Time trends in the mortality of testicular cancer across the BRICS: an age-period-cohort analysis for the GBD 2019.

Testicular cancer (TCa) is a rare but impactful malignancy that primarily affects young men. Understanding the mortality rate of TCa is crucial for improving prevention and treatment strategies to reduce the risk of death among patients. We obtained TCa mortality data by place (5 countries), age (20-79 years), and year (1990-2019) from the Global Burden of Disease Study 2019. Age-period-cohort model was used to estimate the net drift, local drift, age effects, period and cohort effects. In 2019, the global mortality of TCa increased to 10842 (95% UI 9961, 11902), with an increase of 50.08% compared to 1990.The all-age mortality rate for TCa in 2019 increased from 0.17/100,000 (95% UI 0.13, 0.20) in China to 0.48/100,000 (95% UI 0.38, 0.59) in Russian Federation, whereas the age-standardized mortality rate in 2019 was highest in the South Africa 0.47/100,000 (95% UI 0.42, 0.53) and lowest in the China 0.16/100,000 (95% UI 0.13, 0.19). China's aging population shifts mortality patterns towards the elderly, while in Russian Federation, young individuals are primarily affected by the distribution of deaths. To address divergent TCa mortality advancements in BRICS countries, we propose a contextually adaptive and resource-conscious approach to prioritize TCa prevention. Tailoring strategies to contextual diversity, including policy frameworks, human resources, and financial capacities, will enhance targeted interventions and effectiveness in reducing TCa mortality.

Perceived quality of life by patients with immune-mediated inflammatory diseases treated with biological therapies. SACVINFA study.

OBJECTIVES: To evaluate health-related quality of life perceived by patients with the most prevalent immune-mediated inflammatory diseases in Spain: inflammatory bowel disease (IBD), psoriasis (Ps), psoriatic arthritis (AP), rheumatoid arthritis (RA), and spondyloarthropathies (SpAs), and to determine the factors that influence patient quality of life. METHODS: The SACVINFA study (SA=satisfaction, CV=quality of life, IN=immune-mediated, FA=pharmacy) consisted of an observational study conducted in 4 hospitals in the Community of Madrid. A cross-sectional analysis was made for adult patients diagnosed with an immune-mediated inflammatory disease who attended the Pharmacy Service. Quality of life was assessed using the EQ-5D-5L questionnaire (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and specific questionnaires: SIBDQ-9, DLQI, PsAQoL, QoL-RA, and ASQoL. RESULTS: A total of 578 patients were analysed (inflammatory bowel disease=25.3%; psoriasis=19.7%; spondyloarthropathies=18.7%; rheumatoid arthritis=18.5%; psoriatic arthritis=17.8%). The mean age (standard deviation) was 49.8 (12.3) years and 50.7% were male. The average score (standard deviation) for the global EQ-5D-5L was 0.771 (0.2) and the mean (standard deviation) visual analogue scale score was 71.5 (20.0). Type of immune-mediated inflammatory diseases was associated with differences in quality of life showing psoriasis and inflammatory bowel disease higher values of EQ5D-5L than psoriatic arthritis, rheumatoid arthritis, and spondyloarthropathies, p<.05 in all comparisons. Patients with RA, IBD, and Ps achieved 70% of the maximum score, while patients with PsA and SpAs did not reach 50% of the maximum possible score. Female gender, a state of moderate/severe disease severity, an older age, and a higher number of previous treatments were correlated with worse quality of life. Conversely, persistence to current treatment correlated with better quality of life. CONCLUSIONS: Patients with immune-mediated inflammatory diseases have markedly affected quality of life, mainly in the pain/discomfort dimension, especially in those immune-mediated inflammatory diseases with a rheumatological component.

Improvement of neurogenic urinary dysfunctions in female rats treated with an injection of botulinum toxin A at the epicenter of the spinal cord injured site.

OBJECTIVE: To assess the effect of an injection of botulinum toxin A (BoNT/A) at the epicenter of the spinal cord injury (SCI) site on the recovery of lower urinary tract function in female rats with thoracic SCI. MATERIALS AND METHODS: Twenty-four female Wistar rats with Sham (laminectomy at T8/T9 level) or SCI (at T8/T9; 30 g compression for 5 s) were assigned into Sham-SS (injected with 5 µL of saline solution), Sham-BoNT/A (injected with 15 pg/rat, equivalent to 7.5 Units/kg of BoNT/A in 5 µL volume), SCI-SS (injured and injected with saline), SCI-BoNT/A (injured and injected with BoNT/A), N = 6 per group. Weekly evaluation of stereotyped micturition behavior, hind-limb nociception, and locomotor activity was performed 1 week before and during 6 weeks after surgery. Subsequently, all groups underwent simultaneous electromyography of the external urethral sphincter (EUS-EMG) and cystometric (CMG) studies. RESULTS: A compression SCI at the T8/T9 thoracic level significantly impairs sensory and locomotive functions, as well as stereotyped micturition behavior. However, these impairments were improved by BoNT/A injection after SCI. Neither injections of saline solution nor BoNT/A had an appreciable effect on the same parameters evaluated in the Sham groups. The combined EUS-EMG and CMG evaluations revealed important improvements of lower urinary tract physiology, particularly a reduction in the frequency of non-voiding contractions and the properties of EUS bursting activity indicated as the amplitude of the EUS-EMG signal and duration of burst electrical activity during effective voiding. CONCLUSION: The severe impairments on sensory and locomotive functions as well stereotyped micturition caused by an SCI could be potentially attenuated by an injection of a small amount of BoNT/A directly into the epicenter of the SCI region. A reduction in the release of neurotoxic neurotransmitters requiring the SNARE complex may be the mechanism triggered by BoNT/A to reduce neurotoxicity and hyperexcitability created in the SCI area to improve the survival of spinal cord cells involved in micturition.

DICER1-associated central nervous system sarcoma: A comprehensive clinical and genomic characterization of case series of young adult patients.

Background: DICER1 alterations are associated with intracranial tumors in the pediatric population, including pineoblastoma, pituitary blastoma, and the recently described "primary DICER1-associated CNS sarcoma" (DCS). DCS is an extremely aggressive tumor with a distinct methylation signature and a high frequency of co-occurring mutations. However, little is known about its treatment approach and the genomic changes occurring after exposure to chemoradiotherapy. Methods: We collected clinical, histological, and molecular data from eight young adults with DCS. Genomic analysis was performed by Next-generation Sequencing (NGS). Subsequently, an additional germline variants analysis was completed. In addition, an NGS analysis on post-progression tumor tissue or liquid biopsy was performed when available. Multiple clinicopathological characteristics, treatment variables, and survival outcomes were assessed. Results: Median age was 20 years. Most lesions were supratentorial. Histology was classified as fusiform cell sarcomas (50%), undifferentiated (unclassified) sarcoma (37.5%), and chondrosarcoma (12.5%). Germline pathogenic DICER1 variants were present in two patients, 75% of cases had more than one somatic alteration in DICER1, and the most frequent commutation was TP53. Seven patients were treated with surgery, Ifosfamide, Cisplatin, and Etoposide (ICE) chemotherapy and radiotherapy. The objective response was 75%, and the median time to progression (TTP) was 14.5 months. At progression, the most common mutations were in KRAS and NF1. Overall survival was 30.8 months. Conclusions: DCS is an aggressive tumor with limited therapeutic options that requires a comprehensive diagnostic approach, including molecular characterization. Most cases had mutations in TP53, NF1, and PTEN, and most alterations at progression were related to MAPK, RAS and PI3K signaling pathways.

Prognostic significance of telomerase reverse transcriptase promoter gen mutations in high grade meningiomas / Importancia pronóstica de las mutaciones del gen promotor de la transcriptasa inversa de la telomerasa en los meningiomas de alto grado

Introduction: Mutations in the promoter region of telomerase reverse transcriptase occur frequently in meningiomas. Objective: To estimate the prognostic importance of telomerase reverse transcriptase mutations in Colombian patients with grades II and III meningioma. Materials and methods: This was a multicenter retrospective cohort study of patients diagnosed with refractory or recurrent WHO grades II and III meningiomas, recruited between 2011 and 2018, and treated with systemic therapy (sunitinib, everolimus ± octreotide, and bevacizumab). Mutation status of the telomerase reverse transcriptase promoter was established by PCR. Results: Forty patients were included, of which telomerase reverse transcriptase mutations were found in 21 (52.5%), being C228T and C250T the most frequent variants with 87.5 % and 14.3 %, respectively. These were more frequent among patients with anaplastic meningiomas (p=0.18), with more than 2 recurrences (p=0.04); and in patients with parasagittal region and anterior fossa lesions (p=0.05). Subjects characterized as having punctual mutations were more frequently administered with everolimus, sunitinib and bevacizumab drug series (p=0.06). Overall survival was 23.7 months (CI95% 13.1-34.2) and 43.4 months (CI95% 37.5-49.3; p=0.0001) between subjects with and without mutations, respectively. Multivariate analysis showed that the number of recurrences and the presence of telomerase reverse transcriptase mutations were tthe only variables that negatively affected overall survival. Conclusions: Mutations in telomerase reverse transcriptase allows the identification of high-risk patients and could be useful in the selection of the best medical treatment.

Introducción. En los meningiomas, ocurren con frecuencia mutaciones en la región promotora de la transcriptasa inversa de la telomerasa. Objetivo. Estimar la importancia pronóstica de las mutaciones de la transcriptasa inversa de la telomerasa en pacientes colombianos con meningiomas de grados II y III. Materiales y métodos. Es un estudio de cohorte, retrospectivo y multicéntrico, que incluyó pacientes con diagnóstico de meningioma persistente o recidivante, de grados II y III, según la clasificación de la OMS, reclutados entre el 2011 y el 2018, con tratamiento sistémico (sunitinib, everolimus con octreótido o sin él, y bevacizumab). El estado de la mutación del promotor de la transcriptasa inversa de la telomerasa se determinó por medio de la PCR. Resultados. Se incluyeron 40 pacientes, en 21 (52,5 %) de los cuales se encontraron mutaciones en la transcriptasa inversa de la telomerasa, siendo las variantes más frecuentes la C228T (87,5 %) y la C250T (14,3 %). Estas fueron más frecuentes entre los pacientes con meningiomas anaplásicos (p=0,18), en aquellos con más de dos recurrencias (p=0,04), y en los que presentaron lesiones en la región parasagital y la fosa anterior (p=0,05). Los sujetos caracterizados por tener alteraciones puntuales fueron tratados con mayor frecuencia con la serie de medicamentos everolimus, sunitinib y bevacizumab (p=0,06). Tras el inicio del tratamiento médico, la supervivencia global fue de 23,7 meses (IC95% 13,1-34,2) en los pacientes con mutaciones y, de 43,4 meses (IC95% 37,5-49,3), entre aquellos sin mutaciones (p=0,0001). Los resultados del análisis multivariado demostraron que, únicamente, el número de recurrencias y la presencia de mutaciones en el gen de la transcriptasa inversa de la telomerasa, fueron factores que afectaron negativamente la supervivencia global. Conclusiones. Las mutaciones en el gen promotor de la transcriptasa inversa de la telomerasa permiten identificar los pacientes con alto riesgo, cuya detección podría ser de utilidad para seleccionar el mejor esquema terapéutico.

Importancia pronóstica de las mutaciones del gen promotor de la transcriptasa inversa de la telomerasa en los meningiomas de alto grado / Prognostic significance of telomerase reverse transcriptase promoter gen mutations in high grade meningiomas

Introducción. En los meningiomas, ocurren con frecuencia mutaciones en la región promotora de la transcriptasa inversa de la telomerasa. Objetivo. Estimar la importancia pronóstica de las mutaciones de la transcriptasa inversa de la telomerasa en pacientes colombianos con meningiomas de grados II y III. Materiales y métodos. Es un estudio de cohorte, retrospectivo y multicéntrico, que incluyó pacientes con diagnóstico de meningioma persistente o recidivante, de grados II y III, según la clasificación de la OMS, reclutados entre el 2011 y el 2018, con tratamiento sistémico (sunitinib, everolimus con octreótido o sin él, y bevacizumab). El estado de la mutación del promotor de la transcriptasa inversa de la telomerasa se determinó por medio de la PCR. Resultados. Se incluyeron 40 pacientes, en 21 (52,5 %) de los cuales se encontraron mutaciones en la transcriptasa inversa de la telomerasa, siendo las variantes más frecuentes la C228T (87,5 %) y la C250T (14,3 %). Estas fueron más frecuentes entre los pacientes con meningiomas anaplásicos (p=0,18), en aquellos con más de dos recurrencias (p=0,04), y en los que presentaron lesiones en la región parasagital y la fosa anterior (p=0,05). Los sujetos caracterizados por tener alteraciones puntuales fueron tratados con mayor frecuencia con la serie de medicamentos everolimus, sunitinib y bevacizumab (p=0,06). Tras el inicio del tratamiento médico, la supervivencia global fue de 23,7 meses (IC95% 13,1-34,2) en los pacientes con mutaciones y, de 43,4 meses (IC95% 37,5-49,3), entre aquellos sin mutaciones (p=0,0001). Los resultados del análisis multivariado demostraron que, únicamente, el número de recurrencias y la presencia de mutaciones en el gen de la transcriptasa inversa de la telomerasa, fueron factores que afectaron negativamente la supervivencia global. Conclusiones. Las mutaciones en el gen promotor de la transcriptasa inversa de la telomerasa permiten identificar los pacientes con alto riesgo, cuya detección podría ser de utilidad para seleccionar el mejor esquema terapéutico.

Introduction: Mutations in the promoter region of telomerase reverse transcriptase occur frequently in meningiomas. Objective: To estimate the prognostic importance of telomerase reverse transcriptase mutations in Colombian patients with grades II and III meningioma. Materials and methods: This was a multicenter retrospective cohort study of patients diagnosed with refractory or recurrent WHO grades II and III meningiomas, recruited between 2011 and 2018, and treated with systemic therapy (sunitinib, everolimus ± octreotide, and bevacizumab). Mutation status of the telomerase reverse transcriptase promoter was established by PCR. Results: Forty patients were included, of which telomerase reverse transcriptase mutations were found in 21 (52.5%), being C228T and C250T the most frequent variants with 87.5 % and 14.3 %, respectively. These were more frequent among patients with anaplastic meningiomas (p=0.18), with more than 2 recurrences (p=0.04); and in patients with parasagittal region and anterior fossa lesions (p=0.05). Subjects characterized as having punctual mutations were more frequently administered with everolimus, sunitinib and bevacizumab drug series (p=0.06). Overall survival was 23.7 months (CI95% 13.1-34.2) and 43.4 months (CI95% 37.5-49.3; p=0.0001) between subjects with and without mutations, respectively. Multivariate analysis showed that the number of recurrences and the presence of telomerase reverse transcriptase mutations were the only variables that negatively affected overall survival. Conclusions: Mutations in telomerase reverse transcriptase allows the identification of high-risk patients and could be useful in the selection of the best medical treatment.

Continuous administration of leuprolide acetate improves urinary function in male rats with severe thoracic spinal cord injury.

AIMS: To determine if a continuous administration of leuprolide acetate (LA), a synthetic agonist for the gonadotrophin-releasing hormone receptor, facilitates the recovery of urinary function in spinal cord injured male rats. MAIN METHODS: Male Wistar rats were randomized into spinal cord injury (SCI; n = 7), SCI with continuous administration of LA for two weeks via implantation of a subcutaneous osmotic pump (SCI + LA; n = 7), Sham SCI (SH-SCI; n = 6) or no surgery (Intact; n = 6) groups. Micturition, hind-limb nociception and locomotor behaviors were analyzed before and after surgical procedures on days 7, 14, 21 and 28. After behavioral studies, electromyography of the external urethral sphincter (EUS-EMG) and cystometric (CMG) studies were performed in all groups. KEY FINDINGS: SCI significantly decreased frequency of voids and CMG parameters (p < 0.001), abolished the bursting activity of the EUS during CMG, significantly increased hind limb sensory threshold and decreased locomotor performance in comparison to the other groups (p < 0.001). Continuous LA treatment significantly increased the frequency of voids and improved CMG parameters (p < 0.001), exhibiting bursting EUS activity during CMGs, and enhanced locomotor performance in comparison to SCI rats (p < 0.001). SIGNIFICANCE: SCI severely affected behavioral and functional micturition processes, including sensory and locomotor functions. Systemic and uninterrupted treatment with LA improves the recovery of micturition behavior and the synergistic function of the EUS. Furthermore, sensory and locomotor responses were also improved in SCI rats. This procedure may have a therapeutic potential to facilitate urinary function recovery in patients with SCI.

Evaluation of the hospital care quality perceived by patients with immune-mediated inflammatory diseases from the pharmacy service. SACVINFA study.

WHAT IS KNOWN AND OBJECTIVE: Immune-mediated inflammatory diseases (IMIDs) are a group of chronic and highly disabling diseases. The objective is to evaluate the satisfaction with the health care received by patients with the most prevalent IMIDs in Spain: inflammatory bowel disease (IBD), psoriasis (Ps) psoriatic arthritis (PsA), rheumatoid arthritis (RA) and spondyloarthropathies (SpAs), and to determine the factors that influence patient satisfaction. METHODS: This was an observational, cross-sectional, multicentre study in a real-world evidence context conducted in the Pharmacy Service in four hospital centres of the Community of Madrid that belong to the National Health System. The study included adult patients diagnosed with an IMID who had attended the Pharmacy Service at least three times. The patients were grouped according to the main IMID. Health care satisfaction was evaluated using the chronic patient experience assessment (IEXPAC) questionnaire. The responses to IEXPAC are grouped into three factors: productive interactions, new relational model and patient self-management, with a total score from 0 (worst) to 10 (best experience). Health-related quality of life (HRQoL) was also evaluated using the EQ-5D-5L questionnaire, and pharmacological adherence was evaluated through the Morisky-Green test. RESULTS AND DISCUSSION: A total of 578 patients were analysed (IBD = 25.3%; Ps = 19.7%; SpAs = 18.7%; RA = 18.5%; PsA = 17.8%). The mean age (SD) was 49.8 (12.3) years and 50.7% were male. The average score (SD) for the total IEXPAC sample was 6.6 (1.9). RA was the IMID with the lowest score, at 5.83 (2.0), significantly lower than the scores of Ps (SD) [7.01 (1.7); p = 0.003], IBD [6.83 (1, 9); p = 0.012] and SpAs [6.80 (1.6); p = 0.001]. Productive interactions (SD) [8.5 (1.8)] and patient self-management (SD) [7.3 (2.3)] were the factors with the highest scores, and the new relational model had the lowest score (SD) [3.2 (2.7)]. Male gender, a longer time interval between medication administrations and a higher HRQoL were correlated with better patient satisfaction. Current biological therapy (according to the Anatomical Chemical classification system) also had a significant influence; patients treated with tumour necrosis factor inhibitors and interleukin inhibitors showed greater satisfaction than those treated with selective immunosuppressants. WHAT IS NEW AND CONCLUSION: The IEXPAC results show high general satisfaction with care quality reported by patients with IMIDs treated in the Pharmacy Service. However, there are areas of improvement in care quality specially health professional-patient communication, such as increasing access to information, and promoting and facilitating relationships with patients in similar conditions.

Difficult acute lymphoblastic leukaemia diagnosis in a paediatric patient with mixed presentation of COVID-19 acute respiratory failure and multisystemic inflammatory syndrome.

New diagnoses of leukaemia and other malignancies are recently being made in paediatric patients with COVID-19. The rates of mortality and morbidity in some of these children are expected to be higher. In new cases, concurrent diagnosis can be difficult because multisystemic inflammatory syndrome (MIS-C) and malignancies have similar clinical presentations. We present the case of a preteenage child where the diagnosis of leukaemia was complicated and delayed by a multisystem involvement and an inconclusive bone marrow study. Clinical teams managing children with COVID-19 and MIS-C should suspect leukaemia and other malignancies when the clinical course is complicated and bone marrow suppression is persistent. Prompt diagnosis will allow start of treatment on time, minimising complications.

Association of Cancer Diagnosis and Therapeutic Stage With Mortality in Pediatric Patients With COVID-19, Prospective Multicenter Cohort Study From Latin America.

Background: Children with cancer are at risk of critical disease and mortality from COVID-19 infection. In this study, we describe the clinical characteristics of pediatric patients with cancer and COVID-19 from multiple Latin American centers and risk factors associated with mortality in this population. Methods: This study is a multicenter, prospective cohort study conducted at 12 hospitals from 6 Latin American countries (Argentina, Bolivia, Colombia, Ecuador, Honduras and Peru) from April to November 2021. Patients younger than 14 years of age that had an oncological diagnosis and COVID-19 or multisystemic inflammatory syndrome in children (MIS-C) who were treated in the inpatient setting were included. The primary exposure was the diagnosis and treatment status, and the primary outcome was mortality. We defined "new diagnosis" as patients with no previous diagnosis of cancer, "established diagnosis" as patients with cancer and ongoing treatment and "relapse" as patients with cancer and ongoing treatment that had a prior cancer-free period. A frequentist analysis was performed including a multivariate logistic regression for mortality. Results: Two hundred and ten patients were included in the study; 30 (14%) died during the study period and 67% of patients who died were admitted to critical care. Demographics were similar in survivors and non-survivors. Patients with low weight for age (<-2SD) had higher mortality (28 vs. 3%, p = 0.019). There was statistically significant difference of mortality between patients with new diagnosis (36.7%), established diagnosis (1.4%) and relapse (60%), (p <0.001). Most patients had hematological cancers (69%) and they had higher mortality (18%) compared to solid tumors (6%, p= 0.032). Patients with concomitant bacterial infections had higher mortality (40%, p = 0.001). MIS-C, respiratory distress, cardiovascular symptoms, altered mental status and acute kidney injury on admission were associated with higher mortality. Acidosis, hypoxemia, lymphocytosis, severe neutropenia, anemia and thrombocytopenia on admission were also associated with mortality. A multivariate logistic regression showed risk factors associated with mortality: concomitant bacterial infection OR 3 95%CI (1.1-8.5), respiratory symptoms OR 5.7 95%CI (1.7-19.4), cardiovascular OR 5.2 95%CI (1.2-14.2), new cancer diagnosis OR 12 95%CI (1.3-102) and relapse OR 25 95%CI (2.9-214). Conclusion: Our study shows that pediatric patients with new onset diagnosis of cancer and patients with relapse have higher odds of all-cause mortality in the setting of COVID-19. This information would help develop an early identification of patients with cancer and COVID-19 with higher risk of mortality.

Systemic lupus erythematosus complicated with macrophage activation syndrome mimicking COVID-19 multisystemic inflammatory syndrome in children.

BACKGROUND: Macrophage activation syndrome (MAS) is characterized by excessive activation of macrophages and lymphocytes, leading to multiorgan dysfunction. As the initial manifestation of systemic lupus erythematosus (SLE), MAS is rare in children. Due to the COVID-19 pandemic, it is vital to identify the MAS as it shares similar characteristics with the multisystem inflammatory syndrome in children (MIS-C). CASE REPORT: We report the case of an 11-year-old male adolescent with symptoms of MIS-C. Although with negative results of RT-PCR (reverse transcription-polymerase chain reaction) and serology for SARS-CoV-2, contact with a positive COVID-19 relative was reported. When admitted to a referral hospital center, the patient received standard treatment for MIS-C. Although the same scheme was given on three occasions, the patient showed no response to initial therapy. Thus, the patient was classified as a refractory case. When the study was extended to other differential diagnoses, we found MAS associated with SLE. Therefore, the patient was treated with etoposide, cyclosporine, dexamethasone, and methotrexate and showed a good clinical response. CONCLUSIONS: MAS associated with SLE is rare in the pediatric population. MAS shares inflammatory markers with the MIS-C and is often confused with rheumatologic, infectious, and neoplastic entities. Reporting this case is important to identify differential diagnoses in patients presenting as MIS-C and decide on timely treatment, as it could be harmful or even fatal if a definitive diagnosis is not obtained on time.

INTRODUCCIÓN: El síndrome de activación de macrófagos (SAM) se caracteriza por una activación excesiva de los macrófagos y de los linfocitos que conduce a una disfunción multiorgánica. Como manifestación inicial del lupus eritematoso sistémico (LES), el SAM es poco común en la infancia. Debido a la pandemia de COVID-19, es importante identificar el SAM, ya que comparte características similares con el síndrome inflamatorio multisistémico en niños (MIS-C, por sus siglas en inglés). CASO CLÍNICO: Presentamos el caso de un varón de 11 años con síntomas de MIS-C. Resultó negativo en la prueba de reacción en cadena de la polimerasa con retrotranscriptasa y en la serología para SARS-CoV-2, aunque reportó contacto con un familiar positivo para COVID-19. Ingresó en un centro hospitalario de referencia y recibió tratamiento estandarizado para MIS-C. A pesar de recibir el mismo esquema en tres ocasiones, no mostró respuesta a la terapia inicial, por lo que fue clasificado como caso refractario. Al ampliar el estudio para otros diferenciales, se encontró SAM asociado con LES, por lo que el paciente recibió tratamiento con etopósido, ciclosporina, dexametasona y metotrexato, y mostró buena respuesta clínica. CONCLUSIONES: La asociación entre el SAM y el LES es rara en la población pediátrica. El SAM comparte marcadores inflamatorios con el MIS-C y suele confundirse con enfermedades reumatológicas, infecciosas y neoplásicas. La importancia de reportar este caso es identificar los diagnósticos diferenciales en los pacientes que se presentan como MIS-C, y decidir el tratamiento con prontitud, pues podría ser dañino o incluso fatal si no se obtiene un diagnóstico definitivo a tiempo.

Time course for urethral neuromuscular reestablishment and its facilitated recovery by transcutaneous neuromodulation after simulated birth trauma in rats.

The aims of the study were to determine the time-course of urinary incontinence recovery after vaginal distension (VD), elucidate the mechanisms of injury from VD leading to external urethral sphincter (EUS) dysfunction, and assess if transcutaneous electrical stimulation (TENS) of the dorsal nerve of the clitoris facilitates recovery of urinary continence after VD. Rats underwent 4-h VD, 4-h sham VD (SH-VD), VD plus 1-h DNC TENS, and VD plus 1-h sham TENS (SH-TENS). TENS or SH-TENS were applied immediately and at days 2 and 4 post-VD. Micturition behavior, urethral histochemistry and histology, EUS and nerve electrophysiology, and cystometrograms were evaluated. VD induced urine leakage and significantly disrupted EUS fibers and nerve-conduction (VD vs SH-VD group; p < 0.01). Urine leakage disappeared 13 days post-VD (p < 0.001). Structural and functional recovery of EUS neuromuscular circuitry started by day 6 post-VD, but did not fully recover by day 11 post-VD (p > 0.05). TENS significantly decreased the frequency of urine leakage post-VD (days 5-7; p < 0.01). We conclude that rat urinary continence after VD requires 2 weeks to recover, although urethra structure is not fully recovered. TENS facilitated urinary continence recovery after VD. Additional studies are necessary to assess if TENS could be used in postpartum women.

Efficacy of osimertinib plus bevacizumab in glioblastoma patients with simultaneous EGFR amplification and EGFRvIII mutation.

BACKGROUND: Amplification of EGFR and its active mutant EGFRvIII are common in glioblastoma (GB). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors or antibodies has shown limited efficacy. To improve the likelihood of effectiveness, we targeted adult patients with recurrent GB enriched for simultaneous EGFR amplification and EGFRvIII mutation, with osimertinib/bevacizumab at doses described for non-small cell lung cancer. METHODS: We retrospectively explored whether previously described EGFRvIII mutation in association with EGFR gene amplification could predict response to osimertinib/bevacizumab combination in a subset of 15 patients treated at recurrence. The resistance pattern in a subgroup of subjects is described using a commercial next-generation sequencing panel in liquid biopsy. RESULTS: There were ten males (66.7%), and the median patient's age was 56 years (range 38-70 years). After their initial diagnosis, 12 patients underwent partial (26.7%) or total resection (53.3%). Subsequently, all cases received IMRT and concurrent and adjuvant temozolomide (TMZ; the median number of cycles 9, range 6-12). The median follow-up after recurrence was 17.1 months (95% CI 12.3-22.6). All patients received osimertinib/bevacizumab as a second-line intervention with a median progression-free survival (PFS) of 5.1 months (95% CI 2.8-7.3) and overall survival of 9.0 months (95% CI 3.9-14.0). The PFS6 was 46.7%, and the overall response rate was 13.3%. After exposure to the osimertinib/bevacizumab combination, the main secondary alterations were MET amplification, STAT3, IGF1R, PTEN, and PDGFR. CONCLUSIONS: While the osimertinib/bevacizumab combination was marginally effective in most GB patients with simultaneous EGFR amplification plus EGFRvIII mutation, a subgroup experienced a long-lasting meaningful benefit. The findings of this brief cohort justify the continuation of the research in a clinical trial. The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, findings that contribute to the understanding and targeting in a stepwise rational this pathway.

Pediatric acute respiratory distress syndrome: How to protect the lungs during mechanical ventilation? / Síndrome de dificultad respiratoria aguda pediátrica: ¿cómo proteger los pulmones durante la ventilación mecánica?

Abstract Pediatric acute respiratory distress syndrome (PARDS) is a frequent diagnosis in critical care. This inflammatory process has different stages characterized by mild-to-severe hypoxia, and the management will vary according to the severity. New definitions for pediatric patients were published in 2015; new epidemiological evidence revising those definitions has helped understand the mortality associated with PARDS and the impact on ventilation. The strategies to protect the lungs during mechanical ventilation have been successful in reducing mortality and complications. In clinical situations where high levels of critical support are limited, other therapies with a lower level of evidence can be attempted to gain time without worsening the ongoing pulmonary injury. We offer a complete narrative revision of this syndrome, with the critical management of these patients as a priority.

Resumen El síndrome de dificultad respiratoria aguda pediátrica (SDRAP) es un diagnóstico frecuente en cuidados intensivos. Este proceso inflamatorio se caracteriza por diferentes grados de hipoxia, de leve a grave, y el manejo varía de acuerdo con la gravedad. En 2015 se publicaron nuevas definiciones para pacientes pediátricos, así como nueva evidencia epidemiológica, que toma como punto de partida dichas definiciones, lo cual ha ayudado a entender la mortalidad asociada y el impacto del manejo ventilatorio con respecto a la morbilidad en este síndrome. Las estrategias que protegen los pulmones durante la ventilación mecánica han sido exitosas en reducir la mortalidad y las complicaciones subsecuentes. En situaciones en las que existen limitaciones que impiden suministrar altos niveles de soporte crítico se pueden implementar otras medidas de menor evidencia para ganar tiempo e impedir que se extiendan las lesiones pulmonares. A continuación, se ofrece una revisión narrativa completa de este síndrome, con un enfoque que prioriza el manejo crítico de estos pacientes.

Cargas virales en pacientes trasplantados y genotipificación de Citomegalovirus / Viral loads in transplant patients and Cytomegalovirus genotyping

Resumen Objetivo: Determinar el curso de infecciones virales por un periodo de un año, mediante la medición de la carga viral de Adenovirus, virus BK, virus Epstein-Barr, Citomegalovirus y Herpesvirus humano 6, en 30 pacientes del Hospital San Juan de Dios, sometidos a trasplante de riñón o células progenitoras hematopoyéticas. Métodos: Se determinaron las cargas virales en diez muestras de sangre por paciente: una muestra pretransplante, ocho muestras obtenidas cada dos semanas postrasplante y una última muestra a los seis meses posteriores al trasplante. La cuantificación de los virus se realizó por reacción en cadena de la polimerasa en tiempo real y, solo en el caso del Adenovirus, por reacción en cadena de la polimerasa de punto final. También se determinaron los genotipos de Citomegalovirus en los pacientes positivos para este virus, utilizando una reacción en cadena de la polimerasa dirigida al gen de la glicoproteína B y secuenciación de los fragmentos amplificados. Las secuencias obtenidas fueron comparadas y alineadas con una secuencia de referencia, utilizando el programa Clustal Omega. Resultados: Al 77 % de los pacientes se les detectó al menos uno de los cinco virus analizados y el virus con mayor prevalencia fue el Citomegalovirus, con un 57% de positividad del total de la población. El genotipo de Citomegalovirus que más se detectó fue el genotipo 3. Se monitoreó el comportamiento de las cargas virales para cada virus analizado y la proporción de su incidencia entre pacientes masculinos y femeninos. Conclusiones: La cuantificación y caracterización de virus en pacientes de trasplante, permite un mejor manejo clínico del paciente con infecciones oportunistas y también un manejo más adecuado de las terapias farmacológicas.

Summary Aim: The objective of this study was to determine the course of viral infections during a period of one year, by measuring viral loads for Adenovirus, BK virus, Epstein-Barr virus, Cytomegalovirus and Human herpesvirus 6, in 30 patients from the San Juan de Dios National Hospital, undergoing kidney or hematopoietic progenitor cell transplants. Methods: Viral loads were determined in ten blood samples from each patient: a pre- transplant sample, eight samples obtained at two-week intervals post-transplant and one last sample at six months post-transplant. Viral quantification was performed by real-time polymerase chain reaction and, only for Adenovirus, by end-point polymerase chain reaction. Also, Cytomegalovirus genotypes were determined in patients that tested positive for this virus, by polymerase chain reaction directed towards the glycoprotein B gene and sequencing of the amplified fragments. These sequences were compared and aligned with a reference sequence, using the Clustal Omega Program. Results: The results of the study indicated that 77% of the patients had at least one of the five viruses detected and the virus with the highest prevalence was Cytomegalovirus, exhibiting 57% positivity in the total population studied. The most frequent Cytomegalovirus genotype detected was genotype 3. The viral load behavior was monitored for each virus analyzed as well as the incidence proportion between male and female patients. Conclusions. Viral quantification and characterization in transplant patients allows for better clinical management of patients with opportunistic infections and also a better management of pharmacological therapies.

[Cross-sectional study of the clinical characteristics and outcomes of children hospitalized with COVID-19 in Lima, Peru]. / Estudio transversal analítico de las características y desenlaces clínicos de niños hospitalizados con COVID-19 en Lima, Perú.

INTRODUCTION: Coronavirus 2019 (SARS-CoV-2) infection in children occurred in Peru as of March 2020, leading to pediatric patients' hospitalization in areas adapted for this purpose at the Edgardo Rebagliati Martins National Hospital. In the beginning, the demand for hospitalization was low, but it increased gradually. Consistent with international reports, the majority of patients presented mild or moderate symptoms. Nonetheless, there were also severe cases, even fatal ones. OBJECTIVES: To describe the characteristics and clinical outcome of pediatric patients with COVID-19 hospitalized in a referral hospital in Lima, Peru, between March and August 2020. METHODS: A descriptive and inferential cross-sectional study was carried out. The population includes all hospitalized patients in the Department of Pediatrics, with clinical and surgical diagnoses associated with COVID-19. RESULTS: We included 100 patients, with an average age of 83.4 ± 54 months, with a predominance of male patients (55%). Hospitalized patients were grouped into five categories: respiratory failure (17%), multisystemic inflammatory syndrome (MIS-C) (31%), neurological presentation (19%), acute abdomen (20%), and patients with oncological problems (13%). Most of the patients (74%) had comorbidities. Regarding the presenting symptoms, intestinal pain predominated in the appendicitis group (90%, p < 0.001), fever was present in most patients with respiratory failure (64.7%); multisystemic inflammatory syndrome (90.3%), neurological manifestations (15.8%), acute abdomen (50%) and oncological conditions (61.5%) were also present in these patients. Kawasaki symptoms were found in 38.7% of the patients with multisystemic inflammatory syndrome. Mortality was 4%. Respiratory problems (29.4%) and multisystemic inflammatory syndrome (22.6%) required admission to intensive care, more frequently than the other presentations (p = 0.008). CONCLUSIONS: We conclude that the vulnerability in the pediatric population is the one that has preexisting conditions. We divided our patients according to presentation, diagnosis, and complications, which were predominantly respiratory. We also had oncological patients with COVID-19.

INTRODUCCIÓN: La infección por coronavirus 2019 (SARS-CoV-2) en niños se presentó en Perú desde marzo del 2020. Desde entonces fue necesario internar pacientes pediátricos en el Hospital Nacional Edgardo Rebagliati Martins, en el área de hospitalización adaptada para dicho propósito. Al inicio, la demanda de hospitalización era baja y se fue incrementando progresivamente. Coincidiendo con los reportes internacionales, la mayoría presentó cuadros leves o moderados, pero también hubo casos graves e incluso mortales. OBJETIVOS: Describir las características y el desenlace clínico de los pacientes pediátricos con COVID-19 hospitalizados en un hospital de referencia en Lima, Perú, entre marzo y agosto de 2020. MÉTODOS: Se realizó un estudio transversal descriptivo e inferencial. La población incluyó a todos los pacientes que se hospitalizaron en el Departamento de Pediatría Clínica, con diagnósticos clínicos y quirúrgicos asociados a COVID-19. RESULTADOS: Incluimos 100 pacientes, con edad promedio de 83,4 ± 54 meses, con predominio de varones (55%). Los pacientes hospitalizados fueron agrupados en cinco categorías: insuficiencia respiratoria (17%), síndrome inflamatorio multisistémico (31%), presentación neurológica (19%), abdomen agudo (20%) y pacientes con problemas oncológicos (13%). La mayoría de los pacientes (74%) tenían comorbilidades. Respecto a los síntomas de presentación, el dolor intestinal predominó en el grupo de apendicitis (90%, p < 0,001), la fiebre estuvo presente en la mayoría de los pacientes con falla respiratoria (64,7%), el síndrome inflamatorio multisistémico se registró en 90,3%, la sintomatología neurológica en 15,8%, el abdomen agudo 50% y oncológicos en 61,5% de los pacientes. Los síntomas de Kawasaki estuvieron presentes en 38,7% de los pacientes con síndrome inflamatorio multisistémico. La mortalidad fue de 4%. En 29,4% de problemas respiratorios y en 22,6% de síndrome inflamatorio multisistémico, se requirió de admisión en cuidados intensivos, lo que fue más frecuente que las otras presentaciones (p = 0,008). CONCLUSIONES: Se concluye que la población pediátrica vulnerable es aquella con comorbilidades preexistentes. La división de pacientes en nuestro estudio fue definida por la presentación, diagnóstico y complicaciones predominantemente con problemas respiratorios, y en pacientes oncológicos con COVID-19.

Choice of cystometric technique impacts detrusor contractile dynamics in wistar rats.

The objective of the current animal study was to investigate factors contributing to the different phases of the cystometrogram (CMG) in order to address disparities in research data reported in the current literature. Three experiments in 20 female Wistar rats were designed to investigate (1) the effects of anesthesia on the contractile pattern of the bladder during micturition; (2) the impact of the physical characteristics of the CMG technique upon the accuracy of intra-vesical pressure recordings; and (3) identification of physiological and methodological factors associated with the emptying and rebound phases during CMG. Variables tested included awake versus urethane-anesthetized conditions, use of a single catheter for both filling and intra-vesical pressure (Pves) recording versus a separate two catheter approach, and comparisons between ureter, bladder dome, and urethral catheter placements. Both awake and anesthetized conditions contributed to variations in the shape and magnitude of the CMG pressure curves. In addition, catheter size, acute incision of the bladder dome for catheter placement, use of the same catheter for filling and Pves recordings, as well as the placement and positioning of the tubing, all contributed to alterations of the physiological properties and characteristic of the various CMG phases, including the frequent occurrence of an artificial rebound during the third phase of micturition. The present results demonstrate how different experimental conditions lead not only to variability in Pves curves, but consistency of the measurements as well, which needs to be accounted for when interpreting CMG outcome data.

Case Report: Differential Genomics and Evolution of a Meningeal Melanoma Treated With Ipilimumab and Nivolumab.

Primary melanocytic tumors of the CNS are extremely rare conditions, encompassing different disease processes including meningeal melanoma and meningeal melanocytosis. Its incidence range between 3-5%, with approximately 0.005 cases per 100,000 people. Tumor biological behavior is commonly aggressive, with poor prognosis and very low survivability, and a high recurrence rate, even after disease remission with multimodal treatments. Specific genetic alterations involving gene transcription, alternative splicing, RNA translation, and cell proliferation are usually seen, affecting genes like BRAF, TERT, GNAQ, SF3B1, and EIF1AX. Here we present an interesting case of a 59-year-old male presenting with neurologic symptoms and a further confirmed diagnosis of primary meningeal melanoma. Multiple therapy lines were used, including radiosurgery, immunotherapy, and chemotherapy. The patient developed two relapses and an evolving genetic makeup that confirmed the disease's clonal origin. We also provide a review of the literature on the genetic basis of primary melanocytic tumors of the CNS.

Age- and sex-dependent clinical equations to estimate glomerular filtration rates in children and young adults with chronic kidney disease.

Using data (2655 observations from 928 participants) from the Chronic Kidney Disease in Children Study, we developed and internally validated new glomerular filtration rate estimating equations for clinical use in children and young adults: two forms of K × [heigh(ht) / serum creatinine(sCr)] and two forms of K × [1 / cystatin C(cysC)]. For each marker, one equation used a sex-dependent K; in the other, K is sex-and age-dependent. Glomerular filtration rate (GFR) was measured directly by plasma iohexol disappearance. The equations using ht/sCr had sex-specific constants of 41.8 for males and 37.6 for females. In the age- dependent models, K increased monotonically for children 1-18 years old and was constant for young adults 18-25 years. For males, K ranged from 35.7 for one-year-olds to 50.8 for those 18 and older. For females, the values of K ranged from 33.1 to 41.4. Constant K values for cystatin-C equations were 81.9 for males and 74.9 for females. With age-dependency, K varied non-monotonically with the highest values at age 15 for males (K of 87.2) and 12 years for females (K of 79.9). Use of an age-dependent K with ht/sCr models reduced average bias, notably in young children and young adults; age-dependent cystatin-C models produced similar agreement to using a constant K in children under 18 years, but reduced bias in young adults. These age-dependent proposed equations were evaluated alongside estimated GFRs from 11 other published equations for pediatrics and young adults. Only our proposed equations yielded non- significant bias and within 30% accuracy values greater than 85% in both the pediatric and young adult subpopulations.