Dose regimen optimization of cephalothin for surgical prophylaxis against Staphylococcus aureus and coagulase negative staphylococci in dogs by pharmacokinetic/pharmacodynamic modeling.

First generation cephalosporins such cephalothin of cefazolin are indicated for antimicrobial prophylaxis for clean and clean contaminated surgical procedures because its antimicrobial spectrum, relative low toxicity and cost. Anesthesia and surgery could alter the pharmacokinetic behavior of different drugs administered perioperative by many mechanisms that affect distribution, metabolism or excretion processes. Intravenous administration of the antimicrobial within 30 and 60 min before incision is recommended in order to reach therapeutic serum and tissue concentrations and redosing is recommended if the duration of the procedure exceeds two half-life of the antimicrobial. To the author's knowledge there are no pharmacokinetic studies of cephalothin in dogs under anesthesia/surgery conditions. The aim of this study was (1) to evaluate the pharmacokinetics of cephalothin in anesthetized dogs undergoing ovariohysterectomy by a nonlinear mixed-effects model and to determine the effect of anesthesia/surgery and other individual covariates on its pharmacokinetic behavior; (2) to determine the MIC and conduct a pharmacodynamic modeling of time kill curves assay of cephalothin against isolates of Staphylococcus spp. isolated from the skin of dogs; (3) to conduct a PK/PD analysis by integration of the obtained nonlinear mixed-effects models in order to evaluate the antimicrobial effect of changing concentrations on simulated bacterial count; and (4) to determine the PK/PD endpoints and PK/PDco values in order to predict the optimal dose regimen of cephalothin for antimicrobial prophylaxis in dogs. Anesthesia/surgery significantly reduced cephalothin clearance by 18.78%. Based on the results of this study, a cephalothin dose regimen of 25 mg/kg q6h by intravenous administration showed to be effective against Staphylococcus spp. isolates with MIC values ≤2 µg/mL and could be recommended for antimicrobial prophylaxis for clean surgery in healthy dogs.

Concordancia entre las listas de medicamentos esenciales y las guías para diabetes en América Latina y el Caribe / Concordance between essential medicines lists and diabetes guidelines in Latin America and the Caribbean / Concordância entre as listas de medicamentos essenciais e diretrizes para diabetes na América Latina e no Caribe

RESUMEN Objetivo. Analizar la existencia y actualización de las listas de medicamentos nacionales (LMN) y guías de práctica clínica (GPC) para el tratamiento de la diabetes en América Latina y el Caribe (ALC). Comparar los fármacos incluidos en las listas y guías de cada país, entre sí y con los de la Organización Mundial de la Salud (OMS). Métodos. Estudio de corte transversal. Se identificaron las LMN y GPC para diabetes en los sitios web de la Organización Panamericana de la Salud y de las autoridades sanitarias nacionales. Se relevaron los fármacos y se analizaron por grupo farmacológico según el cuarto nivel de la nomenclatura ATC. Se utilizó el puntaje F1 para evaluar la proximidad de las LMN con la lista modelo de medicamentos esenciales (LMME) de la OMS. Resultados. Del total de países, 87,2% cuentan con LMN, y 91% con GPC (78% y 45% actualizadas en los últimos 5 años, respectivamente). En comparación con los 6 grupos de hipoglucemiantes de la LMME, las LMN tenían una mediana (rango) de 6 (4-13) y un puntaje F1 de 0,80; esto indica una consonancia adecuada. Las GPC tenían una mediana (rango) de 12 (1-12) hipoglucemiantes frente a los 8 de las guías de la OMS. Las GPC tuvieron una mediana de 15 fármacos más que las respectivas LMN. Conclusiones. Si bien la mayoría de los países de ALC cuentan con LMN y GPC para diabetes, la falta de concordancia entre ellas limita su eficacia. Es necesario alinear los procesos y criterios de elaboración de estas dos herramientas de la política de medicamentos.

ABSTRACT Objective. Conduct an analysis to determine the existence and updating of national essential medicines lists (EMLs) and clinical practice guidelines (CPGs) for the treatment of diabetes in Latin America and the Caribbean (LAC); and compare the medicines included in each country's list and guidelines both with each other and with those of the World Health Organization (WHO). Methods. Cross-sectional study. EMLs and CPGs for diabetes were found on the websites of the Pan American Health Organization and national health authorities. Medicines were noted and analyzed according to pharmacological group, based on the fourth level of nomenclature of the Anatomical Therapeutic Chemical (ATC) classification system. F1 scoring was used to assess the proximity of EMLs to the WHO Model List of Essential Medicines (MLEM). Results. Of the total number of countries, 87.2% have EMLs, and 91% have CPGs (78% and 45% updated in the last five years, respectively). Compared to the six hypoglycemic groups of the MLEM, the EMLs had a median (range) of 6 (4-13) and an F1 score of 0.80; This indicates proper alignment. CPGs had a median (range) of 12 (1-12) hypoglycemic drugs compared to eight in the WHO guidelines. CPGs had a median of 15 more drugs than their respective EMLs. Conclusions. While most LAC countries have EMLs and CPGs for diabetes, the lack of concordance among them limits their effectiveness. It is necessary to align the processes and criteria for the development of these two tools for policymaking on medicines.

RESUMO Objetivos. Analisar a existência e a atualização das listas nacionais de medicamentos (LNMs) e guias de prática clínica (GPCs) para o tratamento do diabetes na América Latina e no Caribe (ALC). Comparar os medicamentos incluídos nas listas e nas diretrizes de cada país entre si e com as da Organização Mundial da Saúde (OMS). Métodos. Estudo transversal. Foram identificadas LMNs e GPCs para o diabetes nos sites da Organização Pan-Americana da Saúde e das autoridades sanitárias nacionais. Os medicamentos foram pesquisados e analisados por grupo farmacológico de acordo com o quarto nível da classificação ATC. A pontuação F1 foi utilizada para avaliar o grau de proximidade das LMNs com a lista-modelo de medicamentos essenciais (LMME) da OMS. Resultados. Do total de países, 87,2% dispõem de uma LNM e 91%, de GPCs (78% e 45%, respectivamente, atualizadas nos últimos 5 anos). Em comparação com os seis grupos de agentes hipoglicemiantes da LMME, as LMNs tinham uma mediana (intervalo) de 6 (4 a 13) e uma pontuação F1 de 0,80, o que indica uma conformidade adequada. As GPCs tinham uma mediana (intervalo) de 12 (1 a 12) agentes hipoglicemiantes, em comparação com 8 nos guias da OMS. As GPCs tinham uma mediana de 15 medicamentos a mais do que as respectivas LNMs. Conclusões. Embora a maioria dos países da América Latina e do Caribe disponha de LNMs e GPCs para o diabetes, a falta de concordância entre elas limita sua eficácia. É necessário alinhar os processos e os critérios de desenvolvimento dessas duas ferramentas da política de medicamentos.

Activity of domain III-specific antibodies in early convalescence: A case study.

The Dengue virus complex (DENV), formed by four serotypes, constitutes the most important arbovirus affecting humans. The structural domain III of their envelope protein (DIII) elicits strongly neutralizing serotype-specific antibodies. Contrasting results have been obtained regarding their role in the serum neutralizing activity of infected patients. We used a DENV immune serum from a secondary infection to examine the impact of characterizing the anti-DIII antibody response after affinity purification with recombinant DIII proteins to eliminate potential interferences from the interactions with human plasma proteins and other anti-DENV antibodies. Total anti-DENV IgG repertoire and anti-DIIIE antibodies were compared in functionality. In early convalescence, reactivity of anti-DIII antibodies is serotype specific and exhibits the strongest reactivity with infecting serotypes. Purification of anti-DIII antibodies emphasizes the reactivity profile as compared to total IgG fraction and serum. Serotype-specificity of the virus neutralization activity correlated with the apparent kD of the binding to recombinant DIIIs.

An Innovative Scoring System to Select the Optimal Surgery in Breast Cancer after Neoadjuvant Chemotherapy.

INTRODUCTION: The selection of surgery post-neoadjuvant chemotherapy (NACT) is difficult and based on surgeons' expertise. The aim of this study was to create a post-NEoadjuvant Score System (pNESSy) to choose surgery, optimizing oncological and aesthetical outcomes. METHODS: Patients (stage I-III) underwent surgery post-NACT (breast-conserving surgery (BCS), oncoplastic surgery (OPS), and conservative mastectomy (CMR) were included. Data selected were BRCA mutation, ptosis, breast volume, radiological response, MRI, and mammography pre- and post-NACT prediction of excised breast area. pNESSy was created using the association between these data and surgery. Area under the curve (AUC) was assessed. Patients were divided into groups according to correspondence (G1) or discrepancy (G2) between score and surgery; oncological and aesthetic outcomes were analyzed. RESULTS: A total of 255 patients were included (118 BCS, 49 OPS, 88 CMR). pNESSy between 6.896-8.724 was predictive for BCS, 8.725-9.375 for OPS, and 9.376-14.245 for CMR; AUC was, respectively, 0.835, 0.766, and 0.825. G1 presented a lower incidence of involved margins (5-14.7%; p = 0.010), a better locoregional disease-free survival (98.8-88.9%; p < 0.001) and a better overall survival (96.1-86.5%; p = 0.017), and a better satisfaction with breasts (39.8-27.5%; p = 0.017) and physical wellbeing (93.5-73.6%; p = 0.001). CONCLUSION: A score system based on clinical and radiological features was created to select the optimal surgery post-NACT and improve oncological and aesthetic outcomes.

Late Periprosthetic Femoral Stress Fracture Associated with Extra-articular Deformity in a Patient with Fibrous Dysplasia: A Case Report.

CASE: In the setting of a total hip arthroplasty performed in a patient with a proximal femoral deformity, atraumatic periprosthetic femoral stress fracture may arise as a complication. We report a rare case of a late periprosthetic femoral stress fracture around a cemented stem in a patient with a history of fibrous dysplasia of the proximal femur. After a 10-year uneventful period, the patient complained about a subtle, subacute pain in his left thigh induced by exercise but not with daily axial load. Diagnosis of a nondisplaced, incomplete (i.e., only compromising the lateral femoral cortex) periprosthetic femoral stress fracture was made with plain radiographs, blood work, and bone scintigraphy. Surgical treatment consisted of a minimally invasive plate osteosynthesis bridging the femoral deformity plus percutaneous osteoperiosteal decortication. At 5-year follow-up, the patient was asymptomatic with full return to physical activity, with radiographs evidencing callus formation. CONCLUSION: Stress fractures around well-fixed femoral stems, while infrequent, should be addressed in patients with a history of severe proximal femur deformity experiencing atraumatic thigh pain.

Green strategies using solvent-free biodegradable membranes in microfluidic devices. Liquid phase microextraction and electromembrane extraction.

In this work, a novel solvent-free microfluidic method based liquid phase microextraction has been proposed for the first time. A comprehensive study of liquid phase microextraction (LPME) and electromembrane extraction (EME) implemented in microfluidic formats has been carried out to investigate the efficiency of biodegradable membranes (such as agarose) without organic solvent to develop fully environmental microfluidic methods. For this study, non-polar and polar basic compounds (five) were selected as model analytes and different agarose membrane compositions were synthesized and tested with and without organic solvent (solvent-free). Under optimal experimental conditions, the extraction efficiencies obtained using solvent-free LPME-chip devices were similar to the ones obtained using solvent-free EME-chip devices at very low voltages (0.25 V), however, LPME microfluidic format was selected due to its simplicity. The proposed green microfluidic device was successfully applied in urine samples with recoveries between 80 and 93% for all analytes and relative standard deviation below 7% for all analytes. Results were compared with experiments previously conducted using conventional (polypropylene) membranes, observing that solvent-free microfluidic systems based on biodegradable solid support materials have proven to be an attractive alternative and offered the same advantages in terms of membrane stability allowing consecutive extractions compared to supported liquid membranes (SLM) microfluidic methods.

Economic Evaluation of Cataract: A Systematic Mapping Review.

INTRODUCTION: The purpose of this article was to ascertain the existing literature and find the gaps in economic evaluations of cataracts. METHODS: Systematic methods were used to search and collect the published literature on economic evaluations of cataracts. A mapping review of studies published in the following bibliographical databases was performed: the National Library of Medicine (PubMed), EMBASE, Web of Science (WOS), and the Central of Reviews and Dissemination (CRD) database. A descriptive analysis was conducted and relevant studies were classified into different groups. RESULTS: Among 984 studies screened, 56 studies were included in the mapping review. Four research questions were answered. There has been a progressive increase of publications during the last decade. The majority of the included studies were published by authors from institutions in the USA and UK. The most commonly investigated area was cataract surgery followed by intraocular lenses (IOLs). The studies were classified into different categories according to the main outcome evaluated, such as comparisons between different surgical techniques, costs of the cataract surgery, second eye cataract surgery costs, quality of life gain after cataract surgery, waiting time of cataract surgery and costs, and cataract evaluation, follow-up, and costs. In the IOL classification, the most frequently studied area was the comparison between monofocal and multifocal IOLs, followed by the comparison between toric and monofocal IOLs. CONCLUSIONS: Cataract surgery is a cost-effective procedure compared with other non-ophthalmic and ophthalmic interventions and surgery waiting time is an important factor to consider because vision loss has a huge and broad-ranging impact on society. Numerous gaps and inconsistencies are found among the studies included. For this reason, there is a need for further studies according to the classification described in the mapping review.

Intraoperative unfractionated heparin before femoral component cementation should be avoided in femoral neck fracture treated with hybrid total hip arthroplasty.

PURPOSE: To compare the incidence of perioperative thromboembolic events in femoral neck fracture (FNF) patients treated with hybrid total hip arthroplasty (THA) with intraoperative unfractionated heparin (UFH) versus a control group without intraoperative UFH before femoral component cementation. METHODS: We compared 139 cases without UFH (group A) versus 134 who received 10 UI/kg UFH (group B). Indication of UFH before cementation depended on the preferences of the anaesthesiologists in each case. We assessed intraoperative bone cement implantation syndrome (BCIS) and 30-day thromboembolic events, and 90-day and 1-year mortality. BCIS was classified as per Donaldson et al.'s classification according to the degree of hypotension, arterial desaturation or loss of consciousness. RESULTS: BCIS was observed in 51 (18%) cases, including 37 (13%) grade 1 and 14 (5%) grade 2. Forty-seven BCISs (35%) were observed in group B and 4 (3%) in group A (p < 0.001). Multivariate regression showed that intraoperative UFH (OR = 18, CI 95% 6-52) and consumption of oral anticoagulants (OR = 3.3, CI 95% 1-10) increased the risk of BCIS. Five patients further developed a 30-day pulmonary embolism in group B, while 2 presented this complication in group A (p = 0.231). No association between BCIS and 30-day thromboembolic events was found (p = 0.62). 90-day (1% each, p = 0.98) and 1-year (2% vs. 3%, p = 0.38) mortality were similar. CONCLUSIONS: BCIS was a frequent finding in FNF patients treated with hybrid THA. We found a paradoxically significant increase in BCIS with the use of UFH. Heparin did not seem to prevent BCIS, other thromboembolic events and mortality in this group of patients.

Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma.

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-targeted chimeric antigen receptor (CAR) T cells approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We performed a retrospective study to evaluate safety and efficacy of axi-cel and tisa-cel outside the setting of a clinical trial. Data from consecutive patients with R/R LBCL who underwent apheresis for axi-cel or tisa-cel were retrospectively collected from 12 Spanish centers. A total of 307 patients underwent apheresis for axi-cel (n=152) and tisa-cel (n=155) from November 2018 to August 2021, of which 261 (85%) received a CAR T infusion (88% and 82%, respectively). Median time from apheresis to infusion was 41 days for axi-cel and 52 days for tisa-cel (P=0.006). None of the baseline characteristics were significantly different between both cohorts. Both cytokine release syndrome and neurologic events (NE) were more frequent in the axi-cel group (88% vs. 73%, P=0.003, and 42% vs. 16%, P<0.001, respectively). Infections in the first 6 months post-infusion were also more common in patients treated with axi-cel (38% vs. 25%, P=0.033). Non-relapse mortality was not significantly different between the axi-cel and tisa-cel groups (7% and 4%, respectively, P=0.298). With a median follow-up of 9.2 months, median PFS and OS were 5.9 and 3 months, and 13.9 and 11.2 months for axi-cel and tisa-cel, respectively. The 12-month PFS and OS for axi-cel and tisa-cel were 41% and 33% (P=0.195), 51% and 47% (P=0.191), respectively. Factors associated with lower OS in the multivariate analysis were increased lactate dehydrogenase, ECOG ≥2 and progressive disease before lymphodepletion. Safety and efficacy results in our real-world experience were comparable with those reported in the pivotal trials. Patients treated with axi-cel experienced more toxicity but similar non-relapse mortality compared with those receiving tisa-cel. Efficacy was not significantly different between both products.

Single-Fluorophore Indicator to Explore Cellular and Sub-cellular Lactate Dynamics.

Lactate is an energy substrate and an intercellular signal, which can be monitored in intact cells with the genetically encoded FRET indicator Laconic. However, the structural complexity, need for sophisticated equipment, and relatively small fluorescent change limit the use of FRET indicators for subcellular targeting and development of high-throughput screening methodologies. Using the bacterial periplasmic binding protein TTHA0766 from Thermus thermophilus, we have now developed a single-fluorophore indicator for lactate, CanlonicSF. This indicator exhibits a maximal fluorescence change of 200% and a KD of ∼300 µM. The fluorescence is not affected by other monocarboxylates. The lactate indicator was not significantly affected by Ca2+ at the physiological concentrations prevailing in the cytosol, endoplasmic reticulum, and extracellular space, but was affected by Ca2+ in the low micromolar range. Targeting the indicator to the endoplasmic reticulum revealed for the first time sub-cellular lactate dynamics. Its improved lactate-induced fluorescence response permitted the development of a multiwell plate assay to screen for inhibitors of the monocarboxylate transporters MCTs, a pharmaceutical target for cancer and inflammation. The functionality of the indicator in living tissue was demonstrated in the brain of Drosophila melanogaster larvae. CanlonicSF is well suited to explore lactate dynamics with sub-cellular resolution in intact systems.

Allogeneic Stem Cell Transplantation in Mantle Cell Lymphoma; Insights into Its Potential Role in the Era of New Immunotherapeutic and Targeted Therapies: The GETH/GELTAMO Experience.

Allo-SCT is a curative option for selected patients with relapsed/refractory (R/R) MCL, but with significant NRM. We present the long-term results of patients receiving allo-SCT in Spain from March 1995 to February 2020. The primary endpoints were EFS, OS, and cumulative incidence (CI) of NRM, relapse, and GVHD. We included 135 patients, most (85%) receiving RIC. After a median follow-up of 68 months, 5-year EFS and OS were 47 and 50%, respectively. Overall and CR rates were 86 and 80%. The CI of relapse at 1 and 3 years were 7 and 12%. NRM at day 100 and 1 year were 17 and 32%. Previous ASCT and Grade 3-4 aGVHD were associated with a higher NRM. Grade 3-4 aGVHD, donor type (mismatch non-related), and the time-period 2006-2020 were independently related to worse EFS. Patients from 1995-2005 were younger, most from HLA-identical sibling donors, and were pretreated less. Our data confirmed that allo-SCT may be a curative option in R/R MCL with low a CI of relapse, although NRM is still high, being mainly secondary to aGVHD. The arrival of new, highly effective and low toxic immunotherapeutic or targeted therapies inevitably will relegate allo-SCT to those fit patients who fail these therapies, far away from the optimal timing of treatment.

Recent advances on effective and efficient deep learning-based solutions.

This editorial briefly analyses, describes, and provides a short summary of a set of selected papers published in a special issue focused on deep learning methods and architectures and their application to several domains and research areas. The set of selected and published articles covers several aspects related to two basic aspects in deep learning (DL) methods, efficiency of the models and effectiveness of the architectures These papers revolve around different interesting application domains such as health (e.g. cancer, polyps, melanoma, mental health), wearable technologies solar irradiance, social networks, cloud computing, wind turbines, object detection, music, and electricity, among others. This editorial provides a short description of each published article and a brief analysis of their main contributions.

BCL2 translocation in high grade B cell lymphoma (NOS, DH/TH) is associated with reduced progression free survival.

High Grade B Cell Lymphoma, NOS, and High Grade B Cell Lymphoma with Dual Hit or Triple Hit have been recently recategorized in the 2016 revision of the WHO classification of lymphoid neoplasms. In this study we have characterized the genetic, histopathological, and clinical features of a series of this type of lymphoid neoplasia (17 HGBCL NOS and 53 HGBCL DH/TH).HGBCL NOS showed better response to first line treatment than HGBCL with DH/TH but no significant differences in PFS or OS were found between the two categories. Survival analysis in the whole cohort of cases found that only the presence of BCL2 translocation was significantly associated with PFS. Other clinical features such as IPI, LDH or stage were equivalent in both categories. Furthermore, both high grade and DLBCL morphological patterns showed equivalent PFS and OS in this set of High grade BCL NOS/DH/TH.Key pointsBCL2 translocation in High Grade B Cell Lymphoma NOS and High Grade B Cell Lymphoma with DH/TH is associated with reduced progression free survival.Both high grade and DLBCL morphological patterns showed equivalent outcome regarding PFS and OS in HGBCL.

Análisis epidemiológico multicéntrico de las fracturas de cadera en Uruguay: importancia y planificación de un registro nacional / Multicenter epidemiological analysis of hip fractures in Uruguay: importance and planning of a national register / Análise epidemiológica multicêntrica de fraturas de quadril no Uruguai: importância e planejamento de um registro nacional

Introducción: La incidencia de fracturas de cadera presenta un aumento dramático desde la mediana edad, constituyendo un problema de salud prevalente en adultos mayores. Se realizó una revisión bibliográfica de los registros internacionales de fracturas de cadera y un estudio epidemiológico multicéntrico para conocer la incidencia, los costos y la mortalidad de esta patología en nuestro país. Material y métodos: Se realizó una búsqueda, revisión y análisis de todos los registros internacionales de fracturas de cadera existentes en el mundo. Posteriormente, se llevó a cabo un análisis descriptivo observacional retrospectivo y multicéntrico en 4 instituciones de pacientes mayores de 50 años intervenidos quirúrgicamente con osteosíntesis por fractura de cadera en el año 2019. En los datos anonimizados se evaluaron edad, sexo, tipo de fractura, incidencia y costos. Se incluyeron y asociaron, además, datos estadísticos y económicos del Registro del Fondo Nacional de Recursos. Se utilizó el software estadístico SPSS para establecer asociaciones univariadas, bivariadas y multivariadas. Para comparar las proporciones se empleó el test estadístico de chi cuadrado. Resultados: Se resume la revisión de registros en una tabla. El análisis multicéntrico contó con 646 pacientes con fracturas de cadera. Destacamos la alta prevalencia de esta patología en pacientes mayores de 79 años (63,1%) y en el sexo femenino (77,6%), en concordancia con los registros internacionales, con asociación significativa entre ambas variables (p < 0,0001). A diferencia de otros registros, y quizás dato erróneo, la fractura más frecuente fue la del cuello de fémur (43%). El tiempo entre la fractura y la cirugía y los días de internación fueron de 2,6 y 7,2 días, respectivamente, en la institución de asistencia más efectiva. Nuestro cálculo mostró una incidencia de fractura de cadera en Uruguay que oscila entre 235 y 391 en 100.000 habitantes mayores de 50 años. El costo calculado de la serie evaluada fue de unos U$S 2.855.320 y, en general, esta patología provoca un gasto para nuestro país que se aproxima a U$S 20.000.000 por año. Conclusión: La fractura de cadera presenta una elevada incidencia, costos y morbimortalidad en la población de adultos mayores, comparable con datos internacionales. Es necesario contar con un Registro Nacional de Fracturas de Cadera que permita conocer datos estadísticos certeros para poder establecer políticas adecuadas de prevención, tratamiento y control de gastos.

Introduction: The incidence of hip fractures dramatically increases from middle age on, posing a prevalent health problem in elderly people. A literature review of the international hip fracture registers, as well as a multicenter, epidemiological study were carried out in order to assess the incidence, costs, and mortality of this pathology in our country. Material and methods: All international hip fracture registers in the world were searched, reviewed and analyzed. An observational, retrospective, multicenter descriptive analysis was then carried out in 4 health-care centers for patents over 50 years of age who underwent surgery with osteosynthesis due to hip fracture in 2019. Age, sex, type of fracture, incidence and costs were assessed from the anonymized data. Statistical and economic data from the National Resources Fund Register were also included and associated. The SPSS statistical software was used to establish univariate, bivariate, and multivariate associations. The chi-squared statistical test was used to compare proportions. Results: Review of the registers is summarized in a table. The multicenter analysis included 646 patients with hip fractures. Worth of note is the high prevalence of this pathology in patients over 79 years of age (63.1%) and females (77.6%), in line with the international registers, and a significant association between both variables (p < 0.0001). Unlike other registers, and probably due to inaccurate data, the most frequent fracture was that of femoral neck (43%). The time from fracture to surgery and inpatient days were 2.6 and 7.2 days, respectively, in the most effective health care center. Our calculation showed a hip fracture incidence in Uruguay between 235 and 391 per 100,000 inhabitants over 50 years of age. The estimated cost of the assessed series was about U$S 2,855,320, and in general this pathology generates an annual expense of about U$S 20,000,000 for our country. Conclusion: Hip fractures have high incidence, costs and mortality and morbidity in the elderly population comparable with international data. It is necessary to have a National Hip Fracture Register that provides accurate statistical data in order to establish adequate prevention, treatment and cost control policies.

Introdução: A incidência de fraturas de quadril apresenta um aumento dramático a partir da meia-idade, constituindo um problema de saúde prevalente em idosos. Uma revisão bibliográfica dos Registros Internacionais de Fratura de Quadril e um estudo epidemiológico multicêntrico foram realizados para determinar a incidência, os custos e a mortalidade dessa patologia em nosso país. Material e métodos: Foi realizada uma busca, revisão e análise de todos os Registros Internacionais de fraturas de quadril existentes no mundo. Posteriormente, foi realizada uma análise observacional descritiva retrospectiva e multicêntrica, em 4 Instituições, de pacientes maiores de 50 anos, submetidos à cirurgia com osteossíntese, para fratura de quadril em 2019. Nos dados anônimos foram avaliados idade e sexo, tipo de fratura , incidência e custos. Dados estatísticos e econômicos do Registro do Fundo Nacional de Recursos também foram incluídos e associados. O software estatístico SPSS foi usado para estabelecer associações univariadas, bivariadas e multivariadas. O teste estatístico do qui quadrado foi usado para comparar as proporções. Resultados: a revisão dos registros é resumida em uma tabela. A análise multicêntrica incluiu 646 pacientes com fraturas de quadril. Destaca-se a alta prevalência dessa patologia em pacientes maiores de 79 anos (63,1%) e no sexo feminino (77,6%), de acordo com registros internacionais, com associação significativa entre as duas variáveis ​​(p <0,0001). Ao contrário de outros registros, e talvez dados errôneos, a fratura mais frequente foi a do colo do fêmur (43%). O tempo decorrido entre a fratura e a cirurgia e os dias de internação foram de 2,6 e 7,2 dias, respectivamente, na instituição assistencial mais efetiva. Nosso cálculo mostrou uma incidência de fratura de quadril no Uruguai, variando entre 235 e 391 em 100.000 habitantes com mais de 50 anos de idade. O custo calculado da série avaliada foi em torno de US $ 2.855.320 e, em geral, essa patologia acarreta um gasto para o nosso país que é próximo a US $ 20.000.000 por ano. Conclusão: A fratura de quadril tem alta incidência, custo e morbimortalidade na população idosa, comparável a dados internacionais. É necessário um Cadastro Nacional de Fraturas de Quadril, que permita conhecer dados estatísticos precisos, para estabelecer políticas adequadas de prevenção, tratamento e controle de custos.

In-solution buffer-free digestion allows full-sequence coverage and complete characterization of post-translational modifications of the receptor-binding domain of SARS-CoV-2 in a single ESI-MS spectrum.

Subunit vaccines based on the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 provide one of the most promising strategies to fight the COVID-19 pandemic. The detailed characterization of the protein primary structure by mass spectrometry (MS) is mandatory, as described in ICHQ6B guidelines. In this work, several recombinant RBD proteins produced in five expression systems were characterized using a non-conventional protocol known as in-solution buffer-free digestion (BFD). In a single ESI-MS spectrum, BFD allowed very high sequence coverage (≥ 99%) and the detection of highly hydrophilic regions, including very short and hydrophilic peptides (2-8 amino acids), and the His6-tagged C-terminal peptide carrying several post-translational modifications at Cys538 such as cysteinylation, homocysteinylation, glutathionylation, truncated glutathionylation, and cyanylation, among others. The analysis using the conventional digestion protocol allowed lower sequence coverage (80-90%) and did not detect peptides carrying most of the above-mentioned PTMs. The two C-terminal peptides of a dimer [RBD(319-541)-(His)6]2 linked by an intermolecular disulfide bond (Cys538-Cys538) with twelve histidine residues were only detected by BFD. This protocol allows the detection of the four disulfide bonds present in the native RBD, low-abundance scrambling variants, free cysteine residues, O-glycoforms, and incomplete processing of the N-terminal end, if present. Artifacts generated by the in-solution BFD protocol were also characterized. BFD can be easily implemented; it has been applied to the characterization of the active pharmaceutical ingredient of two RBD-based vaccines, and we foresee that it can be also helpful to the characterization of mutated RBDs.

Liquid biopsy: a non-invasive approach for Hodgkin lymphoma genotyping.

The Hodgkin lymphoma (HL) genomic landscape is hardly known due to the scarcity of tumour cells in the tissue. Liquid biopsy employing circulating tumour DNA (ctDNA) can emerge as an alternative tool for non-invasive genotyping. By using a custom next generation sequencing (NGS) panel in combination with unique molecule identifiers, we aimed to identify somatic variants in the ctDNA of 60 HL at diagnosis. A total of 277 variants were detected in 36 of the 49 samples (73·5%) with a good quality ctDNA sample. The median number of variants detected per patient was five (range 1-23) with a median variant allele frequency of 4·2% (0·84-28%). Genotyping revealed somatic variants in the following genes: SOCS1 (28%), IGLL5 (26%), TNFAIP3 (23%), GNA13 (23%), STAT6 (21%) and B2M (19%). Moreover, several poor prognosis features (high LDH, low serum albumin, B-symptoms, IPI ≥ 3 or at an advanced stage) were related to significantly higher amounts of ctDNA. Variant detection in ctDNA by NGS is a feasible approach to depict the genetic features of HL patients at diagnosis. Our data favour the implementation of liquid biopsy genotyping for the routine evaluation of HL patients.

Clinical relevance of incidental focal breast uptake on fluorine-18 fluorodeoxyglucose PET/computed tomography studies: an experience in a high-load center of Spain.

AIM: We aimed to determine the frequency and clinical significance of breast incidental uptake (BIU) detected through fluorine-18 fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) in a single, high-load center. PATIENTS AND METHODS: In this retrospective study, we analyzed a total of 13 763 PET/CT studies performed from January 2017 to January 2020. After excluding 3148 scans, the maximum standardized uptake value (SUVmax) and maximum diameter (cm) of each BIU were measured. Clinical management, ultrasound/mammography and pathology reports were analyzed. RESULTS: We found BIU in 27 scans of 26 patients (0.3% of the studies). Mean age was 62.2 years and 88.5% were women; 84.6% underwent PET/CT for oncological indications. Ultrasound/mammography was consequently performed in 23 patients (88.5%), and histological correlations were available for Breast Imaging Reporting and Data System categories 4 and 5. Finally, lesions were benign in 14 patients (60.9%; two of them with low/intermediate risk of malignancy) and malignant in nine patients (39.1%). The remaining three patients had no ultrasound/mammography reports. Mean SUVmax of benign and malignant lesions were 2.6 ± 1.4 and 5.8 ± 3.5, respectively (P = 0.002). Considering a SUVmax cut-off value of 4.0, the sensitivity and specificity for differentiating benign vs. malignant lesions were 67 and 93%, respectively. Benign lesions were smaller than malignant in CT (maximum diameter:1.3 ± 0.5 cm vs. 2.0 ± 1.0 cm, P = 0.02). CONCLUSION: Although BIU detected by 18F-FDG PET/CT is infrequently found, the risk of malignancy remains very high (39.1%). Both SUVmax and maximum diameter were greater in malignant than in benign lesions. An exhaustive study with ultrasound/mammography and selective histopathological correlation is mandatory after BIU findings, even in small lesions.

R-COMP versus R-CHOP as first-line therapy for diffuse large B-cell lymphoma in patients ≥60 years: Results of a randomized phase 2 study from the Spanish GELTAMO group.

The use of non-pegylated liposomal doxorubicin (Myocet® ) in diffuse large B-cell lymphoma (DLBCL) has been investigated in retrospective and single-arm prospective studies. This was a prospective phase 2 trial of DLBCL patients ≥60 years old with left ventricular ejection fraction (LVEF) ≥55% randomized to standard R-CHOP or investigational R-COMP (with Myocet® instead of conventional doxorubicin). The primary end point was to evaluate the differences in subclinical cardiotoxicity, defined as decrease in LVEF to <55% at the end of treatment. Secondary objectives were efficacy, safety, and variations of troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and LVEF along follow-up. Ninety patients were included, 45 in each group. No differences were observed in the percentage of patients with LVEF <55% at end of treatment (11% in R-CHOP arm vs. 7% in R-COMP arm, p = 0.697) or at 4 months (10% vs. 6%, respectively, p = 0.667) and 12 months (8% vs. 7%, respectively, p = 1). However, a higher percentage of R-CHOP compared with R-COMP patients showed increased troponin levels in cycle 6 (100% vs. 63%, p = 0.001) and at 1 month after treatment (88% vs. 56%, respectively, p = 0.015). Cardiovascular adverse events were seen in five R-CHOP patients (nine episodes, four grade ≥3) and in four R-COMP patients (five episodes, all grade 1-2). No significant differences in efficacy were observed. In conclusion, R-COMP is a feasible immunochemotherapy schedule for DLBCL patients ≥60 years, with similar efficacy to R-CHOP. However, the use of non-pegylated doxorubicin instead of conventional doxorubicin was not associated with less early cardiotoxicity, although some reduced cardiac safety signals were observed. Trial registration: ClinicalTrials.gov Identifier: NCT02012088.