Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial.

BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). PATIENTS AND METHODS: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. RESULTS: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. CONCLUSIONS: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.

[Efficacy of botulinum toxin in infantile esotropia]. / Efficacité de la toxine botulique dans l'estropie de l'enfant.

INTRODUCTION AND OBJECTIVE: Botulinum toxin (BT) is used in a variety of therapeutic applications, including the treatment of strabismus. Two injection techniques coexist - transconjunctival injection and open sky injection. The goal of this study was to evaluate the results of BT injections in esotropia in children under 10 years of age and to compare the two techniques. PATIENTS AND METHOD: This is a retrospective, monocentric study, including children who received BT injections to treat their strabismus by the aforementioned techniques between 2014 and 2017. The results of these injections were recorded, and subgroup analyses (injection technique, age, degree of deviation, type of strabismus) were performed. The primary endpoint was the optimal success rate defined as residual strabismus less than or equal to 10 Δ. RESULTS: The study included 68 children with a mean age of 28.9 months and a mean deviation angle of 34.7 Δ. Patients received 1.2 BT injections. The success rate was 38% at 6 months, 35% at 12 months, and 35% at 24 months. There was 33% transient ptosis and 5% consecutive exotropia. There was no evidence of significant difference in success rate between the transconjunctival and open sky injection methods, baseline angles, age of injection, or type of strabismus. CONCLUSION: BT injection is effective and safe in pediatric esotropia, regardless of the injection method.

Recurrent Anterior Non-necrotizing Scleritis as an Adverse Event of ChAdOx1 nCoV-19 (Vaxzevria) Vaccine.

PURPOSE: To describe a case of anterior scleritis related to SARS-CoV-2 vaccine. SARS-CoV-2 vaccines appear safe; however vaccination has triggered thromboembolic events in predisposed patients. METHODS: A retrospective case report of anterior scleritis in a woman following administration of both ChAdOx1nCoV-19 vaccine doses was studied by complete ophthalmologic examination and complementary tests. RESULTS: The patient has overcome SARS-CoV-2 infection a year prior. Ancillary tests including autoimmune and infectious diseases were negative. The chronology between ChAdOx1nCoV-19 vaccine and the sequential episodes of scleritis may have a cause-and-effect relationship. CONCLUSION: Ophthalmologists may be aware of scleritis as an ocular manifestation following ChAdOx1nCoV-19 vaccine, in otherwise healthy patients.

Features of aerobic granular sludge formation treating fluctuating industrial saline wastewater at pilot scale.

A pilot-scale sequencing batch reactor, with a working volume of 3 m3, was installed in a fish cannery to develop aerobic granular sludge treating the produced effluents. Depending on the nitrogen (N) and organic matter (COD) concentration, the effluents were named in this study as medium-low-strength (Stage I) and high-strength (Stage II) wastewater. The composition of the wastewater was found to be a crucial factor to select granule-forming organisms. With medium-low-strength wastewater as feeding, the first granules were observed after 30 days, but the extremely high COD/N ratios of the wastewater provoked the overgrowth of filamentous bacteria after 4 months of operation (Stage I). When treating high-strength wastewater, stable aggregates with good settleability appeared, but well-shaped granules were not observed since the granulation process was not completed. The system was able to remove both COD (70-95%) and N (30-90%) treating both types of effluents. Biomass growth was the main N removal pathway. The reactor was found to be robust against factory production stops and, thus, a suitable alternative to treat wastewater from industries with discontinuous operation.

On time-discretized versions of the stochastic SIS epidemic model: a comparative analysis.

In this paper, the interest is in the use of time-discretized models as approximations to the continuous-time birth-death (BD) process [Formula: see text] describing the number I(t) of infective hosts at time t in the stochastic [Formula: see text] (SIS) epidemic model under the assumption of an additional source of infection from the environment. We illustrate some simple techniques for analyzing discrete-time versions of the continuous-time BD process [Formula: see text], and we show the similarities and differences between the discrete-time BD process [Formula: see text] of Allen and Burgin (Math Biosci 163:1-33, 2000), which is inspired from the infinitesimal transition probabilities of [Formula: see text], and an alternative discrete-time Markov chain [Formula: see text], which is defined in terms of the number [Formula: see text] of infective hosts at a sequence [Formula: see text] of inspection times. Processes [Formula: see text] and [Formula: see text] can be thought of as a uniformized version and the discrete skeleton of process [Formula: see text], respectively, and are commonly used to derive, in the more general setting of Markov chains, theorems about a continuous-time Markov chain by applying known theorems for discrete-time Markov chains. We shall demonstrate here that the continuous-time BD process [Formula: see text] and its discrete-time counterparts [Formula: see text] and [Formula: see text] behave asymptotically the same in the limit of large time index, while the processes [Formula: see text] and [Formula: see text] differ from the continuous-time BD process [Formula: see text] in terms of the random length of an outbreak, or when considering their dynamics during a predetermined time interval [Formula: see text]. To compare the dynamics of process [Formula: see text] with those of the discrete-time processes [Formula: see text] and [Formula: see text] during [Formula: see text], we consider extreme values (i.e., maximum and minimum number of infectives simultaneously observed during [Formula: see text]) in these three processes. Finally, we illustrate our analytical results by means of a number of numerical examples, where we use the Hellinger distance between two probability distributions to quantify the similarity between the resulting extreme value distributions of either [Formula: see text] and [Formula: see text], or [Formula: see text] and [Formula: see text].

A structured Markov chain model to investigate the effects of pre-exposure vaccines in tuberculosis control.

In this paper, the interest is in a structured Markov chain model to describe the transmission dynamics of tuberculosis (TB) in the setting of small communities of hosts sharing confined spaces, and to explore the potential impact of new pre-exposure vaccines on reducing the number of new TB cases during an outbreak of the disease. The model under consideration incorporates endogenous reactivation of latent tubercle bacilli, exogenous reinfection of latently infected TB hosts, loss of effectiveness of the vaccine protection, and death of hosts due to tubercle bacilli and from causes beyond TB. Various probabilistic measures are defined and analytically studied to describe extreme values and the number of vaccinations during an outbreak, and a random version of the basic reproduction number is used to measure the transmission potential during the initial phase of the epidemic. Our numerical experiments allow us to compare different pre-exposure vaccines versus the level of coverage in terms of these probabilistic measures.

Assessment of a fast method to predict the biochemical methane potential based on biodegradable COD obtained by fractionation respirometric tests.

The biochemical methane potential test (BMP) is the most common analytical technique to predict the performance of anaerobic digesters. However, this assay is time-consuming (from 20 to over than 100 days) and consequently impractical when it is necessary to obtain a quick result. Several methods are available for faster BMP prediction but, unfortunately, there is still a lack of a clear alternative. Current aerobic tests underestimate the BMP of substrates since they only detect the easily biodegradable COD. In this context, the potential of COD fractionation respirometric assays, which allow the determination of the particulate slowly biodegradable fraction, was evaluated here as an alternative to early predict the BMP of substrates. Seven different origin waste streams were tested and the anaerobically biodegraded organic matter (CODmet) was compared with the different COD fractions. When considering adapted microorganisms, the appropriate operational conditions and the required biodegradation time, the differences between the CODmet, determined through BMP tests, and the biodegradable COD (CODb) obtained by respirometry, were not significant (CODmet (57.8026 ± 21.2875) and CODb (55.6491 ± 21.3417), t (5) = 0.189, p = 0.853). Therefore, results suggest that the BMP of a substrate might be early predicted from its CODb in only few hours. This methodology was validated by the performance of an inter-laboratory studyconsidering four additional substrates.

Optimización del manejo del paciente neuroquirúrgico en Medicina Intensiva / Optimization of the neurosurgical patient in Intensive Care

Los pacientes con patología neuroquirúrgica requieren frecuentemente el ingreso en unidades de cuidados intensivos tanto para su manejo en el postoperatorio inmediato como para el control de las complicaciones que puedan presentar. La patología neuroquirúrgica es amplia y requiere profilaxis, tratamiento y monitorización específica. El tratamiento del paciente neuroquirúrgico se basa en asegurar una correcta perfusión tisular cerebral, es decir, mantener un flujo sanguíneo suficiente para aportar energía al parénquima cerebral. Con el objetivo de optimizar el tratamiento y el manejo de estos pacientes, en los últimos años se han desarrollado y perfeccionado diferentes sistemas para monitorizar variables como la presión intracraneal, la actividad eléctrica cerebral (electroencefalografía), el flujo cerebral, la oxigenación del parénquima (presión tisular de oxígeno) o el metabolismo locorregional (microdiálisis). Esta revisión sintetiza el manejo general del paciente neuroquirúrgico así como el de las principales complicaciones que puede desarrollar durante el postoperatorio. Asimismo, se propone un algoritmo de actuación para facilitar la decisión de los profesionales responsables que incluye la neuromonitorización multimodal

Neurosurgical patients frequently require admission to intensive care units, either for postoperative management or for treating complications. Most neurosurgical diseases require specific monitoring and prophylaxis. The basic principle of neurosurgical patient management is to ensure correct brain tissue perfusion, i.e., maintaining a sufficient blood flow to supply energy and oxygen to the brain parenchyma. In the last few years, several systems have been developed and improved for monitoring variables such as intracranial pressure, cerebral electrical activity (electroencephalography), cerebral blood flow, parenchymal oxygenation (tissue oxygen pressure) or locoregional metabolism (microdialysis). The present study provides an overview of the general management of neurosurgical patients and the main complications that may occur during the postoperative period. An interventional algorithm is also proposed to facilitate physician decisions, with the inclusion of multimodal neuromonitoring

Potential of endogenous PHA as electron donor for denitrification.

The use of wastewater streams to obtain polyhydroxyalkanoates (PHA) as high added-value products is widely studied. However, nitrogen removal is not well integrated into this process. In this study, the optimal conditions to track the specific endogenous denitrifying activity (SEDA) driven by PHA as carbon source were selected as: sludge concentration of 0.5-2 g VSS/L, CODPHA/N ratio higher than 5.4 g/g and between 40 and 60 mg NO3--N/L. The seeding biomass used to perform the activity tests was collected from two sequencing batch reactors and was able to store up to 69% wt/wt of PHA. SEDA values of 0.26-0.39 g N2-N/(g VSSact d) were achieved, which proved the potential of PHA-accumulating mixed microbial cultures to be used in nitrogen removal processes. The results indicated that there is not a preference in the consumption of hydroxybutyrate over hydroxyvalerate and that PHA concentrations lower than 5% wt/wt do not allow the obtainment of the maximum SEDA value. Finally, N2O gas production was not detected in the SEDA experiments.

Documento práctico del manejo de la hiponatremia en pacientes críticos / Practical document on the management of hyponatremia in critically ill patients

La hiponatremia es el trastorno electrolítico más prevalente en las Unidades de Cuidados Intensivos. Se asocia a un aumento de la morbilidad, mortalidad y estancia hospitalaria. La mayoría de los estudios publicados hasta el momento son observacionales, retrospectivos y no incluyen pacientes críticos, lo que dificulta la extracción de conclusiones sólidas. Además, debido a la escasa evidencia científica de calidad, incluso las recomendaciones realizadas por distintas sociedades científicas recientemente publicadas difieren en aspectos importantes como son el diagnóstico o el tratamiento de la hiponatremia. Los mecanismos etiopatogénicos en los pacientes críticos suelen ser complejos. Sin embargo, hay que profundizar en ellos para llegar al diagnóstico más probable y a la pauta de tratamiento más adecuada. Todo ello, ha motivado la realización de esta revisión práctica sobre aspectos útiles en el abordaje de la hiponatremia en las Unidades de Cuidados intensivos, con el objetivo de homogeneizar el manejo de esta entidad y disponer de un algoritmo diagnóstico a nivel nacional

Hyponatremia is the most prevalent electrolyte disorder in Intensive Care Units. It is associated with an increase in morbidity, mortality and hospital stay. The majority of the published studies are observational, retrospective and do not include critical patients; hence it is difficult to draw definitive conclusions. Moreover, the lack of clinical evidence has led to important dissimilarities in the recommendations coming from different scientific societies. Finally, etiopathogenic mechanisms leading to hyponatremia in the critical care patient are complex and often combined, and an intensive analysis is clearly needed. A study was therefore made to review all clinical aspects about hyponatremia management in the critical care setting. The aim was to develop a Spanish nationwide algorithm to standardize hyponatremia diagnosis and treatment in the critical care patient

Extreme values in SIR epidemic models with two strains and cross-immunity.

The paper explores the dynamics of extreme values in an SIR (susceptible → infectious → removed) epidemic model with two strains of a disease. The strains are assumed to be perfectly distinguishable, instantly diagnosed and each strain of the disease confers immunity against the second strain, thus showing total cross-immunity. The aim is to derive the joint probability distribution of the maximum number of individuals simultaneously infected during an outbreak and the time to reach such a maximum number for the first time. Specifically, this distribution is analyzed by distinguishing between a global outbreak and the local outbreaks, which are linked to the extinction of the disease and the extinction of particular strains of the disease, respectively. Based on the mass function of the maximum number of individuals simultaneously infected during the outbreak, we also present an iterative procedure for computing the final size of the epidemic. For illustrative purposes, the twostrain SIR-model with cross-immunity is applied to the study of the spread of antibiotic-sensitive and antibiotic-resistant bacterial strains within a hospital ward.

Does the feeding strategy enhance the aerobic granular sludge stability treating saline effluents?

The development and stability of aerobic granular sludge (AGS) was studied in two Sequencing Batch Reactors (SBRs) treating fish canning wastewater. R1 cycle comprised a fully aerobic reaction phase, while R2 cycle included a plug-flow anaerobic feeding/reaction followed by an aerobic reaction phase. The performance of the AGS reactors was compared treating the same effluents with variable salt concentrations (4.97-13.45 g NaCl/L) and organic loading rates (OLR, 1.80-6.65 kg CODs/(m3·d)). Granulation process was faster in R2 (day 34) than in R1 (day 90), however the granular biomass formed in the fully aerobic configuration was more stable to the variable feeding composition. Thus, in R1 solid retention times (SRT), up to 15.2 days, longer than in R2, up to 5.8 days, were achieved. These long SRTs values helped the retention of nitrifying organisms and provoked the increase of the nitrogen removal efficiency to 80% in R1 while it was approximately of 40% in R2. However, the presence of an anaerobic feeding/reaction phase increased the organic matter removal efficiency in R2 (80-90%) which was higher than in R1 with a fully aerobic phase (75-85%). Furthermore, in R2 glycogen-accumulating organisms (GAOs) dominated inside the granules instead of phosphorous-accumulating organisms (PAOs), suggesting that GAOs resist better the stressful conditions of a variable and high-saline influent. In terms of AGS properties an anaerobic feeding/reaction phase is not beneficial, however it enables the production of a better quality effluent.

Simulation of Hypothermic Perfusion of Rabbit Livers for Cryopreservation Applications.

BACKGROUND: In cryopreservation of biological material, it is very important to precise control the perfusion of cryoprotectants (CPA) inside the sample. CPA concentration inside tissues and organs during the process was measured in a few studies. The simulation of the CPA perfusion inside the organ is still necessary to understand and optimize this complex process. OBJECTIVE: This study simulates the diffusion of Me2SO and PBS in a rabbit liver. MATERIALS AND METHODS: The software COMSOL for computational fluid-dynamics has been used. A hypothermic perfusion is simulated where temperature and pressure at the entrance of the organ are constant. RESULTS: The simulation shows that Me2SO concentration increases within the porous medium until saturation. The variation of perfusion speed and pressure inside the organ is almost null with time. CONCLUSION: Finite elements modelling shows that under hypothermic conditions it is possible a full and even loading of this organ with Me2SO, keeping constant the perfusion parameters.

Optimization of the neurosurgical patient in Intensive Care. / Optimización del manejo del paciente neuroquirúrgico en Medicina Intensiva.

Neurosurgical patients frequently require admission to intensive care units, either for postoperative management or for treating complications. Most neurosurgical diseases require specific monitoring and prophylaxis. The basic principle of neurosurgical patient management is to ensure correct brain tissue perfusion, i.e., maintaining a sufficient blood flow to supply energy and oxygen to the brain parenchyma. In the last few years, several systems have been developed and improved for monitoring variables such as intracranial pressure, cerebral electrical activity (electroencephalography), cerebral blood flow, parenchymal oxygenation (tissue oxygen pressure) or locoregional metabolism (microdialysis). The present study provides an overview of the general management of neurosurgical patients and the main complications that may occur during the postoperative period. An interventional algorithm is also proposed to facilitate physician decisions, with the inclusion of multimodal neuromonitoring.

Practical document on the management of hyponatremia in critically ill patients. / Documento práctico del manejo de la hiponatremia en pacientes críticos.

Hyponatremia is the most prevalent electrolyte disorder in Intensive Care Units. It is associated with an increase in morbidity, mortality and hospital stay. The majority of the published studies are observational, retrospective and do not include critical patients; hence it is difficult to draw definitive conclusions. Moreover, the lack of clinical evidence has led to important dissimilarities in the recommendations coming from different scientific societies. Finally, etiopathogenic mechanisms leading to hyponatremia in the critical care patient are complex and often combined, and an intensive analysis is clearly needed. A study was therefore made to review all clinical aspects about hyponatremia management in the critical care setting. The aim was to develop a Spanish nationwide algorithm to standardize hyponatremia diagnosis and treatment in the critical care patient.

Perturbation analysis in finite LD-QBD processes and applications to epidemic models.

In this paper, we adapt arguments from the paper by Caswell [11] to level-dependent quasi-birth-and-death (LD-QBD) processes, which constitute a wide class of structured Markov chains. A LD-QBD process has the special feature that its space of states can be structured by levels (groups of states), so that a tridiagonal-by-blocks structure is obtained for its infinitesimal generator. For these processes, a number of algorithmic procedures exist in the literature in order to compute several performance measures while exploiting the underlying matrix structure; among others, these measures are related to first-passage times to a certain level L(0) and hitting probabilities at this level, the maximum level visited by the process before reaching states of level L(0), and the stationary distribution. For the case of a finite number of states, our aim here is to develop analogous algorithms to the ones analyzing these measures, for their perturbation analysis. This approach uses matrix calculus and exploits the specific structure of the infinitesimal generator, which allows us to obtain additional information during the perturbation analysis of the LD-QBD process by dealing with specific matrices carrying probabilistic insights of the dynamics of the process. We illustrate the approach by means of applying multi-type versions of SI and SIS epidemic models to the spread of antibiotic-sensitive and antibiotic-resistant bacterial strains in a hospital ward.

Novel system configuration with activated sludge like-geometry to develop aerobic granular biomass under continuous flow.

A novel continuous flow system with "flat geometry" composed by two completely mixed aerobic tanks in series and a settler was used to promote the formation of aerobic granular sludge. Making similarities of this system with a typical sequencing batch reactor (SBR), for aerobic granules cultivation, the value of the tank 1/tank 2 vol ratio and the biomass recirculation rate would correspond with the feast/famine length ratio and the length of the operational cycle, respectively, while the settler upflow liquid velocity imposed would be related to the settling time. From the three experiments performed the best results were obtained when the tank 1/tank 2 vol ratio was of 0.28, the sludge recycling ratio of 0.25 and the settler upflow velocity of 2.5 m/h. At these conditions the aggregates had settling velocities between 29 and 113 m/h, sludge volume index at 10 min (SVI10) of 70 mL/g TSS and diameters between 1.0 and 5.0 mm.

[Experience of a single-centre in the preparation of choosing wisely lists in Internal Medicine]. / Experiencia de un centro único en la preparación de listas choosing wisely en Medicina Interna.

OBJECTIVES: To identify areas for improvement, using a local list of interventions with low diagnostic and therapeutic usefulness for the 5 Related Diagnostic Groups, as well as the 5 main diagnoses most frequently seen in the hospital outpatient clinic. METHOD: A literature review method was used, supplemented with a Delphi process with 2 rounds. In the first round, participants in the selection process identified low-value interventions in relation to the most frequently observed diagnoses. In the second round, those interventions with lower usefulness were selected based on their frequency, cost, and risk to the patient. RESULTS: Out of a total of 100 recommendations made by 19 scientific societies, 23 received the highest number of votes in the first round. In the second round, 5 recommendations were selected for inpatients and 5 recommendations for outpatients. CONCLUSIONS: A simple method is described for developing a local guide to reduce the use of unnecessary medical interventions.

Enfermedad de Vogt-Koyanagi-Harada: una causa rara de uveítis / Vogt-Koyanagi-Harada disease: rare cause of uveitis

La enfermedad de Vogt-Koyanagi-Harada es una uveítis granulomatosa difusa bilateral, asociada a poliosis, vitíligo, alopecia y síntomas neurológicos y auditivos. La etiología es probablemente autoinmune contra los melanocitos, determinada por factores genéticos. Es una entidad muy rara en la edad pediátrica. Presentamos un nuevo caso en un paciente de 12 años de edad (AU)

The Vogt-Koyanagi-Harada syndrome (VKH) is a bilateral, diffuse granulomatous uveitis associated with poliosis, vitiligo, alopecia, and central nervous system and auditory signs. This inflammatory syndrome is probably the result of an autoimmune mechanism, influenced by genetic factors, and appears to be directed against melanocytes. In the paper is presented a rare case of probably VHK disease in 12-year old caucasian race boy (AU)

Short- and long-term orange dye effects on ammonium oxidizing and anammox bacteria activities.

The effects of orange azo dye over ammonia oxidizing bacteria (AOB) and anammox bacteria activities were tested. Performed batch tests indicated that concentrations lower than 650 mgorange/L stimulated AOB activity, while anammox bacteria activity was inhibited at concentrations higher than 25 mgorange/L. Long-term performance of a continuous stirred tank reactor (CSTR) for the partial nitritation and a sequencing batch reactor (SBR) for the anammox process was tested in the presence of 50 mgorange/L. In the case of the partial nitritation process, both the biomass concentration and the specific AOB activity increased after 50 days of orange azo dye addition. Regarding the anammox process, specific activity decreased down to 58% after 12 days of operation with continuous feeding of 50 mgorange/L. However, the anammox activity was completely recovered only 54 days after stopping the dye addition in the feeding. Once the biomass was saturated the azo dye adsorption onto the biomass was insignificant in the CSTR for the partial nitritation process fed with 50 mgorange/L. However, in the SBR the absorption was determined as 6.4 mgorange/g volatile suspended solids. No biological decolorization was observed in both processes.