Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) study: ultralow prostate-specific antigen decline with apalutamide plus androgen-deprivation therapy.

OBJECTIVE: To assess the association between achievement of prostate-specific antigen (PSA) levels ≤0.2 ng/mL (henceforth 'ultralow') and clinical outcomes in patients in the 'Targeted Investigational Treatment Analysis of Novel Anti-androgen' (TITAN) study (ClinicalTrials.gov Identifier NCT02489318) with metastatic castration-sensitive prostate cancer (mCSPC). PATIENTS AND METHODS: Patients in the TITAN study with mCSPC were randomised to 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy. This post hoc analysis assessed the achievement of a PSA level of 0.2->0.02 ng/mL ('ultralow one' [UL1]) and ≤0.02 ng/mL ('ultralow two' [UL2]) vs >0.2 ng/mL with apalutamide treatment and its association with radiographic progression-free survival (rPFS), overall survival (OS), time to castration-resistant PC (TTCRPC), and time to PSA progression (TTPP). The landmark analysis and Kaplan-Meier methods were used. RESULTS: By 3 months, more patients achieved UL1 and UL2 with apalutamide (38% and 23%) vs placebo (15% and 5%). In the apalutamide-treated patients, UL2 vs PSA >0.2 ng/mL at landmark 3 months was associated with significantly longer rPFS (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.14-0.54), OS (HR 0.24, 95% CI 0.13-0.43), TTCRPC (HR 0.2, 95% CI 0.11-0.38), and TTPP (HR 0.11, 95% CI 0.04-0.27; nominal P values all <0.001); this association was also observed but less pronounced for UL1. Similar findings were observed at 6 months. Early onset of decline to UL2 by 3 months was associated with improved survival vs PSA >0.2 ng/mL anytime (HR 0.12, 95% CI 0.06-0.22; P < 0.001) in apalutamide-treated patients. CONCLUSIONS: In this post hoc analysis of TITAN, patients with the deepest PSA decline derived the greatest benefit. These results extend our findings of apalutamide efficacy in the overall TITAN population, underscoring the clinical value of PSA kinetics as a marker for treatment efficacy. PATIENT SUMMARY: Patients with metastatic prostate cancer that is sensitive to ongoing hormonal treatment benefited significantly from the addition of apalutamide compared with placebo. Those who achieved rapid and deep PSA reduction had the greatest survival benefit.

Prostate-specific antigen (PSA) decline with apalutamide therapy is associated with longer survival and improved outcomes in individuals with metastatic prostate cancer: a plain language summary of the TITAN study.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from an additional (or post hoc) analysis of the TITAN study. The TITAN study looked at whether the prostate cancer treatment apalutamide could be used to treat individuals with metastatic castration-sensitive prostate cancer (or mCSPC). A total of 1052 participants with mCSPC were included in the TITAN study. Treatment with apalutamide was compared with treatment with placebo. All participants received androgen deprivation therapy (or ADT), which is a type of hormone therapy that has been part of the main treatment for mCSPC for many years. The results showed that apalutamide plus ADT increased the length of time that participants remained alive compared with placebo plus ADT. Apalutamide plus ADT also controlled the growth of the cancer for a longer length of time compared with placebo plus ADT. Additionally, participants who received apalutamide plus ADT experienced a greater reduction in the blood levels of prostate-specific antigen (or PSA), called a deep PSA decline, compared with those who received placebo plus ADT. An additional (or post hoc) analysis was carried out to understand whether a decrease in blood PSA levels, in response to treatment, was associated with improved outcomes, including longer survival time. WHAT WERE THE RESULTS OF THE ADDITIONAL ANALYSIS?: In participants who received apalutamide plus ADT, a deep PSA decline in response to treatment was associated with longer survival time and improved outcomes. WHAT DO THESE RESULTS MEAN FOR INDIVIDUALS WITH MCSPC?: These results demonstrate that individuals with mCSPC can benefit from treatment with apalutamide plus ADT. The association seen between deep PSA decline and the longer survival time and improved outcomes highlights how PSA measurements can be used to help monitor cancer disease evolution in response to treatment. Monitoring PSA levels will assist doctors and other healthcare professionals to understand how effectively a treatment is working for a patient and to tailor their treatment approach to improve PSA decline.

Effects of Sesquiterpene Lactones on Primary Cilia Formation (Ciliogenesis).

Sesquiterpene lactones (SLs), plant-derived metabolites with broad spectra of biological effects, including anti-tumor and anti-inflammatory, hold promise for drug development. Primary cilia, organelles extending from cell surfaces, are crucial for sensing and transducing extracellular signals essential for cell differentiation and proliferation. Their life cycle is linked to the cell cycle, as cilia assemble in non-dividing cells of G0/G1 phases and disassemble before entering mitosis. Abnormalities in both primary cilia (non-motile cilia) and motile cilia structure or function are associated with developmental disorders (ciliopathies), heart disease, and cancer. However, the impact of SLs on primary cilia remains unknown. This study evaluated the effects of selected SLs (grosheimin, costunolide, and three cyclocostunolides) on primary cilia biogenesis and stability in human retinal pigment epithelial (RPE) cells. Confocal fluorescence microscopy was employed to analyze the effects on primary cilia formation (ciliogenesis), primary cilia length, and stability. The effects on cell proliferation were evaluated by flow cytometry. All SLs disrupted primary cilia formation in the early stages of ciliogenesis, irrespective of starvation conditions or cytochalasin-D treatment, with no effect on cilia length or cell cycle progression. Interestingly, grosheimin stabilized and promoted primary cilia formation under cilia homeostasis and elongation treatment conditions. Thus, SLs have potential as novel drugs for ciliopathies and tumor treatment.

Apalutamide plus androgen deprivation therapy in clinical subgroups of patients with metastatic castration-sensitive prostate cancer: A subgroup analysis of the randomised clinical TITAN study.

BACKGROUND: Whether disease burden in patients with metastatic castration-sensitive prostate cancer (mCSPC) predicts treatment outcomes is unknown. We assessed apalutamide treatment effect in TITAN patients with mCSPC by disease volume, metastasis number and timing of metastasis presentation. METHODS: These protocol-defined and post hoc analyses of the phase III randomised TITAN study evaluated clinical outcomes in patients receiving 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy (ADT). Subgroups were defined by volume (high: visceral and ≥1 bone metastases or ≥4 bone lesions with ≥1 beyond vertebral column/pelvis), development of metastases per conventional imaging (synchronous: at initial diagnosis; metachronous: after localised disease) and oligometastases (≤5 bone-only metastases) or polymetastases (>5 in bone ± other locations or ≤5 in bone plus other locations). Overall survival (OS), radiographic or second progression-free survival, and time to prostate-specific antigen progression or castration resistance were assessed using Cox proportional hazards models. RESULTS: Of 1052 patients, 63%, 81%, 54%, 27%, 5.7%, and 8.0% had high-volume, synchronous, synchronous/high-volume, synchronous/low-volume, metachronous/high-volume, and metachronous/low-volume disease, respectively. The OS benefit favoured apalutamide plus ADT versus ADT alone in synchronous/high-volume (hazard ratio = 0.68 [95% confidence interval: 0.53-0.87]; p = 0.002), synchronous/low-volume (0.65 [0.40-1.05]; p = 0.08), metachronous/high-volume (0.69 [0.33-1.44]; p = 0.32) and metachronous/low-volume (0.22 [0.09-0.55]; p = 0.001) subgroups. Apalutamide improved other clinical outcomes regardless of subgroup, with similar safety profiles. Most favourable outcomes were observed in oligometastatic disease. CONCLUSION: TITAN patients derived a robust benefit with apalutamide plus ADT regardless of disease volume and timing of metastasis presentation without differences in safety, supporting early apalutamide intensification in mCSPC. CLINICAL TRIAL REGISTRATION: NCT02489318.

Percutaneous radiofrequency ablation is an effective treatment option for small renal masses, comparable to partial nephrectomy.

OBJECTIVES: The standard therapy for small renal masses (SRMs) remains partial nephrectomy (PN), which is associated with relatively high morbidity and complication rate. Therefore, percutaneous radiofrequency ablation (PRFA) emerges as an alternative therapy. This study aimed to compare the efficacy, safety, and oncological outcomes of PRFA versus PN. METHODS: A multicenter non-inferiority study with retrospective analysis of 291 patients with SRMs (N0M0), who underwent PN or PRFA (2:1), recruited prospectively from two hospitals in the Andalusian Public Health System, Spain, between 2014 and 2021. Comparisons of treatment features were evaluated using the t test, Wilcoxon-Mann-Whitney U test, chi-square test, Fisher test, and Cochran-Armitage trend test. Kaplan-Meier curves depicted overall survival (OS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS) rates in the overall study population. RESULTS: A total of 291 consecutive patients were identified; 111 and 180 patients underwent PRFA and PN, respectively. Median follow-up time was 38 and 48 months, and mean hospitalization days were 1.04 and 3.57 days, respectively. The variables underpinned with high surgical risk were significantly increased in PRFA compared to those in PN (mean age was 64.56 and 57.47 years, the solitary kidney presence was 12.6% and 5.6%, ASA score ≥ 3 was 36% and 14.5%, respectively). The rest of oncological outcomes were comparable amongst PRFA and PN. Patients undergoing PRFA did not improve OS, LRFS, and MFS compared to those undergoing PN. Limitations comprise retrospective design and limited statistical power. CONCLUSION: PRFA for SMRs in high-risk patients is non-inferior in terms of oncological outcomes and safety compared to PN. CLINICAL RELEVANCE STATEMENT: Our study has a direct clinical application as it proves that radiofrequency ablation is an effective and uncomplicated therapeutic option for patients with small renal masses. KEY POINTS: •There are non-inferiority results in overall survival, local recurrence-free survival, and metastasis-free survival between PRFA and PN. •Our two-center study showed that PRFA is non-inferior to PN in oncological outcomes. •Contrast-enhanced power ultrasound-guided PRFA provides an effective therapy for T1 renal tumors.

Imaging in fetal genital anomalies.

Genital anomalies are a heterogeneous group of congenital pathologies that have become increasingly relevant since the Chicago Consensus of 2005. Their postnatal diagnosis has developed significantly in the last two decades, while prenatal diagnosis seems to be underdeveloped, with few protocols available, fragmented scientific literature, and low diagnostic rates. This review aims to examine the current status of this subspecialty from the perspective of prenatal imaging. Indications for the evaluation of fetal genitalia can be divided into medical and non-medical reasons. Medical reasons include sex-linked disorders, detection of other anomalies, relevant family history, or multiple pregnancy. Non-medical reasons include parental request for sex disclosure. Disclosure of fetal sex may be associated with ethical, legal, and medical issues. The main imaging technology used is 2D ultrasound, although there are other complementary techniques such as 3D, MRI, or Color Doppler. Regarding working methodology, several authors have drawn attention to the lack of standardized protocols and guidelines. Most guidelines tend to limit their recommendations to study indications and ethical issues. Technical proposals, measurements, or working methods have not yet been standardized. Fetal sex determination is usually divided into early and late gestation. Early gestation is based on the sagittal sign. Late gestation is based on direct visualization. There are several measurements to describe male and female genitalia, such as penile length, bilabial diameter, or scrotal diameter. Prenatal diagnosis of genital pathologies presents some particularities such as the wide spectrum of phenotypes, the high frequency of associated deformities, or the time of diagnosis. Some of the most frequent pathologies are ambiguous genitalia, fetal sex discordance, hypospadias, micropenis, clitoromegaly, ovarian cysts, hydro(metro)colpos, and cloacal anomalies. Higher-quality studies and direction from scientific societies through the implementation of clinical guidelines are needed.

Trends in mortality from cardiovascular diseases in Chile, 2000-2020 / Tendencias de la mortalidad por enfermedades cardiovasculares en Chile, 2000-2020 / Tendências de mortalidade por doenças cardiovasculares no Chile, 2000-2020

ABSTRACT Objective. To analyze trends in mortality caused by cardiovascular diseases (CVD) in Chile during the period 2000-2020. Methods. Data on age-adjusted mortality rates (AAMR) from CVD per 100 000 population in Chile for 2000-2020 were extracted from the World Health Organization Mortality Database. Joinpoint regression was used to analyze the trends and compute the average annual percent change (AAPC) in Chile. In addition, analyses were conducted by sex and type of CVD. Results. Between 2000 and 2020, the AAMR from CVD decreased in Chile from 159.5 to 94.6 per 100 000 population, with a statistically significant decrease in the AAPC of 2.6% (95% CI [-2.8, -2.4]). No joinpoints were identified. The AAMR from CVD decreased annually by 2.6% (95% CI [-2.8, -2.4]) and 2.8% (95% CI [-3.5, -2.6]) in men and women, respectively. The AAMR from ischemic heart disease reduced annually by 3.6% (95% CI [-4.6, -2.7]) with two joinpoints in 2011 and 2015. In the case of stroke, the mortality rate decreased annually by 3.7% (95% CI [-4.5, -3.0]), with two joinpoints in 2008 and 2011. Conclusions. Cardiovascular disease mortality rates have decreased significantly in Chile, in both sexes, especially in women. This decrease could be explained mainly by a significant reduction in the case fatality in recent decades. These results could be a reference for developing primary prevention and acute management of CVD policies focused on populations with higher mortality.

RESUMEN Objetivo. Analizar las tendencias de la mortalidad por enfermedades cardiovasculares (ECV) en Chile durante el período 2000-2020. Métodos. Los datos sobre la tasa de mortalidad ajustada por la edad (TMAE) por ECV por 100 000 habitantes en Chile durante el período 2000-2020 se extrajeron de la base de datos de mortalidad de la Organización Mundial de la Salud. Se utilizó la regresión de tipo joinpoint (punto de cambio) para analizar las tendencias y calcular el cambio porcentual anual promedio (CPAP) en Chile. Además, se realizaron análisis por sexo y por tipo de ECV. Resultados. Entre el 2000 y el 2020, la TMAE por ECV disminuyó en Chile de 159,5 a 94,6 por 100 000 habitantes, con una disminución del CPAP estadísticamente significativa del 2,6% (IC del 95% [-2,8 a -2,4]). No se detectó ningún punto de cambio (joinpoint). La TMAE por ECV disminuyó anualmente un 2,6% (IC del 95% [-2,8 a -2,4]) en los hombres y un 2,8% (IC del 95% [-3,5 a -2,6]) en las mujeres. La TMAE por cardiopatía isquémica se redujo anualmente en un 3,6 % (IC del 95 % [-4,6 a -2,7]), encontrándose dos puntos de cambio en el 2011 y el 2015. En el caso de los ataques cerebrovasculares, la tasa de mortalidad disminuyó anualmente un 3,7% (IC del 95% [-4,5 a -3,0]), encontrándose dos puntos de cambio en el 2008 y el 2011. Conclusiones. La tasa de mortalidad por ECV ha disminuido significativamente en Chile en ambos sexos, pero en especial en las mujeres. Este descenso podría explicarse principalmente por la reducción significativa de la letalidad observada en las últimas décadas. Estos resultados podrían constituir una referencia para la elaboración de políticas de prevención primaria y manejo de casos agudos de ECV que estén centradas en aquellos grupos poblacionales donde la mortalidad es más alta.

RESUMO Objetivo. Analisar as tendências de mortalidade causada por doenças cardiovasculares (DCV) no Chile no período de 2000 a 2020. Métodos. Taxas de mortalidade por DCV ajustadas por idade no Chile referentes ao período de 2000 a 2020 foram extraídas do Banco de Dados de Mortalidade da Organização Mundial da Saúde. Foi usado um modelo de regressão linear segmentada (joinpoint) para analisar tendências e calcular a variação percentual média anual no Chile. Além disso, foram realizadas análises por sexo e tipo de DCV. Resultados. No Chile, entre 2000 e 2020, a taxa de mortalidade por DCV ajustada por idade caiu de 159,5 para 94,6 por 100 mil habitantes, com uma redução estatisticamente significante da variação percentual média anual de 2,6% (IC de 95% [-2,8; -2,4]). Não foram identificados pontos de inflexão. Anualmente, a taxa de mortalidade por DCV ajustada por idade caiu 2,6% (IC 95% [-2,8; -2,4]) e 2,8% (IC 95% [-3,5; -2,6]) entre homens e mulheres, respectivamente. A taxa de mortalidade por doença cardíaca isquêmica ajustada por idade caiu 3,6% (95% CI [-4,6; -2,7]) por ano, com dois pontos de inflexão (em 2011 e 2015). No caso do acidente vascular cerebral, a taxa de mortalidade diminuiu 3,7% (IC de 95% [-4,5; -3,0]) por ano, com dois pontos de inflexão (em 2008 e 2011). Conclusões. As taxas de mortalidade por doenças cardiovasculares diminuíram significativamente no Chile em ambos os sexos, especialmente nas mulheres. Essa queda pode ser explicada principalmente por uma redução significativa na letalidade observada nas últimas décadas. Esses resultados podem ser uma referência para o desenvolvimento de políticas de prevenção primária e manejo de casos agudos de DCV voltadas para populações com maiores taxas de mortalidade.

Supresión de la visita de tercer trimestre en embarazo de bajo riesgo en la pandemia de SARS-CoV-2 / Third trimester suppression in low-risk pregnancy in the SARS-CoV-2 pandemic

Resumen Objetivo: La pandemia de SARS-CoV-2 ha obligado a una reorganización de las visitas presenciales, y por ese motivo se han minimizado hasta el punto de reconsiderar la realización de la visita del tercer trimestre. Nuestro centro suprimió dicha visita obstétrica y obtuvo datos propios para comparar los resultados perinatales logrados con dicho manejo. Método: Se realizó un estudio de cohortes retrospectivo, en marzo de 2020, con una cohorte con visita presencial única en la semana 40 de gestación (122 gestantes) frente a una cohorte con seguimiento convencional con visita presencial en la semana 36 de gestación (162 gestantes). Se evaluaron la restricción del crecimiento fetal, la edad gestacional al nacimiento, el peso neonatal y las tasas de inducciones, partos eutócicos y cesáreas urgentes en trabajo de parto. Resultados: Se encontraron diferencias leves en la tasa de nuliparidad (p < 0,04), sin hallarlas en el resto de las variables maternas. No hubo diferencias entre las dos cohortes en los resultados neonatales. Conclusiones: No hay diferencias entre los resultados materno-fetales obtenidos en gestantes con seguimiento gestacional con restricción de la visita del tercer trimestre respecto del seguimiento tradicional, excepto en el diagnóstico de las alteraciones de la estática fetal al término de la gestación.

Abstract Objective: The SARS-CoV-2 pandemic has forced a reorganization of face-to-face visits, for this reason they have been minimized to the point of reconsidering the completion of the third trimester visit. Our center eliminated the performance of this obstetric visit and obtained its own data to compare the perinatal results obtained with such management. Method: A retrospective cohort study was carried out in March 2020, with a cohort with a single face-to-face visit at 40th week of gestation (122 pregnant women), versus a cohort with conventional follow-up with face-to-face visit at 36th week of gestation (162 pregnant women). The following were evaluated fetal growth restriction, gestational age at birth, neonatal weight, rate of inductions, of eutocic deliveries, and of urgent cesarean sections in labor. Results: Slight differences were found in the nulliparity rate (p < 0.04), without finding them in the rest of the maternal variables. There were no differences between the two cohorts in neonatal outcomes. Conclusions: There were no differences between the maternal-fetal results obtained in pregnant women with gestational follow-up with restriction of the third trimester visit compared to traditional follow-up, except in the diagnosis of alterations in fetal statics at the end of pregnancy.

The landscape of systemic therapy for early stage triple-negative breast cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with higher risk of disease recurrence and mortality than other breast cancer subtypes. Historically, chemotherapy has been the primary systemic treatment for early stage TNBC. Recent developments in immune checkpoint inhibitors (ICIs) and novel therapeutic agents have transformed the treatment of TNBC. AREAS COVERED: This review provides a comprehensive overview of the current evidence on treatment of early stage TNBC. We highlight the incorporation of ICIs and other targeted therapies in (neo)adjuvant treatment and the ongoing development of novel therapeutic agents. EXPERT OPINION: The landscape of early TNBC treatment is rapidly evolving, which has given rise to the introduction of ICIs and PARP inhibitors into the systemic therapy. Despite modest improvement in the pathologic complete response (pCR) rate, ICI plus chemotherapy significantly improves long-term outcomes and is now used in (neo)adjuvant treatment of patients with TNBC and high risk for disease recurrence. Capecitabine remains the standard adjuvant treatment for residual disease, with olaparib being an option for patients with germline BRCA1/2 mutations. Early detection of minimal residual disease may identify patients requiring additional therapy to prevent recurrence.

Impact of Bubbles on Electrochemically Active Surface Area of Microtextured Gas-Evolving Electrodes.

The adverse effects of electrochemical bubbles on the performance of gas-evolving electrodes have been extensively studied. However, the ways in which bubbles dynamically alter the electrochemically active surface area during bubble evolution are not well understood. Here, we study hydrogen evolution at industrially relevant current densities by using controlled microtexture to examine this fundamental relationship. Surprisingly, the most densely microtextured electrodes have the lowest performance on an active surface area basis. Using high-speed imaging, we show that the benefits of microtexture to release smaller bubbles more consistently are outweighed by the inactivation induced by bubbles growing within the denser microtexture, causing these performance limitations. Additionally, we show that the area beneath adhered bubbles is electrochemically active, contrary to currently held assumptions. Our study therefore has broad implications for electrode design to avoid ineffective use of precious catalyst materials, which is especially critical for porous electrodes and three-dimensional structures with high specific surface areas.

Transient Effects Caused by Gas Depletion during Carbon Dioxide Electroreduction.

The novel use of carbon dioxide (CO2) electroreduction to generate carbon-based products which do not contribute to the greenhouse effect has promoted the vision of carbon dioxide as a renewable feedstock for future clean fuel production. Depending on the material choice for the electrocatalysis, a certain variety of products is expected from the carbon dioxide reduction reaction (CO2RR). However, as the CO2 concentration in areas close to the working electrode (relative to the diffusive boundary layer) decreases as it is being consumed and transformed into other products, the generation of H2 is favored to the detriment of CO2 electroreduction. Therefore, the extent to which H2 is produced can be used as a metric to evaluate the efficiency of CO2RR. This article proposes a model that accounts for the modes in which aqueous gas depletion evolves over time and affects the long-term CO2 electroreduction and the corresponding pH evolution near the electrode's surface. For the latter, two main contributions are distinguished: gas depletion due to CO2 consumption and ion generation in areas close to the electrocatalyst surface. pH is then suggested as an accurate and indirect means to measure CO2 concentration in a liquid electrolyte. We conclude that CO2 depletion causes a strong decay in the electrochemical reaction efficiency. In the end, we discuss several methods which may delay the onset of the adverse effects caused by gas depletion, such as the utilization of pulsed electroreduction, cycling the applied current to electrodes on and off periodically.

Impact of New Systemic Therapies in Overall Survival in Non-Metastatic Castration Resistant Prostate Cancer: Systematic Review and Meta-Analysis.

There was a high medical need for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) when several next-generation anti-androgens (apalutamide, enzalutamide, and darolutamide) demonstrated clinically relevant delays in metastasis onset. However, to date, few publications have assessed the pooled effect of these treatments on overall survival (OS). We performed a systematic review and meta-analysis of all randomized, placebo-controlled studies investigating a systemic treatment in nmCRPC. Publications were identified by searching several databases on April 7, 2021. The primary objective of this analysis was to determine the OS benefit. Secondary outcomes included the relative risk (RR) of adverse events (AEs) and grade 3-4 AEs. A sensitivity analysis with simulated data was also conducted to examine the influence of the study designs on the results. Three randomized controlled studies (SPARTAN, PROSPER, ARAMIS) met our inclusion criteria. Pooled meta-analyses showed a significant benefit in OS with the active agents versus placebo (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.65-0.83), as well as increased risk of any grade (RR 1.09, 95% CI 1.01-1.17) and grade 3-4 AEs (RR 1.50, 95% CI 1.23-1.83). The sensitivity analysis with SPARTAN-like simulated populations demonstrated that when using ARAMIS statistical design, OS would be statistically significant in 98.1% of the cases, at a shorter follow-up and with lower number of events. First-line treatment of nmCRPC patients with anti-androgens increased OS with an acceptable safety profile. In light of the different study designs and follow-up, results should be interpreted separately.

International Neurotrauma Training Based on North-South Collaborations: Results of an Inter-institutional Program in the Era of Global Neurosurgery.

Objective: Shortage of general neurosurgery and specialized neurotrauma care in low resource settings is a critical setback in the national surgical plans of low and middle-income countries (LMIC). Neurotrauma fellowship programs typically exist in high-income countries (HIC), where surgeons who fulfill the requirements for positions regularly stay to practice. Due to this issue, neurosurgery residents and medical students from LMICs do not have regular access to this kind of specialized training and knowledge-hubs. The objective of this paper is to present the results of a recently established neurotrauma fellowship program for neurosurgeons of LMICs in the framework of global neurosurgery collaborations, including the involvement of specialized parallel education for neurosurgery residents and medical students. Methods: The Global Neurotrauma Fellowship (GNTF) program was inaugurated in 2015 by a multi-institutional collaboration between a HIC and an LMIC. The course organizers designed it to be a 12-month program based on adapted neurotrauma international competencies with the academic support of the Barrow Neurological Institute at Phoenix Children's Hospital and Meditech Foundation in Colombia. Since 2018, additional support from the UK, National Institute of Health Research (NIHR) Global Health Research in Neurotrauma Project from the University of Cambridge enhanced the infrastructure of the program, adding a research component in global neurosurgery and system science. Results: Eight fellows from Brazil, Venezuela, Cuba, Pakistan, and Colombia have been trained and certified via the fellowship program. The integration of international competencies and exposure to different systems of care in high-income and low-income environments creates a unique environment for training within a global neurosurgery framework. Additionally, 18 residents (Venezuela, Colombia, Ecuador, Peru, Cuba, Germany, Spain, and the USA), and ten medical students (the United Kingdom, USA, Australia, and Colombia) have also participated in elective rotations of neurotrauma and critical care during the time of the fellowship program, as well as in research projects as part of an established global surgery initiative. Conclusion: We have shown that it is possible to establish a neurotrauma fellowship program in an LMIC based on the structure of HIC formal training programs. Adaptation of the international competencies focusing on neurotrauma care in low resource settings and maintaining international mentoring and academic support will allow the participants to return to practice in their home-based countries.

Pre-existing conditions in Latin America and factors associated with adverse outcomes of COVID-19: A review.

The coronavirus disease 2019 (COVID-19) pandemic, produced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly throughout the world. Latin American and the Caribbean countries have been harshly affected by the pandemic mainly due to less prepared healthcare systems and fragmented social safety nets. In the region, health status population-based indicators are worse than compared to the Organization for Economic Cooperation and Development. Recent evidence suggests that the progression and severity of COVID-19 are associated with the prior health status of individuals, and studies have shown that the case fatality rate is highly stratified among different populations. This narrative review aims to describe factors associated with adverse outcomes of COVID-19 in the context of social determinants of health in Latin American and Caribbean countries. In this review, we state that genetic and biological factors interact in a sophisticated way with social determinants of health, impacting the rapid spread of COVID-19 in Latin American and Caribbean countries. Behavioral factors, such as physical inactivity, smoking, and unhealthy diets, are related to chronic systemic inflammation. Also, air pollution can prolong inflammation and the hyper-activation of the immune system. Air pollutants could facilitate the spread of the virus. Finally, frailty and comorbidities can be associated with COVID-19 severity through increasing vulnerability to stressors and leading to more severe symptoms of COVID-19 disease, including a higher mortality risk. All these factors contribute to increasing the impact of COVID-19 in Latin American and Caribbean countries. We highlight the relevance of considering social determinants of health in Latin American and the Caribbean countries, not only in controlling the likelihood of getting the disease but also its progression and severity. All these social determinants can guide the design and implementation of tailored interventions promoting healthy lifestyle behaviors, which should lower the spread of the disease, its severity, and lethality.

La pandemia de la enfermedad por coronavirus 2019 (COVID-19), producida por el virus SARS-CoV-2, se ha diseminado rápidamente a través del mundo. Los países de Latinoamérica y el Caribe han sido afectados duramente por la pandemia principalmente debido a falta de preparación de sus sistemas de salud y debido al fragmentado sistema de seguridad social. Además, en la región, el estado de salud de la población muestra peores indicadores de salud comparado con los países de la Organización para la Cooperación y el Desarrollo Económico. Evidencia reciente sugiere que la progresión y severidad de la COVID-19 están asociadas con el estado de salud basal del individuo, y algunos estudios han mostrado que la letalidad está altamente estratificada entre diferentes poblaciones. El objetivo de esta revisión narrativa es describir los factores asociados con peor evolución de la COVID-19 en el contexto de los determinantes sociales de la salud en los países de Latinoamérica y el Caribe. En esta revisión, se indica que los factores biológicos y genéticos interactúan de una manera sofisticada con los determinantes sociales de la salud, impactando la rápida diseminación de la COVID-19 en los países de Latinoamérica y el Caribe. Factores del comportamiento, como la inactividad física, fumar, y una dieta poco saludable, están relacionadas con una inflamación sistémica crónica. Además, la contaminación ambiental puede prolonger la inflamación y la hiperactivación del sistema inmune. Las partículas contaminantes del aire pueden facilitar la dispersión del virus. Finalmente, el síndrome de fragilidad y las comorbilidades están asociadas con severidad de la COVID-19, aumentando la vulnerabilidad ante factores estresantes y provocando síntomas más graves de la enfermedad COVID-19, aumentando el riesgo de mortalidad. Todos los factores mencionados, contribuyen a aumentar el impacto de la pandemia por COVID-19 en los países de Latinoamérica y el Caribe. Destacamos la relevancia de considerar los determinantes sociales de la salud en los países de Latinoamérica y el Caribe, no sólo para controlar el riesgo de contagio, sino también la progresión y severidad de la enfermedad. Los determinantes sociales pueden guiar el diseño y la implementación de intervenciones para promover los estilos de vida saludable, que puede contribuir a reducir la diseminación de la enfermedad, su severidad y letalidad.

Apalutamide plus Androgen Deprivation Therapy for Metastatic Castration-Sensitive Prostate Cancer: Analysis of Pain and Fatigue in the Phase 3 TITAN Study.

PURPOSE: We performed an exploratory analysis of prostate cancer-related pain and fatigue on health-related quality of life in patients with metastatic castration-sensitive prostate cancer receiving apalutamide (240 mg/day) or placebo, with continuous androgen deprivation therapy (ADT), in the phase 3, randomized, double-blind, placebo controlled TITAN trial (NCT02489318). MATERIALS AND METHODS: Patient-reported outcomes for pain and fatigue were evaluated using the Brief Pain Inventory-Short Form and Brief Fatigue Inventory. Time to deterioration (TTD) was estimated by Kaplan-Meier method; hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards model. General estimating equations for logistic regression estimated treatment-related differences in the likelihood of worsening pain or fatigue. RESULTS: Compliance for completing the Brief Pain Inventory-Short Form and Brief Fatigue Inventory was high (96% to 97%) in the first year. Median followup times were similar between treatments (19 to 22 months). Median pain TTD was longer with apalutamide than placebo for "pain at its least in the last 24 hours" (28.7 vs 21.8 months, respectively; p=0.0146), "pain interfered with mood" (not estimable vs 22.4 months; p=0.0017), "pain interfered with walking ability" (28.7 vs 20.2 months; p=0.0027), "pain interfered with relations" (not estimable vs 23.0 months; p=0.0139) and "pain interfered with sleep" (28.7 vs 20.9 months; p=0.0167). Likelihood for fatigue and worsening fatigue were similar between groups. CONCLUSIONS: Patients with metastatic castration-sensitive prostate cancer receiving apalutamide plus ADT vs placebo plus ADT reported consistently favorable TTD of pain. No difference for change in fatigue was observed with apalutamide vs placebo.

Genital abnormalities: Contextualization of a neglected area in prenatal diagnosis / Anomalías genitales: contextualización de un campo olvidado en el diagnóstico prenatal

RESUMEN Objetivo: hacer una reflexión sobre el bajo desarrollo que hay actualmente en el campo del diagnóstico prenatal de las anomalías genitales. Materiales y métodos: a partir de la tesis de que el desarrollo del diagnóstico antenatal de las anomalías genitales es escaso, se presenta una comparación con el estado actual de otros campos del diagnóstico prenatal, así como con su contrapartida posnatal; se analizan las distintas causas que pueden haber llevado a esta situación, y se reflexiona sobre formas de mejora de la especialidad. Conclusión: en comparación con otras áreas del diagnóstico prenatal, la detección de anomalías genitales tiene un menor nivel de desarrollo en cuanto a la disponibilidad de herramientas diagnósticas, de protocolos de manejo o investigación clínica. Algunas causas probables son la percepción de baja prevalencia, una importancia limitada o las dificultades para su exploración. Una forma de reforzar este componente de la medicina fetal sería la integración del conocimiento actual, la adquisición de herramientas adecuadas, y una traslación a la medicina clínica.

ABSTRACT Objective: To reflect on how the area of genital abnormalities has fallen behind in prenatal diagnosis. Materials and methods: Based on the thesis that prenatal diagnosis of genital abnormalities has scarcely developed, a comparison with other areas of prenatal diagnosis and with its postnatal counterpart is presented; different explanations for this situation are examined; and a reflection is made on ways to improve the specialty. Conclusion: Compared to other disciplines, prenatal diagnosis of genital abnormalities finds itself lagging behind in terms of diagnostic tools, management protocols and scientific literature. Potential causes include a perception of low prevalence and limited importance, or exploration challenges. Integration of current knowledge, together with the acquisition of the appropriate tools and translation to clinical medicine, would be a way to make this discipline stronger.

Desgarro perineal con mucosa vaginal íntegra tras primera relación sexual / Perineal tear with intact vaginal mucosa after first sexual intercourse

RESUMEN Las lesiones del tracto genital femenino tras relaciones sexuales son un problema frecuente en las urgencias de ginecología, pero poco estudiado salvo su aspecto médico-legal. Su incidencia es desconocida ya que muchas mujeres no llegan a consultar por miedo o pudor. El reconocimiento precoz de estas lesiones y su correcto tratamiento puede evitar la parición de secuelas que acompañarán a nuestra paciente durante el resto de su vida. Presentamos el caso de una paciente de 18 años con un desgarro perineal con mucosa vaginal íntegra tras su primera relación sexual.

ABSTRACT Injuries to the female genital tract after sexual intercourse are a frequent problem in gynecological emergencies, but little studied except for their medico-legal aspect. Its incidence is unknown since many women do not go to their specialist out of fear or embarrassment. Early recognition of these injuries and their correct treatment may prevent the appearance of sequelae that will accompany our patient for the rest of her life. We present the case of an 18-year-old patient with a perineal tear with intact vaginal mucosa after her first sexual intercourse.

Therapeutic and surgical indications for patients with penile cancer in the COVID-19 era

ABSTRACT Purpose: The aim of this work is to review and synthesize the existing evidence and recommendations regarding to the therapeutic and surgical indications as well as monitoring of patients with Penile Cancer in COVID-19 era and to propose an action protocol to facilitate decision-making. Material and Methods: A non-systematic review of the literature regarding the management of penile cancer during the COVID-19 pandemic was performed until April 30, 2020. We propose our recommendations based on this evidence. Results: Penile cancer is an uncommon but aggressive disease. Prognosis is determined by several characteristics, being the most important the presence of lymph nodes, in which case, treatment should not be delayed. For these reasons, an initial evaluation is mandatory. Priority classifications, based on the oncological outcomes when treatment is delayed, have been made in order to separate deferrable disease from the one that needs high priority treatment. In penile cancer with low risk of progression, surgical treatment can be delayed, but other options must be considered, like topical treatment or laser therapy. In cases with intermediate risk of progression, surgical treatment may be delayed up to three months, but we must consider radiation therapy and brachytherapy as effective options. When feasible, follow-up should by telemonitoring. Conclusions: In the COVID 19 era, initial evaluation of the patient is mandatory. Histological diagnosis with local staging is necessary before offering any therapeutic option. In case of superficial non-invasive disease, topical treatment is effective in absence of lymph node involvement. In selected patients, radiotherapy is an organpreserving approach with good results. Non-deferrable surgical treatment must be performed by an experienced surgeon and as an outpatient procedure when possible. When indicated, iLND should not be delayed since it is decisive for patient survival. Follow-up should be by telemonitoring.

Therapeutic and Surgical Indications for Patients with Penile Cancer in the COVID-19 era.

PURPOSE: The aim of this work is to review and synthesize the existing evidence and recommendations regarding to the therapeutic and surgical indications as well as monitoring of patients with Penile Cancer in COVID-19 era and to propose an action protocol to facilitate decision-making. MATERIAL AND METHODS: A non-systematic review of the literature regarding the management of penile cancer during the COVID-19 pandemic was performed until April 30, 2020. We propose our recommendations based on this evidence. RESULTS: Penile cancer is an uncommon but aggressive disease. Prognosis is determined by several characteristics, being the most important the presence of lymph nodes, in which case, treatment should not be delayed. For these reasons, an initial evaluation is mandatory. Priority classifications, based on the oncological outcomes when treatment is delayed, have been made in order to separate deferrable disease from the one that needs high priority treatment. In penile cancer with low risk of progression, surgical treatment can be delayed, but other options must be considered, like topical treatment or laser therapy. In cases with intermediate risk of progression, surgical treatment may be delayed up to three months, but we must consider radiation therapy and brachytherapy as effective options. When feasible, follow-up should by telemonitoring. CONCLUSIONS: In the COVID-19 era, initial evaluation of the patient is mandatory. Histological diagnosis with local staging is necessary before offering any therapeutic option. In case of superficial non-invasive disease, topical treatment is effective in absence of lymph node involvement. In selected patients, radiotherapy is an organ-preserving approach with good results. Non-deferrable surgical treatment must be performed by an experienced surgeon and as an outpatient procedure when possible. When indicated, iLND should not be delayed since it is decisive for patient survival. Follow-up should be by telemonitoring.

Recommendations of the Colombian Consensus Committee for the Management of Traumatic Brain Injury in Prehospital, Emergency Department, Surgery, and Intensive Care (Beyond One Option for Treatment of Traumatic Brain Injury: A Stratified Protocol [BOOTStraP]).

Background Traumatic brain injury (TBI) is a global public health problem. In Colombia, it is estimated that 70% of deaths from violence and 90% of deaths from road traffic accidents are TBI related. In the year 2014, the Ministry of Health of Colombia funded the development of a clinical practice guideline (CPG) for the diagnosis and treatment of adult patients with severe TBI. A critical barrier to the widespread implementation was identified-that is, the lack of a specific protocol that spans various levels of resources and complexity across the four treatment phases. The objective of this article is to present the process and recommendations for the management of patients with TBI in various resource environments, across the treatment phases of prehospital care, emergency department (ED), surgery, and intensive care unit. Methods Using the Delphi methodology, a consensus of 20 experts in emergency medicine, neurosurgery, prehospital care, and intensive care nationwide developed recommendations based on 13 questions for the management of patients with TBI in Colombia. Discussion It is estimated that 80% of the global population live in developing economies where access to resources required for optimum treatment is limited. There is limitation for applications of CPGs recommendations in areas where there is low availability or absence of resources for integral care. Development of mixed methods consensus, including evidence review and expertise points of good clinical practices can fill gaps in application of CPGs. BOOTStraP (Beyond One Option for Treatment of Traumatic Brain Injury: A Stratified Protocol) is intended to be a practical handbook for care providers to use to treat TBI patients with whatever resources are available. Results Stratification of recommendations for interventions according to the availability of the resources on different stages of integral care is a proposed method for filling gaps in actual evidence, to organize a better strategy for interventions in different real-life scenarios. We develop 10 algorithms of management for building TBI protocols based on expert consensus to articulate treatment options in prehospital care, EDs, neurological surgery, and intensive care, independent of the level of availability of resources for care.