Brief Report: Updated Data From IMscin001 Part 2, a Randomized Phase III Study of Subcutaneous Versus Intravenous Atezolizumab in Patients With Locally Advanced or Metastatic NSCLC.

INTRODUCTION: Subcutaneous atezolizumab is approved for the treatment of various solid tumors. Previous results from the IMscin001 study (NCT03735121) revealed that the pharmacokinetics, efficacy, immunogenicity, and safety of subcutaneous and intravenous atezolizumab were consistent (data cutoff: April 26, 2022). We present updated data from this trial (data cutoff: January 16, 2023). METHODS: Eligible patients aged above or equal to 18 years with locally advanced or metastatic NSCLC were randomized (2:1) to receive atezolizumab subcutaneously (1875 mg, n = 247) or intravenously (1200 mg, n = 124) every 3 weeks. Here, we present updated efficacy (overall survival [OS]; progression-free survival; objective response rate; duration of response), safety, and immunogenicity end points, alongside patient-reported outcomes and health care practitioner (HCP) perspectives. RESULTS: In this updated analysis, the median survival follow-up was 9.5 months. Median subcutaneous injection time was 7.1 minutes, with an average subcutaneous injection time of 4 to 8 minutes in most patients (75.7%). OS data were mature: median OS was similar between treatment arms, at 10.7 and 10.1 months in the subcutaneous and intravenous arms, respectively (hazard ratio: 0.88; 95% confidence interval: 0.67-1.16). Other efficacy end points, as well as immunogenicity, patient-reported outcomes, and safety, were similar between arms. Most HCPs found subcutaneous administration convenient (79.5%), easy to administer (89.7%), and were satisfied with the treatment (84.6%); 75.0% of HCPs agreed that administering atezolizumab subcutaneously compared with intravenously could save time. CONCLUSIONS: In this analysis, mature OS data were similar between treatments. The updated efficacy and safety profile of subcutaneous atezolizumab is consistent with previous findings and equivalent to intravenous atezolizumab.

Assessing the impact of digital patient monitoring on health outcomes and healthcare resource usage in addition to the feasibility of its combination with at-home treatment, in participants receiving systemic anticancer treatment in clinical practice: protocol for an interventional, open-label, multicountry platform study (ORIGAMA).

INTRODUCTION: Digital patient monitoring (DPM) tools can enable more effective clinical care and improved patient outcomes in cancer. However, their broad adoption requires ease of use and demonstration of real-world clinical utility/impact. ORIGAMA (MO42720) is an interventional, open-label, multicountry platform study investigating the clinical utility of DPM tools and specific treatments. ORIGAMA will begin with two cohorts that aim to assess the impact of the atezolizumab-specific Roche DPM Module (hosted on the Kaiku Health DPM platform (Helsinki, Finland)) on health outcomes and healthcare resource usage, and its feasibility to support at-home treatment administration, in participants receiving systemic anticancer treatment. Other digital health solutions may be added to future cohorts. METHODS AND ANALYSIS: In Cohort A, participants with metastatic non-small cell lung cancer (NSCLC), extensive-stage SCLC or Child Pugh A unresectable hepatocellular carcinoma will be randomised to a locally approved anticancer regimen containing intravenous atezolizumab (TECENTRIQ, F. Hoffmann-La Roche Ltd/Genentech) and local standard-of-care support, with/without the Roche DPM Module. Cohort B will assess the feasibility of the Roche DPM Module in supporting administration of three cycles of subcutaneous atezolizumab (1875 mg; Day 1 of each 21-day cycle) in the hospital, followed by 13 cycles at home by a healthcare professional (ie, flexible care), in participants with programmed cell-death ligand 1-positive, early-stage NSCLC. The primary endpoints are the mean difference in change of the participant-reported Total Symptom Interference Score at Week 12 from baseline (Cohort A) and flexible care adoption rate at Cycle 6 (Cohort B). ETHICS AND DISSEMINATION: This study will be conducted according to the Declaration of Helsinki, and/or the applicable laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The study received its first Ethics Committee approval in Spain in October 2022. Participants will provide written informed consent in a face-to-face setting. The results of this study will be presented at national and/or international congresses and disseminated via publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05694013.

Combination lurbinectedin and doxorubicin versus physician's choice of chemotherapy in patients with relapsed small-cell lung cancer (ATLANTIS): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Lurbinectedin is a synthetic marine-derived anticancer agent that acts as a selective inhibitor of oncogenic transcription. Lurbinectedin monotherapy (3·2 mg/m2 every 3 weeks) received accelerated approval from the US Food and Drug Administration on the basis of efficacy in patients with small-cell lung cancer (SCLC) who relapsed after first-line platinum-based chemotherapy. The ATLANTIS trial assessed the efficacy and safety of combination lurbinectedin and the anthracycline doxorubicin as second-line treatment for SCLC. METHODS: In this phase 3, open-label, randomised study, adult patients aged 18 years or older with SCLC who relapsed after platinum-based chemotherapy were recruited from 135 hospitals across North America, South America, Europe, and the Middle East. Patients were randomly assigned (1:1) centrally by dynamic allocation to intravenous lurbinectedin 2·0 mg/m2 plus doxorubicin 40·0 mg/m2 administered on day 1 of 21-day cycles or physician's choice of control therapy (intravenous topotecan 1·5 mg/m2 on days 1-5 of 21-day cycles; or intravenous cyclophosphamide 1000 mg/m2, doxorubicin 45·0 mg/m2, and vincristine 2·0 mg on day 1 of 21-day cycles [CAV]) administered until disease progression or unacceptable toxicity. Primary granulocyte-colony stimulating factor prophylaxis was mandatory in both treatment groups. Neither patients nor clinicians were masked to treatment allocation, but the independent review committee, which assessed outcomes, was masked to patients' treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02566993, and with EudraCT, 2015-001641-89, and is complete. FINDINGS: Between Aug 30, 2016, and Aug 20, 2018, 613 patients were randomly assigned to lurbinectedin plus doxorubicin (n=307) or control (topotecan, n=127; CAV, n=179) and comprised the intention-to-treat population; safety endpoints were assessed in patients who had received any partial or complete study treatment infusions (lurbinectedin plus doxorubicin, n=303; control, n=289). After a median follow-up of 24·1 months (95% CI 21·7-26·3), 303 patients in the lurbinectedin plus doxorubicin group and 289 patients in the control group had discontinued study treatment; progressive disease was the most common reason for discontinuation (213 [70%] patients in the lurbinectedin plus doxorubicin group vs 152 [53%] in the control group). Median overall survival was 8·6 months (95% CI 7·1-9·4) in the lurbinectedin plus doxorubicin group versus 7·6 months (6·6-8·2) in the control group (stratified log-rank p=0·90; hazard ratio 0·97 [95% CI 0·82-1·15], p=0·70). 12 patients died because of treatment-related adverse events: two (<1%) of 303 in the lurbinectedin plus doxorubicin group and ten (3%) of 289 in the control group. 296 (98%) of 303 patients in the lurbinectedin plus doxorubicin group had treatment-emergent adverse events compared with 284 (98%) of 289 patients in the control group; treatment-related adverse events occurred in 268 (88%) patients in the lurbinectedin plus doxorubicin group and 266 (92%) patients in the control group. Grade 3 or worse haematological adverse events were less frequent in the lurbinectedin plus doxorubicin group than the control group (anaemia, 57 [19%] of 302 patients in the lurbinectedin plus doxorubicin group vs 110 [38%] of 288 in the control group; neutropenia, 112 [37%] vs 200 [69%]; thrombocytopenia, 42 [14%] vs 90 [31%]). The frequency of treatment-related adverse events leading to treatment discontinuation was lower in the lurbinectedin plus doxorubicin group than in the control group (26 [9%] of 303 patients in the lurbinectedin plus doxorubicin group vs 47 [16%] of 289 in the control group). INTERPRETATION: Combination therapy with lurbinectedin plus doxorubicin did not improve overall survival versus control in patients with relapsed SCLC. However, lurbinectedin plus doxorubicin showed a favourable haematological safety profile compared with control. FUNDING: PharmaMar.

Evolutionary Analysis of Cystatins of Early-Emerging Metazoans Reveals a Novel Subtype in Parasitic Cnidarians.

The evolutionary aspects of cystatins are greatly underexplored in early-emerging metazoans. Thus, we surveyed the gene organization, protein architecture, and phylogeny of cystatin homologues mined from 110 genomes and the transcriptomes of 58 basal metazoan species, encompassing free-living and parasite taxa of Porifera, Placozoa, Cnidaria (including Myxozoa), and Ctenophora. We found that the cystatin gene repertoire significantly differs among phyla, with stefins present in most of the investigated lineages but with type 2 cystatins missing in several basal metazoan groups. Similar to liver and intestinal flukes, myxozoan parasites possess atypical stefins with chimeric structure that combine motifs of classical stefins and type 2 cystatins. Other early metazoan taxa regardless of lifestyle have only the classical representation of cystatins and lack multi-domain ones. Our comprehensive phylogenetic analyses revealed that stefins and type 2 cystatins clustered into taxonomically defined clades with multiple independent paralogous groups, which probably arose due to gene duplications. The stefin clade split between the subclades of classical stefins and the atypical stefins of myxozoans and flukes. Atypical stefins represent key evolutionary innovations of the two parasite groups for which their origin might have been linked with ancestral gene chimerization, obligate parasitism, life cycle complexity, genome reduction, and host immunity.

Passive Immunization Delays Disease Outcome in Gilthead Sea Bream Infected With Enteromyxum leei (Myxozoa), Despite the Moderate Changes in IgM and IgT Repertoire.

Passive immunization constitutes an emerging field of interest in aquaculture, particularly with the restrictions for antibiotic use. Enteromyxum leei is a myxozoan intestinal parasite that invades the paracellular space of the intestinal epithelium, producing a slow-progressing disease, leading to anorexia, cachexia and mortalities. We have previously demonstrated that gilthead sea bream (GSB, Sparus aurata) that survive E. leei infection become resistant upon re-exposure, and this resistance is directly related to the presence of high levels of specific IgM in serum. Thus, the current work was aimed to determine if passive immunization could help to prevent enteromyxosis in GSB and to study in detail the nature of these protective antibodies. Serum from a pool of resistant (SUR) or naïve (NAI) animals was intracoelomically injected 24 h prior to the E. leei-effluent challenge and at 9 days post-challenge (dpc). Effluent challenge lasted for 23 days, and then the injected groups were allocated in separate tanks with clean water. A non-lethal parasite diagnosis was performed at 56 dpc. At the final sampling (100 dpc), blood, serum and tissues were collected for histology, molecular diagnosis and the detection of circulating antibodies. In parallel, we performed an immunoglobulin repertoire analysis of the fish generating SUR and NAI sera. The results showed that, fish injected with parasite-specific antibodies (spAbs) became infected with the parasite, but showed lower disease signs and intensity of infection than the other groups, indicating a later establishment of the parasite. Repertoire analysis revealed that E. leei induced a polyclonal expansion of diverse IgM and IgT subsets that could be in part an evasion strategy of the parasite. Nonetheless, GSB was able to produce sufficient levels of parasite-spAbs to avoid re-infection of surviving animals and confer certain degree of protection upon passive transfer of antibodies. These results highlight the crucial role of spAb responses against E. leei and set the basis for the development of effective treatment or prophylactic methods for aquaculture.

Caracterización clínica de pacientes con morbilidad materna extremadamente grave y su repercusión perinatal. Cienfuegos 2016-2018 / Clinical characterization of patients with extremely severe maternal morbidity and its perinatal impact. Cienfuegos 20016-2018

RESUMEN Fundamento: Estudios realizados dentro y fuera de Cuba demuestran que existe una alta repercusión en la salud del producto de la concepción de madres con morbilidad materna extremadamente grave. Un análisis de esta problemática podría revertirse en una adecuada atención médica y en el logro de resultados perinatales de excelencia. Objetivo: caracterizar a las pacientes con morbilidad materna extremadamente grave y su repercusión perinatal. Métodos: estudio descriptivo, de serie de casos, realizado en el Hospital Dr. Gustavo Aldereguía Lima, de Cienfuegos. La serie estuvo conformada por 145 pacientes con morbilidad materna extremadamente grave, y sus productos de la concepción, atendidos durante el periodo 2016-2018. Se analizó tipo de parto, causas de ingreso, morbilidad materna y neonatal, mortalidad perinatal, entre otras variables. Resultados: predominaron las pacientes sin comorbilidad, no nulíparas y con edad entre los 20 y 34 años. Las causas más frecuentes de ingreso fueron la enfermedad hipertensiva del embarazo (37,9 %) y la hemoragia obstétrica mayor (30,3 %); así como en las terapias neonatales, lo fueron el síndrome de distrés respiratorio (42,5 %) y la asfixia neonatal (400 %). Se observó, además, razón de una paciente con morbilidad materna extremadamente grave por cada 87,4 nacimientos; una muerte materna por cada 72,5 pacientes; y un recién nacido con morbilidad neonatal cada 3,6 pacientes. Conclusión: la morbilidad materna extremadamente grave es una condición de alta repercusión sobre la morbimortalidad perinatal.

ABSTRACT Background: Studies carried out inside and outside of Cuba show that there is a high impact on the health of the product of conception of mothers with extremely serious maternal morbidity. An analysis of this problem could be reverted to adequate medical care and the achievement of excellence perinatal results. Objective: to characterize patients with extremely severe maternal morbidity and its perinatal repercussion. Methods: descriptive study, of a series of cases, carried out at the Dr. Gustavo Aldereguía Lima Hospital, in Cienfuegos. The series consisted of 145 patients with extremely severe maternal morbidity, and their products of conception, treated during the period 2016-2018. Type of delivery, causes of admission, maternal and neonatal morbidity, perinatal mortality, among other variables were analyzed. Results: patients without comorbidity, non-nulliparous and aged between 20 and 34 years predominated. The most frequent causes of admission were hypertensive disease of pregnancy (37.9%) and major obstetric hemorrhage (30.3%); as well as in neonatal therapies, they were the respiratory distress syndrome (42.5%) and neonatal asphyxia (400%). In addition, the ratio of one patient with extremely severe maternal morbidity for every 87.4 births was observed; one maternal death for every 72.5 patients; and one newborn with neonatal morbidity every 3.6 patients. Conclusion: extremely severe maternal morbidity is a condition with a high impact on perinatal morbidity and mortality.

Enterospora nucleophila (Microsporidia) in Gilthead Sea Bream (Sparus aurata): Pathological Effects and Cellular Immune Response in Natural Infections.

Enterospora nucleophila is a microsporidian responsible for an emaciative disease in gilthead sea bream (Sparus aurata). Its intranuclear development and the lack of in vitro and in vivo models hinder its research. This study investigated the associated lesions, its detection by quantitative polymerase chain reaction, and the cellular immune response of naturally infected fish. The intensity of infection in the intestine was correlated with stunted growth and reduced body condition. At the beginning of the outbreaks, infection prevalence was highest in intestine and stomach, and in subsequent months, the prevalence decreased in the intestine and increased in hematopoietic organs and stomach. In heavy infections, the intestine had histologic lesions of enterocyte hypercellularity and proliferation of rodlet cells. Infected enterocytes had E. nucleophila spores in the cytoplasm, and a pyknotic nucleus, karyorhexis or karyolysis. Lymphocytes were present at the base of the mucosa, and eosinophilic granule cells were located between the enterocytes. In intestinal submucosa, macrophage aggregates containing spores were surrounded by lymphocytes and granulocytes, with submucosal infiltration of granulocytes. Macrophage aggregates appeared to develop into granulomata with necrotic areas containing parasite remnants. Immunohistochemistry revealed mast cells as the main type of granulocyte involved. Abundant IgM+ and IgT+ cells were identified by in situ hybridization in the submucosa when intracytoplasmic stages were present. This study describes the lesions of E. nucleophila in gilthead sea bream, an important aquaculture species.

[Noonan syndrome: genetic and clinical update and treatment options]. / Síndrome de Noonan: actualización genética, clínica y de opciones terapéuticas.

Noonan syndrome (NS) is a relatively common genetic condition characterised by short stature, congenital heart defects, and distinctive facial features. NS and other clinically overlapping conditions such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, or Costello syndrome, are caused by mutations in genes encoding proteins of the RAS-MAPKinases pathway. Because of this shared mechanism, these conditions have been collectively termed «RASopathies¼. Despite the recent advances in molecular genetics, nearly 20% of patients still lack a genetic cause, and diagnosis is still made mainly on clinical grounds. NS is a clinically and genetically heterogeneous condition, with variable expressivity and a changing phenotype with age, and affects multiple organs and systems. Therefore, it is essential that physicians involved in the care of these patients are familiarised with their manifestations and the management recommendations, including management of growth and development. Data on growth hormone treatment efficacy are sparse, and show a modest response in height gains, similar to that observed in Turner syndrome. The role of RAS/MAPK hyper-activation in the pathophysiology of this group of disorders offers a unique opportunity for the development of targeted approaches.

Síndrome De Embolia Grasa Postraumática, Síntomas Neurológicos Sin Clínica Respiratoria En Ausencia De Foramen Oval Permeable / Posttraumatic Fat Embolism Syndrome, Neurological Symptoms Without Respiratory Symptoms In The Absence Of Permeable Foramen Ovale

Resumen El síndrome de embolia grasa es una complicación potencialmente catastrófica de las fracturas de huesos largos. La tríada clásica de síntomas son erupciones cutáneas petequiales, hipoxemia y anomalías neurológicas, que generalmente ocurren dentro de las 24 a 72 horas posteriores a la fractura. El componente respiratorio se presenta en prácticamente la totalidad de los reportes. Presentamos el caso de un paciente con embolia grasa postraumática con clínica neurológica preponderante, sin afectación respiratoria en ausencia de foramen oval permeable.

Abstract Fat embolism syndrome is a potentially catastrophic complication of long-bone fractures. The classic triad of symptoms are petechial skin rashes, hypoxemia, and neurological abnormalities, which usually occur within 24 to 72 hours after the fracture. The respiratory component occurs in practically all of the reports. We present the case of a patient with posttraumatic fat embolism with predominant neurological symptoms, without respiratory involvement in the absence of patent foramen ovale.

Disruption of gut integrity and permeability contributes to enteritis in a fish-parasite model: a story told from serum metabolomics.

BACKGROUND: In the animal production sector, enteritis is responsible for serious economic losses, and intestinal parasitism is a major stress factor leading to malnutrition and lowered performance and animal production efficiency. The effect of enteric parasites on the gut function of teleost fish, which represent the most ancient bony vertebrates, is far from being understood. The intestinal myxozoan parasite Enteromyxum leei dwells between gut epithelial cells and causes severe enteritis in gilthead sea bream (Sparus aurata), anorexia, cachexia, growth impairment, reduced marketability and increased mortality. METHODS: This study aimed to outline the gut failure in this fish-parasite model using a multifaceted approach and to find and validate non-lethal serum markers of gut barrier dysfunction. Intestinal integrity was studied in parasitized and non-parasitized fish by immunohistochemistry with specific markers for cellular adhesion (E-cadherin) and tight junctions (Tjp1 and Cldn3) and by functional studies of permeability (oral administration of FITC-dextran) and electrophysiology (Ussing chambers). Serum samples from parasitized and non-parasitized fish were analyzed using non-targeted metabolomics and some significantly altered metabolites were selected to be validated using commercial kits. RESULTS: The immunodetection of Tjp1 and Cldn3 was significantly lower in the intestine of parasitized fish, while no strong differences were found in E-cadherin. Parasitized fish showed a significant increase in paracellular uptake measured by FITC-dextran detection in serum. Electrophysiology showed a decrease in transepithelial resistance in infected animals, which showed a diarrheic profile. Serum metabolomics revealed 3702 ions, from which the differential expression of 20 identified compounds significantly separated control from infected groups in multivariate analyses. Of these compounds, serum inosine (decreased) and creatine (increased) were identified as relevant and validated with commercial kits. CONCLUSIONS: The results demonstrate the disruption of tight junctions and the loss of gut barrier function, a metabolomic profile of absorption dysfunction and anorexia, which further outline the pathophysiological effects of E. leei.

Estrategias para reducir infecciones, uso de antimicrobianos y sus efectos en una unidad de neonatología / Strategies to reduce infections and antibiotic use and its effects in a neonatal care unit

Introduction: Late onset sepsis (LOS) remains an important cause of morbidity and mortality in neonatal intensive care units (NICU). The empirical use of vancomycin and other broad spectrum antibiotics is very frequent and is associated with the emergence of resistant agents, infection by gram-negative bacilli (GNB), fungal infections and increased morbidity and mortality. Objective: To evaluate the impact of 5 intervention protocols designed to reduce infections and promote the rational use of antibiotics (AB) in a single NICU. Patients and Method: Retrospective analysis included all hospitalized patients before (year 2012) and after interventions (August 2013 through July 2014). All episodes of positive cultures (blood, urine, tracheal and spinal fluid) were considered as late onset infections. Results: After intervention, a significant decrease of late onset infections was observed from 14.3 to 8.5 per 1,000 live births (p < 0.01); with a decrease in LOS from 5.7 to 2.9 per 1,000 live births, although no significant. There was a decrease in vancomycin and 3rd generation cephalosporin use without Candida spp infections in the intervention period. Mortality rates and length of hospital stay were similar in both study periods. Conclusion: After interventions, there was an important reduction in overall late onset infections and AB related costs.

Introducción: La sepsis tardía sigue siendo una causa importante de morbilidad y mortalidad en las unidades de cuidados intensivos neonatales. El uso de vancomicina y otros antimicrobianos de amplio espectro es frecuente y se asocia a la aparición de agentes resistentes, infecciones por bacilos gramnegativos, infecciones por hongos y una mayor morbimortalidad. Objetivo: Evaluar el impacto de cinco protocolos de intervención para reducir la incidencia de infecciones y promover el uso racional de antimicrobianos. Pacientes y Método: Análisis retrospectivo pre (control) y post intervenciones. Se revisaron todos los episodios de infecciones con cultivos positivos (sangre, orina, tráquea y líquido cefalorraquídeo) en pacientes hospitalizados entre enero de 2012 y junio de 2014. Resultados: Después de la intervención, hubo una disminución significativa en las infecciones tardías de 14,3 a 8,5 por 1.000 RNV (p < 0,01); con disminución de la sepsis tardía de 5,7 a 2,8 por 1.000 RNV, sin alcanzar significancia estadística. Hubo una disminución significativa del uso de vancomicina y de cefalosporinas de tercera generación, así como la desaparición de infecciones por Candida spp. La mortalidad y la estadía hospitalaria fueron similares en ambos períodos. Conclusión: Al incorporar estas intervenciones, se logró una disminución significativa de las infecciones tardías y de los costos asociados al uso de antimicrobianos.

Glutathione and mitochondria determine acute defense responses and adaptive processes in cadmium-induced oxidative stress and toxicity of the kidney.

Cadmium (Cd(2+)) induces oxidative stress that ultimately defines cell fate and pathology. Mitochondria are the main energy-producing organelles in mammalian cells, but they also have a central role in formation of reactive oxygen species, cell injury, and death signaling. As the kidney is the major target in Cd(2+) toxicity, the roles of oxidative signature and mitochondrial function and biogenesis in Cd(2+)-related stress outcomes were investigated in vitro in cultured rat kidney proximal tubule cells (PTCs) (WKPT-0293 Cl.2) for acute Cd(2+) toxicity (1-30 µM, 24 h) and in vivo in Fischer 344 rats for sub-chronic Cd(2+) toxicity (1 mg/kg CdCl2 subcutaneously, 13 days). Whereas 30 µM Cd(2+) caused ~50 % decrease in cell viability, apoptosis peaked at 10 µM Cd(2+) in PTCs. A steep, dose-dependent decline in reduced glutathione (GSH) content occurred after acute exposure and an increase of the oxidized glutathione (GSSG)/GSH ratio. Quantitative PCR analyses evidenced increased antioxidative enzymes (Sod1, Gclc, Gclm), proapoptotic Bax, metallothioneins 1A/2A, and decreased antiapoptotic proteins (Bcl-xL, Bcl-w). The positive regulator of mitochondrial biogenesis Pparγ and mitochondrial DNA was increased, and cellular ATP was unaffected with Cd(2+) (1-10 µM). In vivo, active caspase-3, and hence apoptosis, was detected by FLIVO injection in the kidney cortex of Cd(2+)-treated rats together with an increase in Bax mRNA. However, antiapoptotic genes (Bcl-2, Bcl-xL, Bcl-w) were also upregulated. Both GSSG and GSH increased with chronic Cd(2+) exposure with no change in GSSG/GSH ratio and augmented expression of antioxidative enzymes (Gpx4, Prdx2). Mitochondrial DNA, mitofusin 2, and Pparα were increased indicating enhanced mitochondrial biogenesis and fusion. Hence, these results demonstrate a clear involvement of higher mitochondria copy numbers or mass and mitochondrial function in acute defense against oxidative stress induced by Cd(2+) in renal PTCs as well as in adaptive processes associated with chronic renal Cd(2+) toxicity.

A mathematical model for HIV and hepatitis C co-infection and its assessment from a statistical perspective.

The hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) are a clear threat for public health, with high prevalences especially in high risk groups such as injecting drug users. People with HIV infection who are also infected by HCV suffer from a more rapid progression to HCV-related liver disease and have an increased risk for cirrhosis and liver cancer. Quantifying the impact of HIV and HCV co-infection is therefore of great importance. We propose a new joint mathematical model accounting for co-infection with the two viruses in the context of injecting drug users (IDUs). Statistical concepts and methods are used to assess the model from a statistical perspective, in order to get further insights in: (i) the comparison and selection of optional model components, (ii) the unknown values of the numerous model parameters, (iii) the parameters to which the model is most 'sensitive' and (iv) the combinations or patterns of values in the high-dimensional parameter space which are most supported by the data. Data from a longitudinal study of heroin users in Italy are used to illustrate the application of the proposed joint model and its statistical assessment. The parameters associated with contact rates (sharing syringes) and the transmission rates per syringe-sharing event are shown to play a major role.

Evaluación y Control del Riesgo Nutricional en Pacientes Quirúrgicos del Hospital Central de Ivirgarzama / Risk Assessment and Control of Nutrition in Surgical Patients of The Hospital Central Ivirgarzama

Se realizó un estudio analítico, de casos y controles, doble ciego, en 228 pacientes ingresados en los diferentes servicios Quirúrgicos del Hospital Central de Ivirgarzama desde Julio 2009 hasta junio 2010, con el objetivo de evaluar y controlar el riesgo nutricional y su relación con la incidencia de las complicaciones post operatorias. La muestra fue dividida en 2 subgrupos: el primero recibió un manejo nutricional personalizado aplicando el factor de injuria en el cálculo de requerimientos basales; por su parte el segundo grupo recibió el aporte nutricional postoperatorio estándar, correspondiendo al grupo control. Los resultados más significativos fueron: 43,9% correspondieron al Riesgo Bajo, el 16,67% al Riesgo Intermedio y la misma proporción 16,67% al Riesgo Elevado; solo un 22,8% se presentaron sin riesgo nutricional en el preoperatorio. La incidencia de complicaciones por grupo de estudio fue: el 3,1% en pacientes con manejo nutricional según Riesgo Nutricional; el 7,5% en pacientes con manejo nutricional convencional; y 20% en aquellos pacientes que no fueron evaluados. Las complicaciones más frecuentes encontradas en estos pacientes son infecciones locales 31 %, íleo abdominal 22%, abscesos locales 19%, fístulas 13%, dehiscencia de sutura 9% y el shock séptico en el 6% de los pacientes. Llegándose a las siguientes conclusiones que los pacientes con un manejo nutricional general sin base en una evaluación de riesgo nutricional presentaron mayores complicaciones que el grupo que recibió un manejo estándar y el grupo que no fue evaluado, siendo la sepsis local la más frecuente de estas en los tres grupos.

We performed an analytical study of cases and controls, double-blind study in 228 patients admitted to different services Surgical Ivirgarzama Central Hospital from July 2009 to June 2010, with the aim of assessing and monitoring nutritional risk and its relationship with incidence of postoperative complications. The sample was divided into 2 subgroups: one received a personalized nutritional management with the factor of injury in the calculation of baseline requirements, for its part, the second group received standard postoperative nutritional support, corresponding to the control group.The most significant results were:43.9% were at low risk, 16.67% at intermedíate risk, and the same proportion 16.67% of the high risk, only 22.8% had no preoperative nutritional risk.The incidence of complications study group: 3.1% in patients with nutritional management as nutritional risk, 7.5% in patients with conventional nutritional management, and 20% in patients who were not evaluated. The most common complications found in these patients are 31% local infections, ileus, abdominal 22%, 19% local abscesses, fístulas 13%, 9% suture dehiscence and septic shock in 6% of patients. Reached the following conclusions that patients with general nutritional management not based on nutritional risk assessment had more complications than the group receiving standard management and the group was not assessed, local sepsis being the most common of these in the three groups.

[Hemodynamic and inflammatory markers of sleep apnea-hypopnea syndrome and nocturnal hypoxemia: effects of treatment with nasal continuous positive airway pressure]. / Marcadores hemodinámicos e inflamatorios del síndrome de apneas-hipopneas durante el sueño e hipoxemia nocturna. Efectos del tratamiento nasal con presión positiva continua de la vía aérea nasal.

OBJECTIVE: In this study, we assessed factors associated with cardiovascular risk in patients with sleep apnea-hypopnea syndrome (SAHS) through analysis of plasma concentrations of N-terminal prohormone brain natriuretic peptide (NTproBNP) and high-sensitivity C-reactive protein (hsCRP). In addition, we analyzed the effect of nasal continuous positive airway pressure (nCPAP) on these markers. PATIENTS AND METHODS: Forty-two patients with SAHS (mild to moderate in 15 cases and severe in 27) were compared with 14 individuals without SAHS. The participants were not receiving drug treatment and they did not have diabetes, hypertension, marked dyslipidemia, or cardiovascular disease, which was ruled out both clinically and by echocardiography and (99m)Tc-tetrofosmin scintigraphy at rest and during exercise. The effects of nCPAP in patients with severe SAHS were analyzed after 6 months of treatment. RESULTS: Following adjustment for age, body mass index, and smoking habit, the mean concentrations of markers were not significantly higher in patients with severe SAHS than in those with mild-to-moderate SAHS or in control subjects. Nevertheless, in patients with SAHS the main factor influencing NTproBNP concentrations was the percentage of time with a nocturnal arterial oxygen saturation of less then 90% (r=0.37, P=.017). No variables predictive of hsCRP concentration were identified. The concentrations of the markers were reduced by nCPAP, but the differences were not statistically significant. CONCLUSIONS: While nocturnal hypoxemia in SAHS is responsible for variations in the plasma concentration of NTproBNP (as a result of cardiovascular changes), SAHS appears not to be associated with the inflammatory marker hsCRP when patients with heart disease, cardiovascular risk factors, or those receiving pharmacologic treatment are excluded.