Mortality prediction models after radical cystectomy for bladder tumour: A systematic review and critical appraisal.

INTRODUCTION: To identify risk-predictive models for bladder-specific cancer mortality in patients undergoing radical cystectomy and assess their clinical utility and risk of bias. METHODS: Systematic review (CRD42021224626:PROSPERO) in Medline and EMBASE (from their creation until 31/10/2021) was screened to include articles focused on the development and internal validation of a predictive model of specific cancer mortality in patients undergoing radical cystectomy. CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies (CHARMS) and Prediction model Risk Of Bias ASsessment Tool (PROBAST) were applied. RESULTS: Nineteen observational studies were included. The main predictors were sociodemographic variables, such as age (18 studies, 94.7%) and sex (17, 89.5% studies), tumour characteristics (TNM stage (18 studies, 94.7%), histological subtype/grade (15 studies, 78.9%), lymphovascular invasion (10 studies, 52.6%) and treatment with chemotherapy (13 studies, 68.4%). C-index values were presented in 14 studies. The overall risk of bias assessed using PROBAST led to 100% of studies being classified as high risk (the analysis domain was rated to be at high risk of bias in all the studies), and 52.6% showed low applicability. Only 5 studies (26.3%) included an external validation and 2 (10.5%) included a prospective study design. CONCLUSIONS: Using clinical predictors to assess the risk of bladder-specific cancer mortality is a feasibility alternative. However, the studies showed a high risk of bias and their applicability is uncertain. Studies should improve the conducting and reporting, and subsequent external validation studies should be developed.

Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency.

Mitochondrial complex I deficiency results in a plethora of often severe clinical phenotypes manifesting in early childhood. Here, we report on three complex-I-deficient adult subjects with relatively mild clinical symptoms, including isolated, progressive exercise-induced myalgia and exercise intolerance but with normal later development. Exome sequencing and targeted exome sequencing revealed compound-heterozygous mutations in TMEM126B, encoding a complex I assembly factor. Further biochemical analysis of subject fibroblasts revealed a severe complex I deficiency caused by defective assembly. Lentiviral complementation with the wild-type cDNA restored the complex I deficiency, demonstrating the pathogenic nature of these mutations. Further complexome analysis of one subject indicated that the complex I assembly defect occurred during assembly of its membrane module. Our results show that TMEM126B defects can lead to complex I deficiencies and, interestingly, that symptoms can occur only after exercise.

A Heterozygous NDUFV1 Variant Aggravates Mitochondrial Complex I Deficiency in a Family with a Homoplasmic ND1 Variant.

We demonstrate that a heterozygous nuclear variant in the gene encoding mitochondrial complex I subunit NDUFV1 aggravates the cellular phenotype in the presence of a mitochondrial DNA variant in complex I subunit ND1. Our findings suggest that heterozygous variants could be more significant in inherited mitochondrial diseases than hitherto assumed.

Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and failure to thrive.

COX5A is a nuclear-encoded subunit of mitochondrial respiratory chain complex IV (cytochrome c oxidase). We present patients with a homozygous pathogenic variant in the COX5A gene. Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension, lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented. We show that the variant lies within the evolutionarily conserved COX5A/COX4 interface domain, suggesting that it alters the interaction between these two subunits during complex IV biogenesis. In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its subunits are reduced. Lentiviral complementation rescues complex IV deficiency. The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV biogenesis. A potential therapeutic lead is demonstrated by showing that copper supplementation leads to partial rescue of complex IV deficiency in patient fibroblasts.

Unraveling the complexity of mitochondrial complex I assembly: A dynamic process.

Mammalian complex I is composed of 44 different subunits and its assembly requires at least 13 specific assembly factors. Proper function of the mitochondrial respiratory chain enzyme is of crucial importance for cell survival due to its major participation in energy production and cell signaling. Complex I assembly depends on the coordination of several crucial processes that need to be tightly interconnected and orchestrated by a number of assembly factors. The understanding of complex I assembly evolved from simple sequential concept to the more sophisticated modular assembly model describing a convoluted process. According to this model, the different modules assemble independently and associate afterwards with each other to form the final enzyme. In this review, we aim to unravel the complexity of complex I assembly and provide the latest insights in this fundamental and fascinating process. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.

Mutations in mitochondrial complex I assembly factor NDUFAF3 cause Leigh syndrome.

NDUFAF3 is an assembly factor of mitochondrial respiratory chain complex I. Variants in NDUFAF3 have been identified as a cause of severe multisystem mitochondrial disease. In a patient presenting with Leigh syndrome, which has hitherto not been described as a clinical feature of NDUFAF3 deficiency, we identified a novel homozygous variant and confirmed its pathogenicity in patient fibroblasts studies. Furthermore, we present an analysis of complex I assembly routes representative of each functional module and, thereby, link NDUFAF3 to a specific step in complex I assembly. Therefore, our report expands the phenotype of NDUFAF3 deficiency and further characterizes the role of NDUFAF3 in complex I biogenesis.

Cell survival during complete nutrient deprivation depends on lipid droplet-fueled ß-oxidation of fatty acids.

Cells exposed to stress of different origins synthesize triacylglycerols and generate lipid droplets (LD), but the physiological relevance of this response is uncertain. Using complete nutrient deprivation of cells in culture as a simple model of stress, we have addressed whether LD biogenesis has a protective role in cells committed to die. Complete nutrient deprivation induced the biogenesis of LD in human LN18 glioblastoma and HeLa cells and also in CHO and rat primary astrocytes. In all cell types, death was associated with LD depletion and was accelerated by blocking LD biogenesis after pharmacological inhibition of Group IVA phospholipase A2 (cPLA2α) or down-regulation of ceramide kinase. Nutrient deprivation also induced ß-oxidation of fatty acids that was sensitive to cPLA2α inhibition, and cell survival in these conditions became strictly dependent on fatty acid catabolism. These results show that, during nutrient deprivation, cell viability is sustained by ß-oxidation of fatty acids that requires biogenesis and mobilization of LD.

Genitourinary Lesions Due to Monkeypox.

BACKGROUND: Since May 2022, 31 000 cases of monkeypox infection have been reported in nonendemic areas. OBJECTIVE: To describe a series of cases of monkeypox with genitourinary involvement. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective observational study of men diagnosed with monkeypox disease with genitourinary involvement. RESULTS AND LIMITATIONS: A total of 14 patients were recruited. The median age was 42 yr. Of these patients, 43% sought a consultation for genitourinary symptomatology, and 71% had engaged in sex with other men. Eight patients (57%) were positive for human immunodeficiency virus, one diagnosed synchronously; the remainder had a median CD4 count of 663/µl. Six patients (43%) had a different sexually transmitted disease. Penile oedema was present in 43% of patients and two patients required surgical exploration. CONCLUSIONS: Genitourinary involvement is frequent in monkeypox disease and is often the reason for the consultation visit. PATIENTS SUMMARY: In this report we looked at how monkeypox disease can affect the genitourinary area, causing swelling of the penis or skin lesions.

Efficacy, tolerance and predictors of response to the treatment with hyperbaric oxygen therapy for patients with hemorrhagic radiation cystitis.

OBJECTIVES: The aim was to study the efficacy and tolerance in patients with haemorrhagic radiation-induced cystitis (HRC) treated with hyperbaric oxygen therapy (HOT) and analyze which factors were related to the response to the treatment. MATERIAL AND METHODS: We performed a retrospective cohort study of patients treated with HOT for HRC symptoms in a provincial referral centre from 2010 to 2020. We evaluated clinical response to treatment, number of hospitalizations due to HRC and subjective response using the PGI-I questionnaire. RESULTS: We treated 52 patients, with a median of 30 sessions, during 6 months and 40 months (6-68 months) of follow-up. 69.2%of patients responded completely and 21,2% partially. The 53.2% of patients improved before the first 10 sessions. Reduction of hospitalizations/per year due to haematuria from 2.8 to 1.1 (p=0,001). The 73,5% of patients stated that they were "very much better" or "much better" after treatment. During the follow-up, 15.4% of patients had recurrence of HRC. 9.6% of the patients required salvage cystectomy. The patients with a highest RTOG-EORTC scale had more risk to still with symptoms (OR 3.01 (IC95 1.48 - 6.16). All patients were able to complete the proposed treatment plan with good tolerance to HOT. CONCLUSIONS: These results show the clinical benefit of HOT in the treatment of HRC, with a reduction of the number of hospitalizations and a subjective improvement.

Molecular mechanisms of ß-cell dysfunction and death in monogenic forms of diabetes.

Monogenetic forms of diabetes represent 1%-5% of all diabetes cases and are caused by mutations in a single gene. These mutations, that affect genes involved in pancreatic ß-cell development, function and survival, or insulin regulation, may be dominant or recessive, inherited or de novo. Most patients with monogenic diabetes are very commonly misdiagnosed as having type 1 or type 2 diabetes. The severity of their symptoms depends on the nature of the mutation, the function of the affected gene and, in some cases, the influence of additional genetic or environmental factors that modulate severity and penetrance. In some patients, diabetes is accompanied by other syndromic features such as deafness, blindness, microcephaly, liver and intestinal defects, among others. The age of diabetes onset may also vary from neonatal until early adulthood manifestations. Since the different mutations result in diverse clinical presentations, patients usually need different treatments that range from just diet and exercise, to the requirement of exogenous insulin or other hypoglycemic drugs, e.g., sulfonylureas or glucagon-like peptide 1 analogs to control their glycemia. As a consequence, awareness and correct diagnosis are crucial for the proper management and treatment of monogenic diabetes patients. In this chapter, we describe mutations causing different monogenic forms of diabetes associated with inadequate pancreas development or impaired ß-cell function and survival, and discuss the molecular mechanisms involved in ß-cell demise.

[Metabolic alterations and stones in patients with orthotopic ileal diversions. Case description.] / Alteraciones metabólicas y litiasis en pacientes con derivación ileal ortotópica. A propósito de un caso.

OBJECTIVE: Bacterial presence, anatomic anomalies and metabolic alterations increase the risk of stone formation in patients with neobladders. These patients sometimes require medical or surgical procedures. The aim of the current work is to analyze those alterations and medical treatment associated to it. METHODS: A case of a 66 yo male who had undergone a cystectomy with neobladder 3 years ago. Currently present with a staghorn stone on the right kidney. Past medical history of stone formation as well as double J calcification. RESULTS: The combination of medical and surgical treatment for stone was performed. Medical therapy will allow prevention of new stones. CONCLUSIONS: Metabolic and chronic infections in patients with neobladders treated should decreased the new stone formation in patients with neobladders.

OBJETIVO: La colonización bacteriana, las alteraciones anatómicas y las anomalías metabólicas aumentan el riesgo de litiasis en los pacientes con neovejiga, precisando en muchas ocasiones de un abordaje médico y quirúrgico complejo. El objetivo del trabajo es analizar dichas alteraciones y el tratamiento médico de las mismas. MÉTODOS: Se presenta el caso de un varón de 66 años con antecedente de cistectomía más derivación ortotópica desde hace tres años, el cual presenta litiasis coraliforme en riñón derecho. Antecedentes de varias litiasis, así como calcificación de doble J. RESULTADO: Mediante la combinación de tratamientos médicos y quirúrgicos se tratan las litiasis del paciente, siendo especialmente importante el manejo médico en la prevención de futuros eventos litiásicos. CONCLUSIONES: Diagnosticar y tratar las alteraciones metabólicas y las infecciones crónicas en pacientes con neovejiga puede reducir la aparición de litiasis en los pacientes con neovejiga.

Transurethral Drainage of Prostatic Abscess Using 120 W Holmium Laser Technology.

Introduction: Prostatic abscess is an infrequent but serious pathology that could be treated by ultrasound-guided puncture, transurethral resection, or open surgery. Case Report: We present a case of a 72-year-old male with a 3x5 cm prostatic abscess in the right lobe showed in abdominal computed tomography (CT). In the blood test, he presented coagulopathy. Urgent transurethral drainage by holmium laser was decided to be performed. It started with incision and opening of the right prostatic lobe with an energy of 1.2 J and a frequency of 20 Hz with a total power of 24 W. A 550-micron fiber was used for this technique. Coagulation of the area was performed with a power of 20 W. The postoperative course was uneventful. Conclusion: The holmium laser appears to be an effective alternative in the treatment of this pathology in patients with coagulation disorders by providing adequate hemostatic control.

TMEM70 functions in the assembly of complexes I and V.

Protein complexes from the oxidative phosphorylation (OXPHOS) system are assembled with the help of proteins called assembly factors. We here delineate the function of the inner mitochondrial membrane protein TMEM70, in which mutations have been linked to OXPHOS deficiencies, using a combination of BioID, complexome profiling and coevolution analyses. TMEM70 interacts with complex I and V and for both complexes the loss of TMEM70 results in the accumulation of an assembly intermediate followed by a reduction of the next assembly intermediate in the pathway. This indicates that TMEM70 has a role in the stability of membrane-bound subassemblies or in the membrane recruitment of subunits into the forming complex. Independent evidence for a role of TMEM70 in OXPHOS assembly comes from evolutionary analyses. The TMEM70/TMEM186/TMEM223 protein family, of which we show that TMEM186 and TMEM223 are mitochondrial in human as well, only occurs in species with OXPHOS complexes. Our results validate the use of combining complexome profiling with BioID and evolutionary analyses in elucidating congenital defects in protein complex assembly.

[Androgen deprivation therapy in advanced prostate cancer. Multicenter study.] / Terapia de deprivación androgénica en cáncer de próstata avanzado. Estudio multicéntrico.

OBJECTIVES: Advanced prostate cancer (PC) is a frequent entity. The objectives of this paper are the presentation of a sample of patients with PC undergoing treatment with androgen deprivation therapy (ADT) in usual clinical practice and the determination of parameters associated with the development of resistance to castration (CRPC). MATERIAL AND METHODS: Multicenter, observational, retrospective study that analyzes patients treated with ADT from January 2016 to January 2017. Descriptive analysis of the most relevant clinical variables and univariante analysis and progression times by Kaplan-Meier test. RESULTS: Sample of 952 patients. At PC diagnosis median age 74 years. Median PSA at PC diagnosis 23 ng/ml, when begining ADT 20.2 ng/ml. 80.2% of patients were biopsied at PC diagnosis: 28.2% Gleason score group 1, 38.7% groups 2 and 3 and 33.1% groups 4 and 5. Initial treatment of PC: 75.9% ADT, radical prostatectomy 8.4% and radiotherapy 15.1%. Of the 952 patients, 281 (29.6%) fulfilled CRPC criteria.In this group 21.7% achieved undetectable PSA (group in which it was 59.9%. Increased probability of progression to CRPC in: PSA >30ng/ml at PC diagnosis (p=0.000, OR 2.78), Gleason score group 4-5 (p=0.000, OR 2.33), and not to reach undetectable PSA after ADT (p <0.001, OR 3.32). The initial ADT group presents progression to metastatic CRPC more rapidly in unfavourable histology and when not reached undetectable PSA after ADT. CONCLUSIONS: We present a sample of patients with advanced PC in treatment with ADT that shows heterogeneity in usual clinical practice. In our sample, elevated PSA at PC diagnosis, unfavorable histology and failure to achieve a PSA<0.1 ng/ml after ADT is presented as an indicator of progression to the CRPC stage.

OBJETIVO: El cáncer de próstata (CP) avanzado es una entidad frecuente. Los objetivos de este trabajo son la presentación de una serie de pacientes con CP en tratamiento con Terapia de Deprivación Androgénica (TDA) en práctica clínica habitual y la determinación de parámetros asociados al desarrollo de resistencia a la castración (CPRC).MATERIAL Y MÉTODOS: Estudio multicéntrico,  observacional, retrospectivo que analiza pacientes tratados con TDA desde enero 2016 hasta enero 2017. Análisis descriptivo de las variables clínicas más relevantes, análisis univariante y supervivencia libre de progresión mediante test Kaplan-Meier. RESULTADOS: Muestra 952 pacientes. Al diagnóstico del CP edad mediana 74 años. Mediana de PSA al diagnóstico de CP 23 ng/ml, al inicio TDA 20,2 ng/ml. El 80,2% de pacientes tenían biopsia al diagnóstico del CP: 28,2% grado pronóstico Gleason grupo 1, 38,7% grados 2 y 3 y 33,1% grados 4 y 5. Tratamiento inicial del CP: 75,9% TDA, prostatectomía radical 8,4% y radioterapia 15,1%.De los 952 pacientes, 281 (29,6%) cumplían criterios de CPRC. En este grupo el 21,7% alcanzó PSA indetectable (<0,1 ng/ml) con la TDA 20,2  frente al grupo no CPRC en el que lo alcanzaron el 59,9%. Encontramos mayor probabilidad de progresión a CPRC en pacientes con PSA al diagnóstico de CP >30 ng/ml (p=0,000, OR 2,78), grado pronóstico Gleason grupos 4-5 (p=0,000, OR 2,33) y en aquellos que no alcanzan PSA indetectable tras TDA (p<0,01, OR 3,32) variables que se relacionan con los tiempos de progresión a CPRC y especialmente al estadio metastásico. CONCLUSIONES: Se presenta una serie de pacientes CP avanzado en tratamiento con TDA que muestra heterogeneidad de características y de manejo según práctica clínica habitual. En nuestra serie el PSA elevado al diagnóstico, histología desfavorable y no alcanzar un PSA<0,1 ng/ml tras la TDA se presentan como indicadores de progresión a estadio CPRC.

NDUFAF4 variants are associated with Leigh syndrome and cause a specific mitochondrial complex I assembly defect.

Mitochondrial respiratory chain complex I consists of 44 different subunits and can be subgrouped into three functional modules: the Q-, the P- and the N-module. NDUFAF4 (C6ORF66) is an assembly factor of complex I that associates with assembly intermediates of the Q-module. Via exome sequencing, we identified a homozygous missense variant in a complex I-deficient patient with Leigh syndrome. Supercomplex analysis in patient fibroblasts revealed specifically altered stoichiometry. Detailed assembly analysis of complex I, indicative of all of its assembly routes, showed an accumulation of parts of the P- and the N-module but not the Q-module. Lentiviral complementation of patient fibroblasts with wild-type NDUFAF4 rescued complex I deficiency and the assembly defect, confirming the causal role of the variant. Our report on the second family affected by an NDUFAF4 variant further characterizes the phenotypic spectrum and sheds light into the role of NDUFAF4 in mitochondrial complex I biogenesis.