Results of an Early Access Treatment Protocol of Daratumumab Monotherapy in Spanish Patients With Relapsed or Refractory Multiple Myeloma

Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16 mg/kg) was administered to 73 patients who had >= 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03-13.17) months, with a median number of 12 (range: 1-25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatmentemergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma

Arritmias Supraventriculares y Síndrome de Brugada

El síndrome de Brugada está constituido por un patrón electrocardiográfico característico y tendencia a presentar síncopes o paro cardiaco por arritmias ventriculares malignas. La asociación de fibrilación auricular es de un 10%. En los últimos 6 años atendimos 15 pacientes (13 masculinos), portadores de esa entidad; en dos se constataron episodios de fibrilación auricular y otro tenía documentado una taquicardia intranodal. El primero había presentado un síncope, la estimulación eléctrica programada desde ventrículo derecho desencadenó fibrilación ventricular autolimitada, se le implantó un desfibrilador automático; el segundo aquejaba palpitaciones irregulares, de corta duración, se le indujo fibrilación auricular por manipulación de catéteres, la estimulación eléctrica programada no provocó arritmias. Al paciente con taquicardia intranodal se le realizó ablación exitosa de la vía lenta, previa estimulación eléctrica programada desde ventrículo derecho negativa. Ninguno de ellos tenía antecedentes familiares de muerte súbita. En el seguimiento entre 3 y 15 meses, el primer paciente al que se implantó el desfibrilador automático presentó dos descargas eléctricas del mismo por episodios nocturnos de fibrilación ventricular, el segundo paciente presentó otro episodio similar de palpitaciones autolimitadas y el tercero se mantiene asintomático, sin fármacos. La incidencia de arritmias supraventriculares en esta entidad es elevada. Las manifestaciones clínicas, la documentación de la taquicardia y la estimulación eléctrica programada nos permitirán diagnosticarlas y tratarlas adecuadamente

Arritmias Supraventriculares y Síndrome de Brugada

El síndrome de Brugada está constituido por un patrón electrocardiográfico característico y tendencia a presentar síncopes o paro cardiaco por arritmias ventriculares malignas. La asociación de fibrilación auricular es de un 10%. En los últimos 6 años atendimos 15 pacientes (13 masculinos), portadores de esa entidad; en dos se constataron episodios de fibrilación auricular y otro tenía documentado una taquicardia intranodal. El primero había presentado un síncope, la estimulación eléctrica programada desde ventrículo derecho desencadenó fibrilación ventricular autolimitada, se le implantó un desfibrilador automático; el segundo aquejaba palpitaciones irregulares, de corta duración, se le indujo fibrilación auricular por manipulación de catéteres, la estimulación eléctrica programada no provocó arritmias. Al paciente con taquicardia intranodal se le realizó ablación exitosa de la vía lenta, previa estimulación eléctrica programada desde ventrículo derecho negativa. Ninguno de ellos tenía antecedentes familiares de muerte súbita. En el seguimiento entre 3 y 15 meses, el primer paciente al que se implantó el desfibrilador automático presentó dos descargas eléctricas del mismo por episodios nocturnos de fibrilación ventricular, el segundo paciente presentó otro episodio similar de palpitaciones autolimitadas y el tercero se mantiene asintomático, sin fármacos. La incidencia de arritmias supraventriculares en esta entidad es elevada. Las manifestaciones clínicas, la documentación de la taquicardia y la estimulación eléctrica programada nos permitirán diagnosticarlas y tratarlas adecuadamente

Potassium‐ion‐selective fluorescent sensors to detect cereulide, the emetic toxin of B. cereus, in food samples and HeLa cells

We report the development of new chemical probes for cereulide, a toxic metabolite produced by specific strains of Bacillus cereus, through displacement of potassium cations from a preformed specific complex and a subsequent change in the fluorescence emission. For this purpose, we designed fluorescent probes for potassium cations that were suitable for displacement assays with cereulide from organic extracts. The fluorescence detection of natural cereulide in rice samples was achieved by using synthetic cereulide as a reference and a potassium fluorescent reporter, and this was found to be useful as a portable and fast method for the in situ detection of cereulide in food extracts. To study the fate of cereulide in live cells, we designed a procedure that was suitable for live‐cell microscopy imaging of HeLa cells by comparing the cellular location of the potassium fluorogenic probe, which stained intracellular endolysosomes, in the absence and presence of cereulide; we concluded that in the presence of cereulide, the fluorescence of the probe was decreased because of complexation of the potassium ions by cereulide.Ministerio de Econom&a y Competitividad, Spain (Projects CTQ2015-71353-R and AES-PI16/000496), Junta de Castilla y Lejn, Consejer&a de Educaci jn y Cultura y Fondo Social Europeo (Project BU232U13), and the European Commission, Seventh Framework Programme (Project SNIFFER FP7-SEC-2012–312411

Automated Force Volume Image Processing for Biological Samples

Atomic force microscopy (AFM) has now become a powerful technique for investigating on a molecular level, surface forces, nanomechanical properties of deformable particles, biomolecular interactions, kinetics, and dynamic processes. This paper specifically focuses on the analysis of AFM force curves collected on biological systems, in particular, bacteria. The goal is to provide fully automated tools to achieve theoretical interpretation of force curves on the basis of adequate, available physical models. In this respect, we propose two algorithms, one for the processing of approach force curves and another for the quantitative analysis of retraction force curves. In the former, electrostatic interactions prior to contact between AFM probe and bacterium are accounted for and mechanical interactions operating after contact are described in terms of Hertz-Hooke formalism. Retraction force curves are analyzed on the basis of the Freely Jointed Chain model. For both algorithms, the quantitative reconstruction of force curves is based on the robust detection of critical points (jumps, changes of slope or changes of curvature) which mark the transitions between the various relevant interactions taking place between the AFM tip and the studied sample during approach and retraction. Once the key regions of separation distance and indentation are detected, the physical parameters describing the relevant interactions operating in these regions are extracted making use of regression procedure for fitting experiments to theory. The flexibility, accuracy and strength of the algorithms are illustrated with the processing of two force-volume images, which collect a large set of approach and retraction curves measured on a single biological surface. For each force-volume image, several maps are generated, representing the spatial distribution of the searched physical parameters as estimated for each pixel of the force-volume image

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised