Development and Validation of a Prediction Model for 1-Year Mortality in Patients With a Hematologic Malignancy Admitted to the ICU.

OBJECTIVES: To develop and validate a prediction model for 1-year mortality in patients with a hematologic malignancy acutely admitted to the ICU. DESIGN: A retrospective cohort study. SETTING: Five university hospitals in the Netherlands between 2002 and 2015. PATIENTS: A total of 1097 consecutive patients with a hematologic malignancy were acutely admitted to the ICU for at least 24 h. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We created a 13-variable model from 22 potential predictors. Key predictors included active disease, age, previous hematopoietic stem cell transplantation, mechanical ventilation, lowest platelet count, acute kidney injury, maximum heart rate, and type of malignancy. A bootstrap procedure reduced overfitting and improved the model's generalizability. This involved estimating the optimism in the initial model and shrinking the regression coefficients accordingly in the final model. We assessed performance using internal-external cross-validation by center and compared it with the Acute Physiology and Chronic Health Evaluation II model. Additionally, we evaluated clinical usefulness through decision curve analysis. The overall 1-year mortality rate observed in the study was 62% (95% CI, 59-65). Our 13-variable prediction model demonstrated acceptable calibration and discrimination at internal-external validation across centers (C-statistic 0.70; 95% CI, 0.63-0.77), outperforming the Acute Physiology and Chronic Health Evaluation II model (C-statistic 0.61; 95% CI, 0.57-0.65). Decision curve analysis indicated overall net benefit within a clinically relevant threshold probability range of 60-100% predicted 1-year mortality. CONCLUSIONS: Our newly developed 13-variable prediction model predicts 1-year mortality in hematologic malignancy patients admitted to the ICU more accurately than the Acute Physiology and Chronic Health Evaluation II model. This model may aid in shared decision-making regarding the continuation of ICU care and end-of-life considerations.

There is More to Length of Survival than Survival: Endpoints in Oncology Trials.

Progression free survival as a primary endpoint for comparative trials does not fully capture the therapeutic risk/benefit ratio. Additionally, summarization of the treatment effect via a hazard ratio is problematic when the proportional hazards assumption is violated. Restricted mean survival time metrics may address these challenges but have other limitations.

Egyptian Dynasties to Biologics: A Historical Review of Nasal Polyposis.

The history of nasal polyposis originates even before Hippocrates described a nasal mass that he likened to a sea polyp. References to sinonasal disease and treatment can be found in ancient texts, such as the Ebers Papyrus and the Edwin Smith Papyrus of Ancient Egypt, as well as in the foundational texts of Ayurvedic medicine. Greek philosophers marked a significant shift away from the belief that illness was a result of divine intervention and embraced medical theory. Over the subsequent millennia, the understanding of nasal polyposis expanded, resulting in notable progress in surgical procedures and medical treatments. However, the complex pathophysiology of this condition remained enigmatic until breakthroughs in basic science and immunology. This historical journey takes us from the tomb of the first rhinologist in 2500 BC to the development of immune-modulating biologics.

A Phase I Trial of Enzalutamide Plus Selective Glucocorticoid Receptor Modulator Relacorilant in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity. RESULTS: Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response. CONCLUSIONS: This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.

Fresh Frozen Plasma Versus Solvent Detergent Plasma for Cardiopulmonary Bypass Priming in Neonates and Infants Undergoing Cardiac Surgery: A Retrospective Cohort Study.

OBJECTIVE: Compared with fresh frozen plasma (FFP), Omniplasma has been attributed to an increased coagulation potential and an increased fibrinolytic potential. This study aimed to compare Omniplasma and FFP used for cardiopulmonary bypass (CPB) priming regarding the incidence of postoperative thrombotic or hemorrhagic complications and outcomes in pediatric patients undergoing cardiac surgery. DESIGN: A retrospective observational cohort study SETTING: This single-center study was performed at the University Medical Center Groningen. PARTICIPANT: All pediatric patients up to 10 kg undergoing cardiac surgery with CPB. INTERVENTIONS: Procedures in which FFP was used for CPB priming were compared with those in which Omniplasma was used. MEASUREMENTS AND MAIN RESULTS: The primary outcome parameter was a composite endpoint consisting of the following: (1) pediatric intensive care unit (PICU) mortality, (2) thromboembolic complications, and (3) hemorrhagic complications during PICU stay. The authors included 143 procedures in the analyses, 90 (63%) in the FFP group and 53 (37%) in the Omniplasma group. The occurrence of the combined primary endpoint (FFP 20% v Omniplasma 11%, p = 0.18) and its components did not differ between the used CPB priming agent). Omniplasma for CPB priming was associated with decreased unfractionated heparin administration per kg bodyweight (585 IU v 510 IU, p = 0.03), higher preoperative and postoperative activated clotting times (ACT) discrepancy (90% v 94%, p = 0.03), a lower postoperative ACT value (125 v 118 seconds, p = 0.01), and less red blood cell transfusion per kilogram bodyweight (78 v 55 mL, p = 0.02). However, none of the variables differed statistically significantly in the multivariate logistic regression analyses. CONCLUSIONS: The authors did not find an association between the plasma used for CPB priming and thromboembolic and hemorrhagic complications and death in neonates and infants undergoing cardiac surgery. Omniplasma seems to be safe to use in this population.

Immune reconstitution inflammatory syndrome-associated lymphoma: A retrospective Brazilian cohort.

After initiating combined antiretroviral therapy (cART), individuals with human immunodeficiency virus (HIV) may develop Hodgkin/non-Hodgkin lymphoma due to immune reconstitution inflammatory syndrome (IRIS). This retrospective cohort study evaluated the incidence, clinical features and prognosis of IRIS-associated lymphomas in Brazilian patients. Incidence in 2000-2019 was 9.8% (27/276 patients with HIV and lymphoma; viral load drop >1 log). Time between HIV diagnosis and cART initiation was <1 year in 70.3% of cases. Time between cART initiation and lymphoma diagnosis was <3 months in 11 cases and 3-6 months in 16 cases. Overall and progression-free survival rates were similar between cases of non-IRIS-associated lymphoma and IRIS-associated lymphoma.

[Prevention of dementia]. / Prävention demenzieller Erkrankungen.

With increasing life expectancy, the prevalence of dementia is increasing worldwide. Dementia is among the greatest challenges for healthcare and social systems of the future. Approximately 40% of newly diagnosed cases of dementia are associated with risk factors that can potentially be influenced by preventive measures. Based on the evidence from longitudinal studies, systematic reviews and meta-analyses, the Lancet commission on dementia prevention, intervention and care has defined 12 risk factors that are associated with an increased risk for dementia: low level of education, hearing impairment, traumatic brain injury, arterial hypertension, diabetes mellitus, smoking, excessive alcohol consumption, depression, obesity, social isolation, and air pollution.

Bladder-Preserving Trimodality Therapy With Capecitabine.

INTRODUCTION: Many patients with muscle-invasive bladder cancer are poor candidates for radical cystectomy or trimodality therapy with maximal transurethral resection of bladder tumor (TURBT) and chemoradiotherapy with cisplatin or mitomycin C. Given the benefit of chemotherapy in bladder-preserving therapy, less-intense concurrent chemotherapy regimens are needed. This study reports on efficacy and toxicity for patients treated with trimodality therapy using single-agent concurrent capecitabine. MATERIALS AND METHODS: Patients deemed ineligible for radical cystectomy or standard chemoradiotherapy by a multidisciplinary tumor board and patients who refused cystectomy were included. Following TURBT, patients received twice-daily capecitabine (goal dose 825 mg/m2) concurrent with radiotherapy to the bladder +/- pelvis depending on nodal staging and patient risk factors. Toxicity was evaluated prospectively in weekly on-treatment visits and follow-up visits by the treating physicians. Descriptive statistics are provided. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival were estimated using the Kaplan-Meier method. RESULTS: Twenty-seven consecutive patients met criteria for inclusion from 2013 to 2023. The median age was 79 with 9 patients staged cT3-4a and 7 staged cN1-3. The rate of complete response in the bladder and pelvis was 93%. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival at 2 years were estimated as 81%, 65%, 91%, 75%, and 92%, respectively. There were 2 bladder recurrences, both noninvasive. There were 7 grade 3 acute hematologic or metabolic events but no other grade 3+ toxicities. CONCLUSION: Maximal TURBT followed by radiotherapy with concurrent capecitabine offers a high rate of bladder control and low rates of acute and late toxicity.

PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness.

BACKGROUND: Recently approved treatments and updates to genetic testing recommendations for prostate cancer have created a need for correlated analyses of patient outcomes data via germline genetic mutation status. Genetic registries address these gaps by identifying candidates for recently approved targeted treatments, expanding clinical trial data examining specific gene mutations, and understanding effects of targeted treatments in the real-world setting. METHODS: The PROMISE Registry is a 20-year (5-year recruitment, 15-year follow-up), US-wide, prospective genetic registry for prostate cancer patients. Five thousand patients will be screened through an online at-home germline testing to identify and enroll 500 patients with germline mutations, including: pathogenic or likely pathogenic variants and variants of uncertain significance in genes of interest. Patients will be followed for 15 years and clinical data with real time patient reported outcomes will be collected. Eligible patients will enter long-term follow-up (6-month PRO surveys and medical record retrieval). As a virtual study with patient self-enrollment, the PROMISE Registry may fill gaps in genetics services in underserved areas and for patients within sufficient insurance coverage. RESULTS: The PROMISE Registry opened in May 2021. 2114 patients have enrolled to date across 48 US states and 23 recruiting sites. 202 patients have met criteria for long-term follow-up. PROMISE is on target with the study's goal of 5000 patients screened and 500 patients eligible for long-term follow-up by 2026. CONCLUSIONS: The PROMISE Registry is a novel, prospective, germline registry that will collect long-term patient outcomes data to address current gaps in understanding resulting from recently FDA-approved treatments and updates to genetic testing recommendations for prostate cancer. Through inclusion of a broad nationwide sample, including underserved patients and those unaffiliated with major academic centers, the PROMISE Registry aims to provide access to germline genetic testing and to collect data to understand disease characteristics and treatment responses across the disease spectrum for prostate cancer with rare germline genetic variants.

Paediatric sepsis survivors are resistant to sepsis-induced long-term immune dysfunction.

BACKGROUND AND PURPOSE: Sepsis-surviving adult individuals commonly develop immunosuppression and increased susceptibility to secondary infections, an outcome mediated by the axis IL-33/ILC2s/M2 macrophages/Tregs. Nonetheless, the long-term immune consequences of paediatric sepsis are indeterminate. We sought to investigate the role of age in the genesis of immunosuppression following sepsis. EXPERIMENTAL APPROACH: Here, we compared the frequency of Tregs, the activation of the IL-33/ILC2s axis in M2 macrophages and the DNA methylation of epithelial lung cells from post-septic infant and adult mice. Likewise, sepsis-surviving mice were inoculated intranasally with Pseudomonas aeruginosa or by subcutaneous inoculation of the B16 melanoma cell line. Finally, blood samples from sepsis-surviving patients were collected and the concentration of IL-33 and Tregs frequency were assessed. KEY RESULTS: In contrast to 6-week-old mice, 2-week-old mice were resistant to secondary infection and did not show impairment in tumour controls upon melanoma challenge. Mechanistically, increased IL-33 levels, Tregs expansion, and activation of ILC2s and M2-macrophages were observed in 6-week-old but not 2-week-old post-septic mice. Moreover, impaired IL-33 production in 2-week-old post-septic mice was associated with increased DNA methylation in lung epithelial cells. Notably, IL-33 treatment boosted the expansion of Tregs and induced immunosuppression in 2-week-old mice. Clinically, adults but not paediatric post-septic patients exhibited higher counts of Tregs and seral IL-33 levels. CONCLUSION AND IMPLICATIONS: These findings demonstrate a crucial and age-dependent role for IL-33 in post-sepsis immunosuppression. Thus, a better understanding of this process may lead to differential treatments for adult and paediatric sepsis.

Optimizing the doses of cancer drugs after usual dose finding.

Since the middle of the 20th century, oncology's dose-finding paradigm has been oriented toward identifying a drug's maximum tolerated dose, which is then carried forward into phase 2 and 3 trials and clinical practice. For most modern precision medicines, however, maximum tolerated dose is far greater than the minimum dose needed to achieve maximal benefit, leading to unnecessary side effects. Regulatory change may decrease maximum tolerated dose's predominance by enforcing dose optimization of new drugs. Dozens of already approved cancer drugs require re-evaluation, however, introducing a new methodologic and ethical challenge in cancer clinical trials. In this article, we assess the history and current landscape of cancer drug dose finding. We provide a set of strategic priorities for postapproval dose optimization trials of the future. We discuss ethical considerations for postapproval dose optimization trial design and review three major design strategies for these unique trials that would both adhere to ethical standards and benefit patients and funders. We close with a discussion of financial and reporting considerations in the realm of dose optimization. Taken together, we provide a comprehensive, bird's eye view of the postapproval dose optimization trial landscape and offer our thoughts on the next steps required of methodologies and regulatory and funding regimes.

Effects of gamma radiation on the electrical properties of InAs/InGaAs quantum dot-based laser structures grown on GaAs and Si substrates by molecular beam epitaxy.

This study investigates the impact of gamma radiation on the electrical properties of InAs/InGaAs quantum dot-based laser structures grown on both GaAs (Sample A) and Si (Sample B) substrates using molecular beam epitaxy. The research explores the electrical characteristics of the lasers before and after being exposed to gamma radiation employing current-voltage (I-V), capacitance-voltage (C-V), deep level transient spectroscopy (DLTS) and Laplace DLTS techniques. The results show that the electrical properties of the lasers change due to gamma radiation exposure, and the extent of the change depends on the substrate used for growth. The I-V results revealed that the ideality factor (n) and built-in voltage were increased in Sample A and Sample B after radiation. Nonetheless, the series resistance (Rs) at room temperature decreased in both samples after radiation. Overall, this study provides valuable insights into the effects of gamma radiation on the electrical properties of InAs/InGaAs quantum dot lasers and highlights the importance of considering substrate materials in the design of radiation-hardened electronic devices.

The predictive value of the modified early warning score for admission to the intensive care unit in patients with a hematologic malignancy - A multicenter observational study.

OBJECTIVES: The modified early warning score (MEWS) is used to detect clinical deterioration of hospitalized patients. We aimed to investigate the predictive value of MEWS and derived quick Sequential Organ Failure Assessment (qSOFA) scores for intensive care unit admission in patients with a hematologic malignancy admitted to the ward. DESIGN: Retrospective, observational study in two Dutch university hospitals. SETTING: Data from adult patients with a hematologic malignancy, admitted to the ward over a 2-year period, were extracted from electronic patient files. MAIN OUTCOME MEASURES: Intensive care admission. RESULTS: We included 395 patients with 736 hospital admissions; 2% (n = 15) of admissions resulted in admission to the intensive care unit. A higher MEWS (OR 1.5; 95 %CI 1.3-1.80) and qSOFA (OR 4.4; 95 %CI 2.1-9.3) were associated with admission. Using restricted cubic splines, a rise in the probability of admission for a MEWS ≥ 6 was observed. The AUC of MEWS for predicting admission was 0.830, the AUC of qSOFA was 0.752. MEWS was indicative for intensive care unit admission two days before admission. CONCLUSIONS: MEWS was a sensitive predictor of ICU admission in patients with a hematologic malignancy, superior to qSOFA. Future studies should confirm cut-off values and identify potential additional characteristics, to further enhance identification of critically ill hemato-oncology patients. IMPLICATIONS FOR CLINICAL PRACTICE: The Modified Early Warning Score (MEWS) can be used as a tool for healthcare providers to monitor clinical deterioration and predict the need for intensive care unit admission in patients with a hematologic malignancy. Yet, consistent application and potential reevaluation of current thresholds is crucial. This will enable bedside nurses to more effectively identify patients needing adjunctive care, facilitating timely interventions and improved outcome.

Synthesis and photothermal performance of non-stoichiometric molybdenum oxide (MoO3-x) prepared by gamma radiation.

This work reports the interaction of γ-rays with MoO3 in several solvents to obtain non-stoichiometric (sub-oxide) MoO3-x through a one-pot synthesis. The effect of different doses of γ-radiation (30-90 kGy) with different protic solvents (water, N,N-dimethylformamide and formic acid) was investigated. Structural modifications were characterized by X-ray diffractometry and scanning electron microscopy while optical properties were investigated by UV-Vis spectroscopy. The analysis of the highly intense (020), (040) and (060) diffraction peaks suggests that there is a reduction in water and formic acid allowing the formation of MoO3-x nanosheets. Additionally, the photothermal response of MoO3-x obtained under different conditions was characterized, and a possible mechanism to explain the interaction of γ-rays with solvents and the oxide structure by oxidative/reductive processes in the solution was proposed.

Limitaciones de los puntajes de riesgo cardiovascular en prevención primaria. ¿Una oportunidad para los moduladores de riesgo? / Limitations of cardiovascular risk scores in primary prevention. An opportunity for risk modulators?

RESUMEN Introducción : Los puntajes de riesgo cardiovascular tienen limitaciones relacionadas con la calibración, la discriminación y la baja sensibilidad. Se han identificado diferentes "moduladores de riesgo" que permiten mejorar la estratificación del riesgo cardiovascular: placa aterosclerótica carotídea (PAC), puntaje de calcio arterial coronario (pCAC) y lipoproteína(a) [Lp(a)]. Objetivos : 1) determinar la prevalencia de los moduladores de riesgo citados en una población en prevención primaria; 2) determinar la concordancia entre los 2 métodos de detección de aterosclerosis subclínica; 3) establecer qué proporción de pacientes deberían recibir estatinas inicialmente, según su puntaje de riesgo, y posteriormente con el conocimiento de los moduladores de riesgo. Material y métodos : Se incluyeron individuos de 18 a 79 años, que asistieron para una evaluación de riesgo cardiovascular y que no estaban recibiendo tratamiento hipolipemiante. Se calculó el puntaje de riesgo (ASCVD Risk Estimator) en cada paciente. Se evaluó la presencia de PAC, el pCAC y el nivel plasmático de Lp(a). Resultados : Se incluyeron 348 pacientes (edad media 55,6 ± 12,2 años, 45,4% hombres). En la población total, 29,8%, 36,8% y 53,2% de los pacientes mostraron un valor de Lp(a) ≥ 50 mg/dL, PAC o un pCAC > 0, respectivamente. La prevalencia de PAC y pCAC fue progresivamente mayor según la categoría de riesgo cardiovascular; sin embargo, la proporción de sujetos de bajo riesgo que tenían moduladores de riesgo fue considerable (Lp(a) ≥ 50 mg/dl: 25,7%; PAC: 22%; pCAC > 0: 33%). En los 60 individuos menores de 45 años la prevalencia de pCAC > 0 y PAC fue de 18,3% y 10%, respectivamente. La concordancia entre los dos métodos para determinar la presencia de ateromatosis subclínica fue discreta (kappa 0,33). La indicación del tratamiento con estatinas aumentó un 31,6% luego de evaluar la presencia de moduladores. Conclusión : La presencia de moduladores de riesgo fue frecuente en esta población en prevención primaria, incluso en sujetos de bajo riesgo o menores de 45 años. La detección de moduladores de riesgo podría mejorar la estratificación inicial y llevar a reconsiderar el tratamiento con estatinas.

ABSTRACT Background : Cardiovascular risk scores have limitations related to calibration, discrimination, and low sensitivity. Different "risk modulators" have been identified to improve cardiovascular risk stratification: carotid atherosclerotic plaque (CAP), coronary artery calcium (CAC) score and lipoprotein(a) [Lp(a)]. Objectives : The aims of this study were: 1) to determine the prevalence of risk modulators mentioned in a primary prevention population; 2) determine the concordance between the 2 methods of detecting subclinical atherosclerosis; and 3) establish which proportion of patients should receive statins according to the initial risk stratification and after being recategorized by screening for risk modulators. Methods : Individuals aged 18 to 79 years who consulted for cardiovascular risk assessment and who were not receiving lipid-lowering treatment were included. The risk score was calculated in each patient using ASCVD Risk Estimator. The presence of CAP, CAC score and Lp(a) level were evaluated. Results : The cohort was made up of 348 patients; mean age was 55.6 ± 12.2 years and 45.4% were men. In the total population, 29.8%, 36.8%, and 53.2% of patients showed Lp(a) value ≥50 mg/dL, CAP, or a CAC score >0, respectively. The prevalence of CAP and CAC score was progressively higher according to the cardiovascular risk category; however, the proportion of low-risk subjects who had risk modulators was considerable (Lp(a) ≥50 mg/dl: 25.7%; CAP: 22%; CAC score >0: 33%). In the 60 subjects <45 years, the prevalence of CAC score >0 and CAP was 18.3% and 10%, respectively. The agreement between the two methods for quantifying subclinical atheromatosis was fair (kappa= 0.33). The indication for statin treatment increased by 31.6% after evaluating the presence of modulators. Conclusion : The presence of risk modulators was common in this population in primary prevention, even in low-risk subjects or < 45 years. Detection of risk modulators could improve initial stratification and lead to reconsideration of statin treatment.

La prueba cardiopulmonar de ejercicio contribuye a determinar con precisión el riesgo en pacientes con hipertensión pulmonar de bajo riesgo / Cardiopulmonary Exercise Testing Contributes to Accurate Risk Assessment in Patients with Low-risk Pulmonary Hypertension

RESUMEN Introducción : Las guías europeas de hipertensión arterial pulmonar (HAP) estratifican el riesgo valiéndose de características clínicas y estudios complementarios entre los cuales está la prueba cardiopulmonar de ejercicio (PCPE), de la cual toma en cuenta 3 parámetros: el consumo de O2 (VO2) pico, su porcentaje respecto del predicho y la pendiente ventilación minuto/ producción de dióxido de carbono (VE/VCO2). Sin embargo, ninguno de los modelos que validaron esta forma de estratificar el riesgo incluyeron la PCPE entre sus variables. Objetivos : Determinar qué proporción de pacientes con HAP del grupo I considerados de bajo riesgo y que caminan >440 metros en la prueba de caminata de 6 minutos (PC6M) tienen en la PCPE parámetros considerados de riesgo moderado o alto. Material y métodos : Se incluyeron pacientes >18 años con diagnóstico de HAP del grupo I considerados de bajo riesgo con una PC6M >400 metros a los que se les realizó una PCPE en la que se registró el VO2 pico, su porcentaje respecto del VO2 predicho y la pendiente VE/VCO2. Se determinó qué proporción de pacientes presentaban estos parámetros en un estrato de riesgo mayor a bajo riesgo (VO2 pico <15 ml/kg/min, su porcentaje respecto del predicho <65% y la pendiente VE/VCO2 >36). Resultados : Se incluyeron 18 pacientes. A pesar de ser pacientes de bajo riesgo y con buena clase funcional todos presentaron un VO2 pico menor al 85% del predicho, lo cual determina un deterioro al menos leve de la capacidad funcional. Un único paciente (6%) presentó los tres parámetros evaluados en bajo riesgo, 8 pacientes (44%) tuvieron al menos un parámetro alterado, 7 pacientes (39%) presentaron 2 parámetros alterados y en 2 pacientes (11%) todos los parámetros estuvieron alterados. Los parámetros que más frecuentemente se vieron alterados fueron el porcentaje respecto del VO2 predicho y la pendiente VE/VCO2, en el 67% de los casos. Solo 4 pacientes presentaron un VO2 pico <15 ml/k/m. Ningún paciente presentó valores de VO2 pico o porcentaje respecto del predicho en la categoría de alto riesgo. Sin embargo, 6 pacientes (33%) presentaron una pendiente VE/VCO2 considerada de alto riesgo. Conclusión : El 94% de los pacientes considerados de bajo riesgo presentaron al menos una variable en la PCPE que no corresponde a un perfil de riesgo bajo. La pendiente VE/VCO2 y el porcentaje de VO2 pico respecto del predicho fueron las variables más frecuentemente alteradas. La pendiente VE/VCO2 fue la única que mostró valores considerados de alto riesgo. La PCPE podría tener un lugar en la estratificación de precisión de pacientes de bajo riesgo. El valor de este hallazgo deberá ser evaluado en estudios prospectivos, al tiempo que genera las bases para el planteo de hipótesis respecto de la estratificación de riesgo y la intensidad del tratamiento en pacientes que aparentan estar en bajo riesgo.

ABSTRACT Background : European guidelines for pulmonary arterial hypertension (PAH) stratify the risk using clinical characteristics and complementary studies, including the cardiopulmonary exercise test (CPET). This takes into account 3 parameters: peak O2 consumption (peak VO2), its percentage with respect to the predicted VO2, and the minute ventilation/carbon dioxide production (VE/VCO2) slope. However, none of the models that validated this way of stratifying risk included PCPE among their variables. Objectives : To determine what proportion of patients with group I PAH considered to be at low risk and who walk >440 meters in the 6-minute walk test (6MWT) have parameters considered to be of moderate or high risk in the PCPE. Methods : Patients >18 years of age, diagnosed with group I PAH at low risk of events, who walked >440 meters in the 6MWT and had NT-proBNP value <300 pg/dL were included. A CPET was performed in which the peak VO2, its percentage with respect to the predicted VO2, and the VE/VCO2 slope were recorded. It was determined what proportion of patients presented these parameters in a higher than low risk stratum (peak VO2 consumption ≤15 ml/min/Kg, its percentage with respect to the predicted VO2 ≤65% and the VE/VCO2 slope ≥36). Results : Eighteen patients were included. Despite being low-risk patients with a good functional class, all patients presented a peak VO2 less than 85% of predicted, which determines a deterioration of functional capacity. A single patient (6%) presented the three parameters evaluated at low risk, 8 patients (44%) had at least one altered parameter, 7 patients (39%) presented 2 altered parameters and in 2 patients (11%) all parameters were altered. The parameters that were most frequently altered were the percentage of predicted peak VO2 and the VE/VCO2 slope in 67% of the cases. Only 4 patients presented a peak VO2 <15 ml/kg/m. No patient presented peak VO2 values or percentage of predicted VO2 in the high-risk category. However, 6 patients (33%) presented a high-risk VE/VCO2 slope. Conclusion : Majority (92%) of the patients considered low risk and who walk more than 440 meters in 6 minutes presented at least one altered variable in the CPET. The VE/VCO2 slope and the percentage of predicted peak VO2 consumption were the most frequently altered variables. The VE/VCO2 slope was the only one that showed values considered high risk. CPET could have a place in the precision stratification of low-risk patients. The value of this finding should be evaluated in prospective studies.

Heterozygous midnolin knockout attenuates severity of nonalcoholic fatty liver disease in mice fed a Western-style diet high in fat, cholesterol, and fructose.

Although midnolin has been studied for over 20 years, its biological roles in vivo remain largely unknown, especially due to the lack of a functional animal model. Indeed, given our recent discovery that the knockdown of midnolin suppresses liver cancer cell tumorigenicity and that this antitumorigenic effect is associated with modulation of lipid metabolism, we hypothesized that knockout of midnolin in vivo could potentially protect from nonalcoholic fatty liver disease (NAFLD) which has become the most common cause of chronic liver disease in the Western world. Accordingly, in the present study, we have developed and now report on the first functional global midnolin knockout mouse model. Although the overwhelming majority of global homozygous midnolin knockout mice demonstrated embryonic lethality, heterozygous knockout mice were observed to be similar to wild-type mice in their viability and were used to determine the effect of reduced midnolin expression on NAFLD. We found that global heterozygous midnolin knockout attenuated the severity of NAFLD in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism. Collectively, our results support a role for midnolin in regulating cholesterol/lipid metabolism in the liver. Thus, midnolin may represent a novel therapeutic target for NAFLD. Finally, our observation that midnolin was essential for survival underscores the broad importance of this gene beyond its role in liver biology.NEW & NOTEWORTHY We have developed and now report on the first functional global midnolin knockout mouse model. We found that global heterozygous midnolin knockout attenuated the severity of nonalcoholic fatty liver disease (NAFLD) in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism.

Enrollment Barriers for Molecular Targeted Trials.

This quality improvement study examines the difficulties of patient accrual among patients with cancer and SETD2 variants.

[Prevention of dementia]. / Prävention demenzieller Erkrankungen.

With increasing life expectancy, the prevalence of dementia is increasing worldwide. Dementia is among the greatest challenges for healthcare and social systems of the future. Approximately 40% of newly diagnosed cases of dementia are associated with risk factors that can potentially be influenced by preventive measures. Based on the evidence from longitudinal studies, systematic reviews and meta-analyses, the Lancet commission on dementia prevention, intervention and care has defined 12 risk factors that are associated with an increased risk for dementia: low level of education, hearing impairment, traumatic brain injury, arterial hypertension, diabetes mellitus, smoking, excessive alcohol consumption, depression, obesity, social isolation, and air pollution.

Near-infrared spectroscopy and processed electroencephalogram monitoring for predicting peri-operative stroke risk in cardiothoracic surgery: An observational cohort study.

BACKGROUND: Stroke is a feared complication after cardiothoracic surgery, with an incidence of around 2 to 3%. Anaesthesia and postoperative sedation may obscure clinical symptoms of stroke and thus delay diagnosis and timely intervention. OBJECTIVES: The objective was to assess the value of intra-operative neuromonitoring and blood pressure monitoring for predicting the occurrence of peri-operative stroke within 3 days after cardiothoracic surgery. DESIGN: Single-centre retrospective observational cohort study. SETTING: Academic tertiary care medical centre. PATIENTS: All consecutive patients with cardiothoracic surgery and intra-operative neuromonitoring admitted postoperatively to the Intensive Care Unit (ICU) between 2008 and 2017. MAIN OUTCOME MEASURES: The primary endpoint was the occurrence of any stroke confirmed by brain imaging within 3 days postcardiothoracic surgery. Areas under the curve (AUC) of intra-operative mean arterial pressure (MAP), cerebral oxygen saturation (ScO 2 ) and bispectral index (BIS) below predefined thresholds were calculated, and the association with early stroke was tested using logistic regression analyses. RESULTS: A total of 2454 patients admitted to the ICU after cardiothoracic surgery had complete intra-operative data for ScO 2 , BIS and MAP and were included in the analysis. In 58 patients (2.4%), a stroke was confirmed. In univariate analysis, a larger AUC MAP<60 mmHg [odds ratio (OR) 1.43; 95% confidence interval (CI), 1.21 to 1.68) and larger AUC BIS<25 (OR 1.51; 95% CI, 1.24 to 1.83) were associated with the occurrence of postoperative stroke while ScO 2 less than 50% or greater than 20% reduction from individual baseline was not (OR 0.91; 95% CI, 0.50 to 1.67). After multivariable analysis, AUC BIS<25 (OR 1.45; 95% CI, 1.12 to 1.87) and longer duration of MAP less than 60 mmHg (OR 1.52; 95% CI, 1.02 to 2.27) remained independently associated with stroke occurrence. CONCLUSION: Cumulative intra-operative BIS values below 25 and longer duration of MAP below 60 mmHg were associated with the occurrence of peri-operative stroke within 3 days after cardiothoracic surgery. Prospective studies are warranted to evaluate a causal relationship between low BIS and stroke to establish whether avoiding intra-operative BIS values below 25 might reduce the incidence of peri-operative stroke.