In recent periods, despite therapeutic optimization, deaths from toxicity continue to occur, mainly from CVD and SMN. Risk-factor monitoring should be intensified, prevention programs developed, and therapeutic optimization of LH investigated, especially in two vulnerable groups: those aged <30 years at diagnosis, and women.

Using the Synergy between HPLC-MS and MALDI-MS Imaging to Explore the Lipidomics of Clear Cell Renal Cell Carcinoma.

Lipid imaging mass spectrometry (LIMS) has been tested in several pathological contexts, demonstrating its ability to segregate and isolate lipid signatures in complex tissues, thanks to the technique's spatial resolution. However, it cannot yet compete with the superior identification power of high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS), and therefore, very often, the latter is used to refine the assignment of the species detected by LIMS. Also, it is not clear if the differences in sensitivity and spatial resolution between the two techniques lead to a similar panel of biomarkers for a given disease. Here, we explore the capabilities of LIMS and HPLC-MS to produce a panel of lipid biomarkers to screen nephrectomy samples from 40 clear cell renal cell carcinoma patients. The same set of samples was explored by both techniques, and despite the important differences between them in terms of the number of detected and identified species (148 by LIMS and 344 by HPLC-MS in negative-ion mode) and the presence/absence of image capabilities, similar conclusions were reached: using the lipid fingerprint, it is possible to set up classifiers that correctly identify the samples as either healthy or tumor samples. The spatial resolution of LIMS enables extraction of additional information, such as the existence of necrotic areas or the existence of different tumor cell populations, but such information does not seem determinant for the correct classification of the samples, or it may be somehow compensated by the higher analytical power of HPLC-MS. Similar conclusions were reached with two very different techniques, validating their use for the discovery of lipid biomarkers.

A systematic review about the role of preoperative 18F-FDG PET/CT for prognosis and risk stratification in patients with endometrial cancer.

OBJECTIVE: To analyse the available literature on the prognostic value of preoperative 18F-FDG PET/CT metabolic parameters and their usefulness in risk stratification in patients with endometrial cancer (EC). MATERIAL AND METHODS: Pubmed searches used "(endometr* OR uter*) AND (PET OR FDG)" as keywords from January-2000 to June-2020. References in included articles were checked for possible publications not included in the first search. Studies evaluating the prognostic value of preoperative 18F-FDG PET/CT and its role for risk stratification in patients with EC were included. Non-original articles (reviews, editorials, letters, legal cases, interviews, case reports, etc.) were not included. RESULTS: Twenty-six studies (1918 patients) were selected according to the inclusion criteria in this review. Thirteen studies (939 patients) related to the prognostic role of preoperative 18F-FDG PET/CT and 14 studies (1036 patients) related to its role in risk stratification were included. Parameters such as SUVmax, metabolic tumour volume (MTV) and total lesion glycolysis (TLG) of the primary tumour were analysed. CONCLUSIONS: Preoperative SUVmax is useful for non-invasive diagnosis and for deciding the appropriate therapeutic strategy, as it could be used as an independent prognostic marker for recurrence and survival in EC. In addition, both preoperative VTM and GTL could be independent prognostic factors for predicting recurrence and survival, but there is still insufficient scientific evidence. The usefulness of SUVmax for risk stratification is limited (there is insufficient literature that 18F-FDG PET/CT can replace surgical staging), although VTM and GTL are more accurate and have a valuable role in risk stratification of EC. However, larger multicentre studies with adequate follow-up time are needed to confirm these findings.

Over-the-scope-clip (OTSC®) as a rescue treatment for gastrointestinal bleeding secondary to peptic ulcer disease.

BACKGROUND AND AIMS: over-the-scope-clips (OTSC®) have been proposed as a rescue treatment for bleeding peptic ulcers. However, their effectiveness has not been evaluated in Spain. METHODS: this retrospective and single-center study (January 2018-December 2021) assessed the technical success, clinical success and safety of the device within 30 days. All patients with upper gastrointestinal bleeding due to a peptic ulcer and treated with the OTSC® clip (OVESCO) as a rescue therapy were included in the study. RESULTS: a total of eleven patients were included in the study, nine due to rebleeding and two due to persistent bleeding. Technical success was 81.9 % (9/11, confidence interval [CI] 95 %: 52-95 %). The per-protocol and intention-to-treat clinical success were 88.9 % (8/9, CI 95 %: 57-98 %) and 72.7 % (8/11, CI 95 %: 43-90 %), respectively. No device-related adverse effects were recorded. CONCLUSION: the OTSC® clip was an effective and safe rescue therapy for bleeding peptic ulcers.

Cien años de la Revista Panamericana de Salud Pública: visualización de sus contenidos / One hundred years of the Pan American Journal of Public Health: visualizing its content / Cem anos da Revista Pan-Americana de Saúde Pública: visualização do seu conteúdo

RESUMEN Objetivos. Explorar la alineación del contenido de los artículos publicados por la Revista Panamericana de Salud Pública durante sus 100 años de existencia, con los temas sanitarios claves de la Organización Panamericana de la Salud (OPS). Métodos. Se llevó a cabo un análisis bibliométrico con visualización de sus resultados. Se recuperó la información sobre los artículos publicados en la Revista a partir del Repositorio Institucional para Intercambio de Información (IRIS) de la OPS para los primeros 75 años y de Scopus para los últimos 25 años hasta febrero del 2022; para establecer los temas claves de la OPS se usaron referencias a documentos de los Cuerpos Directivos y declaraciones de los directores. Resultados. Se obtuvieron inicialmente 12 573 publicaciones y se consideraron para el análisis 9 289 para el período 1922 a 1996 y 3 208 para el período 1997 a 2022. Para el análisis bibliométrico de la información de Scopus se tuvieron en cuenta indicadores como los autores y su procedencia, el idioma de las publicaciones, y el número y la procedencia de las citas. Para las visualizaciones, se dividieron las publicaciones en cinco períodos a fin de que estos coincidieran con los períodos establecidos para el análisis de los temas prioritarios de la OPS. Se realizaron mapas de coocurrencia de palabras claves para observar la evolución de los temas de las publicaciones y relacionarlos con los enfoques de la salud pública en cada período. Conclusión. Las temáticas publicadas en la Revista Panamericana de Salud Pública y sus boletines precursores reflejan la historia de la salud pública regional y su evolución a lo largo del tiempo, así como los temas sanitarios claves de la Organización Panamericana de la Salud.

ABSTRACT Objectives. Explore how the content of the articles published by the Pan American Journal of Public Health during its 100 years of existence has aligned with the key health issues of the Pan American Health Organization (PAHO). Methods. A bibliometric analysis was carried out, with visualization of its results. Information on articles published in the Journal was retrieved from PAHO's Institutional Repository for Information Sharing (IRIS) for the first 75 years and Scopus for the last 25 years, until February 2022; References to Governing Bodies documents and statements by the directors were used to establish PAHO's key themes. Results. Initially, 12 573 publications were obtained and 9 289 were considered for analysis for the period 1922 to 1996, and 3 208 for the period 1997 to 2022. For the bibliometric analysis of the Scopus information, indicators such as the authors and their origin, language of publication, and number and origin of citations were considered. For the visualizations, publications were divided into five periods so that they coincided with the periods established for the analysis of PAHO's priority themes. Keyword co-occurrence maps were made to observe the evolution of published topics and relate them to public health approaches in each period. Conclusion. The topics published in the Pan American Journal of Public Health and its precursor bulletins reflect the history of regional public health and its evolution over time, as well as the key health issues of the Pan American Health Organization.

RESUMO Objetivos. Explorar o alinhamento do conteúdo dos artigos publicados na Revista Pan-Americana de Saúde Pública em seus 100 anos de existência com os principais temas de saúde da Organização Pan-Americana da Saúde (OPAS). Métodos. Fez-se uma análise bibliométrica com visualização de seus resultados. Informações sobre os artigos publicados na revista foram recuperadas do Repositório Institucional para o Intercâmbio de Informações (IRIS, na sigla em inglês) da OPAS para os primeiros 75 anos, e da base de dados Scopus para os últimos 25 anos, até fevereiro de 2022. Para estabelecer os principais temas da OPAS, foram usadas referências a documentos dos órgãos diretores e declarações dos diretores. Resultados. Inicialmente, foram obtidas 12 573 publicações - 9 289 foram consideradas na análise para o período de 1922 a 1996, e 3 208 para o período de 1997 a 2022. Para a análise bibliométrica das informações da Scopus, foram levados em consideração indicadores como os autores e sua procedência, o idioma das publicações e o número e a procedência das citações. Para as visualizações, as publicações foram divididas em cinco períodos para que coincidissem com os períodos estabelecidos para a análise dos temas prioritários da OPAS. Mapeou-se a co-ocorrência de palavras-chave para observar a evolução dos temas das publicações e para relacioná-los com os enfoques de saúde pública em cada período. Conclusão. Os temas publicados na Revista Pan-Americana de Saúde Pública e nos boletins que a antecederam refletem o histórico da saúde pública regional e sua evolução ao longo do tempo, bem como os principais temas de saúde da Organização Pan-Americana da Saúde.

Effectiveness, Toxicity, and Survival Predictors of Regorafenib in Metastatic Colorectal Cancer: A Multicenter Study of Routinely Collected Data.

OBJECTIVES: To assess the effectiveness and toxicity of regorafenib in patients with metastatic colorectal cancer (mCRC) in routine clinical practice, as well as predictive factors of effectiveness. METHODS: This was a retrospective multicenter study in patients with mCRC who received regorafenib from November 2013 to May 2020. Effectiveness was evaluated by overall survival (OS) and progression-free survival (PFS) using the Kaplan-Meier method. Cox regression was performed to determine survival predictors. RESULTS: Ninety patients were enrolled (median age, 64.3 years). Fifty-two patients (57.8%) were male, and 57 (63.3%) had an ECOG performance status (PS) of 0 to 1. Median follow-up was 2.80 months. Median OS was 8.03 months (95% CI, 5.90-10.17), and median PFS was 2.90 months (95% CI, 2.59-3.21). Eighty-eight patients (97.8%) experienced drug-related adverse events. The most frequent were fatigue in 66 patients (73.3%), followed by palmar-plantar erythrodysesthesia in 40 (44.4%). Low liver tumor burden score (LTBS) and good ECOG PS were independent OS predictive factors. CONCLUSIONS: Patients taking regorafenib had OS and PFS rates similar to those reported in previous randomized trials; the agent had a poor toxicity profile. We identified low LTBS and good ECOG PS as possible predictive factors of better OS, useful in selecting patients with mCRC who might benefit from regorafenib.

Severe Acute Hepatitis of Unknown Origin in Children: What Do We Know Today?

In May 2022, the UK International Health Regulations National Focal Point notified World Health Organization of 176 cases of severe acute hepatitis of unknown etiology in children under 10 years of age. From that moment on, cases of severe acute hepatitis of unknown origin in children began to be reported in several countries. As of June 17, 2022, a total of 991 cases had been reported in 35 countries worldwide, 50 children needed a liver transplant and 28 patients died. According to information published by ECDC, 449 cases have been detected in 21 EU countries. The children were between 1 month and 16 years of age. Adenovirus was detected in 62.2% of the analyzed samples. So far, the cause of these cases is unknown and many hypotheses remain open, but hepatitis A-E viruses and COVID-19 vaccines have been ruled out. A possible hypothesis has been published to explain the cause of these cases of severe hepatitis, according to which it could be a consequence of adenovirus infection in the intestine in healthy children previously infected with SARS-CoV-2. No other clear epidemiological risk factors have been identified to date. Thus, at this time, the etiology of the current cases of hepatitis remains under active investigation.

Brief Research Report: Anti-SARS-CoV-2 Immunity in Long Lasting Responders to Cancer Immunotherapy Through mRNA-Based COVID-19 Vaccination.

Cancer patients (CPs) have been identified as particularly vulnerable to SARS-CoV-2 infection, and therefore are a priority group for receiving COVID-19 vaccination. From the patients with advanced solid tumors, about 20% respond very efficiently to immunotherapy with anti-PD1/PD-L1 antibodies and achieve long lasting cancer responses. It is unclear whether an efficient cancer-specific immune response may also correlate with an efficient response upon COVID-19 vaccination. Here, we explored the antiviral immune response to the mRNA-based COVID-19 vaccine BNT162b2 in a group of 11 long-lasting cancer immunotherapy responders. We analysed the development of SARS-CoV-2-specific IgG serum antibodies, virus neutralizing capacities and T cell responses. Control groups included patients treated with adjuvant cancer immunotherapy (IMT, cohort B), CPs not treated with immunotherapy (no-IMT, cohort C) and healthy controls (cohort A). The median ELISA IgG titers significantly increased after the prime-boost COVID vaccine regimen in all cohorts (Cohort A: pre-vaccine = 900 (100-2700), 3 weeks (w) post-boost = 24300 (2700-72900); Cohort B: pre-vaccine = 300 (100-2700), 3 w post-boost = 8100 (300-72900); Cohort C: pre-vaccine = 500 (100-2700), 3 w post-boost = 24300 (300-72900)). However, at the 3 w post-prime time-point, only the healthy control group showed a statistically significant increase in antibody levels (Cohort A = 8100 (900-8100); Cohort B = 900 (300-8100); Cohort C = 900 (300-8100)) (P < 0.05). Strikingly, while all healthy controls generated high-level antibody responses after the complete prime-boost regimen (Cohort A = 15/15 (100%), not all CPs behaved alike [Cohort B= 12/14 (84'6%); Cohort C= 5/6 (83%)]. Their responses, including those of the long-lasting immunotherapy responders, were more variable (Cohort A: 3 w post-boost (median nAb titers = 95.32 (84.09-96.93), median Spike-specific IFN-γ response = 64 (24-150); Cohort B: 3 w post-boost (median nAb titers = 85.62 (8.22-97.19), median Spike-specific IFN-γ response (28 (1-372); Cohort C: 3 w post-boost (median nAb titers = 95.87 (11.8-97.3), median Spike-specific IFN-γ response = 67 (20-84)). Two long-lasting cancer responders did not respond properly to the prime-boost vaccination and did not generate S-specific IgGs, neutralizing antibodies or virus-specific T cells, although their cancer immune control persisted for years. Thus, although mRNA-based vaccines can induce both antibody and T cell responses in CPs, the immune response to COVID vaccination is independent of the capacity to develop an efficient anti-cancer immune response to anti PD-1/PD-L1 antibodies.

Targeting of genomic and negative-sense strands of viral RNA contributes to antiviral resistance mediated by artificial miRNAs and promotes the emergence of complex viral populations.

Technology based on artificial small RNAs, including artificial microRNAs (amiRNAs), exploits natural RNA silencing mechanisms to achieve silencing of endogenous genes or pathogens. This technology has been successfully employed to generate resistance against different eukaryotic viruses. However, information about viral RNA molecules effectively targeted by these small RNAs is rather conflicting, and factors contributing to the selection of virus mutants escaping the antiviral activity of virus-specific small RNAs have not been studied in detail. In this work, we transformed Nicotiana benthamiana plants with amiRNA constructs designed against the potyvirus plum pox virus (PPV), a positive-sense RNA virus, and obtained lines highly resistant to PPV infection and others showing partial resistance. These lines have allowed us to verify that amiRNA directed against genomic RNA is more efficient than amiRNA targeting its complementary strand. However, we also provide evidence that the negative-sense RNA strand is cleaved by the amiRNA-guided RNA silencing machinery. Our results show that the selection pressure posed by the amiRNA action on both viral RNA strands causes an evolutionary explosion that results in the emergence of a broad range of virus variants, which can further expand in the presence, and even in the absence, of antiviral challenges.