Incidence of Erectile Dysfunction and Testosterone Deficiency in Testicular Cancer Survivors.

PURPOSE: This project aims to characterize the incidence of men's health disorders, specifically focusing on the incidence of erectile dysfunction (ED) and testosterone deficiency (TD) in a large, nationwide study of Testicular cancer (TC) survivors treated in a centralized healthcare system. PATIENTS AND METHODS: We conducted a retrospective cohort study of US Veterans diagnosed with TC from 1990 to 2021. These were compared to an age and race-matched control group of US Veterans without a diagnosis of TC. ED and TD were defined by the presence of diagnosis codes or at least a 6-months prescription for medications treating these conditions or both. Time was measured from date of TC diagnosis (for TC patients, and matched TC patient date for the corresponding non-cancer controls). Impact of chemotherapy among TC survivors on ED and TD was evaluated using multivariable Cox regression models. RESULTS: The cohort included 1754 patients with TC compared to 7117 non-cancer controls, with a mean age at diagnosis of 42 years. TC patients were significantly more likely than controls to experience ED (hazard ratio 2.97, 95% CI 2.68 to 3.28, P < .001) and TD (hazard ratio 6.71, 95% CI 5.78-7.81, P < .001). However, within the TC group, there was no significant difference in the incidence of ED and TD when stratified by receipt of chemotherapy (P = .9 and P = .066, respectively). CONCLUSIONS: Men's health disorders arise commonly in the lives of TC survivors. It is important for treating physicians to identify these and conduct sexual health assessments as part of survivorship care.

Defining and Improving Outcomes Measurement for Virtual Care: Report from the VHA State-of-the-Art Conference on Virtual Care.

Virtual care, including synchronous and asynchronous telehealth, remote patient monitoring, and the collection and interpretation of patient-generated health data (PGHD), has the potential to transform healthcare delivery and increase access to care. The Veterans Health Administration (VHA) Office of Health Services Research and Development (HSR&D) convened a State-of-the-Art (SOTA) Conference on Virtual Care to identify future virtual care research priorities. Participants were divided into three workgroups focused on virtual care access, engagement, and outcomes. In this article, we report the findings of the Outcomes Workgroup. The group identified virtual care outcome areas with sufficient evidence, areas in need of additional research, and areas that are particularly well-suited to be studied within VHA. Following a rigorous process of literature review and consensus, the group focused on four questions: (1) What outcomes of virtual care should we be measuring and how should we measure them?; (2) how do we choose the "right" care modality for the "right" patient?; (3) what are potential consequences of virtual care on patient safety?; and (4) how can PGHD be used to benefit provider decision-making and patient self-management?. The current article outlines key conclusions that emerged following discussion of these questions, including recommendations for future research.

Improving Veteran Engagement with Virtual Care Technologies: a Veterans Health Administration State of the Art Conference Research Agenda.

Although the availability of virtual care technologies in the Veterans Health Administration (VHA) continues to expand, ensuring engagement with these technologies among Veterans remains a challenge. VHA Health Services Research & Development convened a Virtual Care State of The Art (SOTA) conference in May 2022 to create a research agenda for improving virtual care access, engagement, and outcomes. This article reports findings from the Virtual Care SOTA engagement workgroup, which comprised fourteen VHA subject matter experts representing VHA clinical care, research, administration, and operations. Workgroup members reviewed current evidence on factors and strategies that may affect Veteran engagement with virtual care technologies and generated key questions to address evidence gaps. The workgroup agreed that although extensive literature exists on factors that affect Veteran engagement, more work is needed to identify effective strategies to increase and sustain engagement. Workgroup members identified key priorities for research on Veteran engagement with virtual care technologies through a series of breakout discussion groups and ranking exercises. The top three priorities were to (1) understand the Veteran journey from active service to VHA enrollment and beyond, and when and how virtual care technologies can best be introduced along that journey to maximize engagement and promote seamless care; (2) utilize the meaningful relationships in a Veteran's life, including family, friends, peers, and other informal or formal caregivers, to support Veteran adoption and sustained use of virtual care technologies; and (3) test promising strategies in meaningful combinations to promote Veteran adoption and/or sustained use of virtual care technologies. Research in these priority areas has the potential to help VHA refine strategies to improve virtual care user engagement, and by extension, outcomes.

Ultra-photostable DNA FluoroCubes: Mechanism of Photostability and Compatibility with FRET and Dark Quenching.

DNA-based FluoroCubes were recently developed as a solution to photobleaching, a ubiquitous limitation of fluorescence microscopy (Niekamp; ; Stuurman; ; Vale Nature Methods, 2020). FluoroCubes, that is, compact ∼4 × 4 × 5.4 nm3 four-helix bundles coupled to ≤6 fluorescent dyes, remain fluorescent up to ∼50× longer than single dyes and emit up to ∼40× as many photons. The current work answers two important questions about the FluoroCubes. First, what is the mechanism by which photostability is enhanced? Second, are FluoroCubes compatible with Förster resonance energy transfer (FRET) and similar techniques? We use single particle photobleaching studies to show that photostability arises through interactions between the fluorophores and the four-helix DNA bundle. Supporting this, we discover that smaller ∼4 × 4 × 2.7 nm3 FluoroCubes also confer ultraphotostability. However, we find that certain dye-dye interactions negatively impact FluoroCube performance. Accordingly, 4-dye FluoroCubes lacking these interactions perform better than 6-dye FluoroCubes. We also demonstrate that FluoroCubes are compatible with FRET and dark quenching applications.

Sisyphus observed: Unraveling the high ATP usage of an RNA chaperone.

DEAD-box proteins are nonprocessive RNA helicases that can function as RNA chaperones by coupling ATP binding and hydrolysis to structural reorganization of RNA. Here, Jarmoskaite et al. quantify the ATP utilization of an RNA chaperone during refolding of a misfolded ribozyme substrate. Strikingly, 100 ATP hydrolysis events are needed per successfully refolded ribozyme, suggesting that each round of unfolding requires ten ATP molecules, since 90% of substrate unfolding cycles only lead back to the kinetically favored misfolded state. This near-Sisyphean effort reveals a potentially conserved model for RNA reorganization by RNA chaperones.

Tumor histology is an independent prognostic factor in locally advanced cervical carcinoma: A retrospective study.

BACKGROUND: Even with different histologic origins, squamous cell carcinoma (SCC) and adenocarcinoma (AC) are considered a single entity, and the first-line treatment is the same. Locally advanced disease at the diagnosis of cervical cancer is the most important prognostic factor, the recurrence rate is high, making it necessary to evaluate prognostic factors other than clinical or radiological staging; histology could be one of them but continues to be controversial. The aim of this study was to evaluate tumor histology as a prognostic factor in terms of treatment outcomes, disease-free survival (DFS) and overall survival (OS) in a retrospective cohort of patients with Locally Advanced Cervical Carcinoma (LACC). METHODS: The records of 1291patients with LACC were reviewed, all of them were treated with 45-50 Gy of external beam radiotherapy with concurrent chemotherapy and brachytherapy. A descriptive and comparative analysis was conducted. Treatment response was analyzed by the chi-square test; DFS and OS were calculated for each histology with the Kaplan-Meier method and compared with the log-rank test; and the Cox model was applied for the multivariate analysis. RESULTS: We included 1291 patients with LACC treated from 2005 to 2014, of which 1154 (89·4%) had SCC and 137 (10·6%) had AC. Complete response to treatment was achieved in 933 (80·8%) patients with SCC and 113 (82·5%) patients with AC. Recurrence of the disease was reported in 29·9% of SCC patients and 31·9% of AC patients. Five-year DFS was 70% for SCC and 62·2% for AC. The five-year OS rates were 74·3% and 60% for SCC and AC, respectively. The mean DFS was 48·8 months for SCC vs 46·10 for AC (p = 0·043), the mean OS was 50·8 for SCC and 47·0 for AC (p = 0·002). CONCLUSION: Our findings support the hypothesis that SCC and AC are different clinical entities. TRIAL REGISTRATION: NCT04537273 .

The use of readily available laboratory tests for the identification of the emerging yeast Candida auris in Mexico.

Identification of the emerging multidrug-resistant yeast Candida auris is challenging. Here, we describe the role of the Mexico national reference laboratory Instituto de Diagnóstico y Referencia Epidemiológicos Dr. Manuel Martínez Báez (InDRE) and the Mexican national laboratory network in the identification of C. auris. Reference identification of six suspected isolates was done based on phenotypic and molecular laboratory methods, including growth in special media, evaluation of isolate micromorphology, and species-specific PCR and pan-fungal PCR and sequencing. The four C. auris isolates identified were able to grow on modified Sabouraud agar with 10% NaCl incubated at 42 °C. With one exception, isolates of C. auris were spherical to ovoid yeast-like cells and blastoconidia, with no hyphae or pseudohyphae on cornmeal agar. C. auris isolates were resistant to fluconazole. Species-specific and pan-fungal PCR confirmed isolates as C. auris. Sequence analysis revealed the presence of two different C. auris clades in Mexico, clade I (South Asia) and clade IV (South America).

Complete genome sequence of a coxsackievirus type A24 variant causing an outbreak of acute haemorrhagic conjunctivitis in southeastern Mexico in 2017.

Cases of acute haemorrhagic conjunctivitis (AHC) caused by a coxsackie virus A24 variant (CV-A24v) in Mexico have been reported since 1987; however, no molecular data on the causative strains have been available. Here, we report the identification of the etiological agent responsible for the most recent AHC outbreak in southeastern Mexico (at the end of 2017) as well as the complete genome sequences of seven isolates, using next-generation sequencing (NGS). Phylogenomic analysis of the CV-A24v sequences reported here showed similarity to contemporary strains causing AHC outbreaks in French Guiana and Uganda, forming a novel clade related to genotype IV. Moreover, a specific mutational pattern in the non-structural proteins was identified in the 2017 isolates. This is the first report of genetic characterization of CV-A24v isolates obtained in Mexico.

The role of heparin in endovascular repair of blunt thoracic aortic injury.

OBJECTIVE: Early diagnosis and treatment are essential to improve survival of patients with blunt thoracic aortic injury (BTAI). Often, aortic surgical intervention may be delayed because of increased risk of bleeding with heparin, particularly in polytrauma victims. We believe that surgical delay may be remedied by proceeding without heparinization. This study reviewed the outcome of patients subjected to thoracic endovascular aortic repair (TEVAR) under full, low-dose, and no intraoperative systemic heparinization. METHODS: There were 77 cases of confirmed BTAI identified and retrospectively analyzed at a high-volume urban trauma center during a period of 15 years (March 2003-September 2017). Patients were stratified into three groups on the basis of the intraoperative use of heparin during TEVAR, as follows: full heparin (FH), low-dose heparin (LH), and no heparin (NH). Baseline characteristics including the patients' demographics, diagnostic laboratory data and imaging studies, operative reports, postoperative complications, embolic and bleeding outcomes, and mortality data were reviewed. RESULTS: Of the 77 total patients who underwent TEVAR for BTAI, 42 patients received full-dose heparinization, 18 received low-dose heparin, and 17 had no use of systemic heparin. There was no significant difference in age, sex, body mass index, or smoking history. The most common mechanism of injury was motor vehicle collision. Grade 3 (pseudoaneurysm) was the predominant type of BTAI (FH, 69.0%; LH, 61.1%; NH, 76.5%; P = .23). The mean interval between admission and repair was three times longer in the FH group than in the NH group (FH, 2.33 days; NH, 0.76 day; P = .091). The mean time in the intensive care unit was shorter in the NH group vs the FH group (15 days vs 26.21 days; P = .025). Thromboembolic and bleeding outcomes and mortality rates were comparable in all three groups; 57 patients continued follow-up for a mean time of 30.99 months. CONCLUSIONS: Our study shows no statistically significant difference in outcomes between the heparinized and nonheparinized groups. The primary benefit of the NH group is seen in time to repair. Although not statistically significant, the mean time to repair was three times longer in the FH group. Patients in the NH group also benefited from prompt intervention and treatment. Therefore, intraoperative heparinization in critically ill patients with BTAI undergoing TEVAR remains at the surgeon's discretion, although the lack of heparinization appears to be a safe and potentially faster alternative, particularly in the polytrauma patient.

Escherichia coli DnaK Allosterically Modulates ClpB between High- and Low-Peptide Affinity States.

ClpB and DnaKJE provide protection to Escherichia coli cells during extreme environmental stress. Together, this co-chaperone system can resolve protein aggregates, restoring misfolded proteins to their native form and function in solubilizing damaged proteins for removal by the cell's proteolytic systems. DnaK is the component of the KJE system that directly interacts with ClpB. There are many hypotheses for how DnaK affects ClpB-catalyzed disaggregation, each with some experimental support. Here, we build on our recent work characterizing the molecular mechanism of ClpB-catalyzed polypeptide translocation by developing a stopped-flow FRET assay that allows us to detect ClpB's movement on model polypeptide substrates in the absence or presence of DnaK. We find that DnaK induces ClpB to dissociate from the polypeptide substrate. We propose that DnaK acts as a peptide release factor, binding ClpB and causing the ClpB conformation to change to a low-peptide affinity state. Such a role for DnaK would allow ClpB to rebind to another portion of an aggregate and continue nonprocessive translocation to disrupt the aggregate.

Genotypic variability analysis of DENV-1 in Mexico reveals the presence of a novel Mexican lineage.

Here, we report for the first time the circulation of dengue virus type 1 (DENV-1) belonging to the lineage IV of genotype V (African American genotype) based on phylogenetic analysis of nucleotide sequences from 10 DENV-1-positive samples obtained in Mexico between 2012 and 2014. Our data revealed that the lineages III and IV of DENV-1 genotype V were found circulating during the same period, probably explaining the rise in the number of cases of severe dengue during that period.

The cluster [Re6Se8I6]3- penetrates biological membranes: drug-like properties for CNS tumor treatment and diagnosis.

Tumorigenic cell lines are more susceptible to [Re6Se8I6]3- cluster-induced death than normal cells, becoming a novel candidate for cancer treatment. Still, the feasibility of using this type of molecules in human patients remains unclear and further pharmacokinetics analysis is needed. Using coupled plasma optical emission spectroscopy, we determined the Re-cluster tissue content in injected mice, as a biodistribution measurement. Our results show that the Re-cluster successfully reaches different tissues, accumulating mainly in heart and liver. In order to dissect the mechanism underlying cluster biodistribution, we used three different experimental approaches. First, we evaluate the degree of lipophilicity by determining the octanol/water partition coefficient. The cluster mostly remained in the octanol fraction, with a coefficient of 1.86 ± 0.02, which indicates it could potentially cross cell membranes. Then, we measured the biological membrane penetration through a parallel artificial membrane permeability assays (PAMPA) assay. The Re-cluster crosses the artificial membrane, with a coefficient of 122 nm/s that is considered highly permeable. To evaluate a potential application of the Re-cluster in central nervous system (CNS) tumors, we analyzed the cluster's brain penetration by exposing cultured blood-brain-barrier (BBB) cells to increasing concentrations of the cluster. The Re-cluster effectively penetrates the BBB, reaching nearly 30% of the brain side after 24 h. Thus, our results indicate that the Re-cluster penetrates biological membranes reaching different target organs-most probably due to its lipophilic properties-becoming a promising anti-cancer drug with high potential for CNS cancer's diagnosis and treatment.

[Primary squamous cell carcinoma of the stomach. Report of three cases]. / Carcinoma epidermoide primario del estómago. Reporte de tres casos.

Gastric squamous cell carcinoma (SCC) is a rare type of cancer. We report three patients with the tumor. A 65 years old male presenting with weight los and heartburn. An upper gastrointestinal endoscopy revealed an ulcerated tumor whose biopsy disclosed a gastric epidermoid carcinoma. The patient was operated and chemotherapy was attempted, but he died five months later. A 39 years old male with an antral tumor corresponding to an epidermoid carcinoma. He was operated and received chemotherapy and radiotherapy and died one year later. A 79 years old female with a distal antral tumor corresponding to a undifferentiated epidermoid carcinoma. She received palliative therapy and died two months later.

Avidity for Polypeptide Binding by Nucleotide-Bound Hsp104 Structures.

Recent Hsp104 structural studies have reported both planar and helical models of the hexameric structure. The conformation of Hsp104 monomers within the hexamer is affected by nucleotide ligation. After nucleotide-driven hexamer formation, Hsp104-catalyzed disruption of protein aggregates requires binding to the peptide substrate. Here, we examine the oligomeric state of Hsp104 and its peptide binding competency in the absence of nucleotide and in the presence of ADP, ATPγS, AMPPNP, or AMPPCP. Surprisingly, we found that only ATPγS facilitates avid peptide binding by Hsp104. We propose that the modulation between high- and low-peptide affinity states observed with these ATP analogues is an important component of the disaggregation mechanism of Hsp104.

Molecular characterization of atypical antigenic variants of canine rabies virus reveals its reintroduction by wildlife vectors in southeastern Mexico.

Rabies is an infectious viral disease that is practically always fatal following the onset of clinical signs. In Mexico, the last case of human rabies transmitted by dogs was reported in 2006 and canine rabies has declined significantly due to vaccination campaigns implemented in the country. Here we report on the molecular characterization of six rabies virus strains found in Yucatan and Chiapas, remarkably, four of them showed an atypical reaction pattern when antigenic characterization with a reduced panel of eight monoclonal antibodies was performed. Phylogenetic analyses on the RNA sequences unveiled that the three atypical strains from Yucatan are associated with skunks. Analysis using the virus entire genome showed that they belong to a different lineage distinct from the variants described for this animal species in Mexico. The Chiapas atypical strain was grouped in a lineage that was considered extinct, while the others are clustered within classic dog variants.

Fatal Psychrobacter sp. infection in a pediatric patient with meningitis identified by metagenomic next-generation sequencing in cerebrospinal fluid.

The genus Psychrobacter contains environmental, psychrophilic and halotolerant gram-negative bacteria considered rare opportunistic pathogens in humans. Metagenomics was performed on the cerebrospinal fluid (CSF) of a pediatric patient with meningitis. Nucleic acids were extracted, randomly amplified, and sequenced with the 454 GS FLX Titanium next-generation sequencing (NGS) system. Sequencing reads were assembled, and potential virulence genes were predicted. Phylogenomic and phylogenetic studies were performed. Psychrobacter sp. 310 was identified, and several virulence genes characteristic of pathogenic bacteria were found. The phylogenomic study and 16S rRNA gene phylogenetic analysis showed that the closest relative of Psychrobacter sp. 310 was Psychrobacter sanguinis. To our knowledge, this is the first report of a meningitis case associated with Psychrobacter sp. identified by NGS metagenomics in CSF from a pediatric patient. The metagenomic strategy based on NGS was a powerful tool to identify a rare unknown pathogen in a clinical case.

Association between Eating Behavior and Academic Performance in University Students.

OBJECTIVE: To determine the association between academic performance and eating behavior in university students in Chile. METHODS: A total of 680 college students, 409 (60%) women and 271 (40%) men, were randomly recruited and the mean age of the entire sample was 26. The Three-Factor Eating Questionnaire (TFEQ), which evaluates 3 dimensions of eating behavior-cognitive restriction (limiting own intake), uncontrolled eating (inclination to eat), and emotional eating (control of food intake in the context of negative emotions)-was used. Academic performance was measured by the grade point average (GPA) and was associated with eating behavior. RESULTS: Women had significantly higher scores in the "emotional eating" dimension than men (p = 0.002). The eating behavior analysis showed that female students with higher GPAs (above 5.5) had statistically significantly lower uncontrolled eating scores (p = 0.03) and higher cognitive restriction scores (p = 0.05) than women with lower academic performance (below 5.5). There were no significant associations between eating behavior and academic performance in men. CONCLUSIONS: A positive association between eating behavior and academic performance was observed in female university students in Chile. Further studies are needed to explore the causes of this association and determine how to improve the nutritional habits of this population.

Escherichia coli ClpB is a non-processive polypeptide translocase.

Escherichia coli caseinolytic protease (Clp)B is a hexameric AAA+ [expanded superfamily of AAA (ATPase associated with various cellular activities)] enzyme that has the unique ability to catalyse protein disaggregation. Such enzymes are essential for proteome maintenance. Based on structural comparisons to homologous enzymes involved in ATP-dependent proteolysis and clever protein engineering strategies, it has been reported that ClpB translocates polypeptide through its axial channel. Using single-turnover fluorescence and anisotropy experiments we show that ClpB is a non-processive polypeptide translocase that catalyses disaggregation by taking one or two translocation steps followed by rapid dissociation. Using single-turnover FRET experiments we show that ClpB containing the IGL loop from ClpA does not translocate substrate through its axial channel and into ClpP for proteolytic degradation. Rather, ClpB containing the IGL loop dysregulates ClpP leading to non-specific proteolysis reminiscent of ADEP (acyldepsipeptide) dysregulation. Our results support a molecular mechanism where ClpB catalyses protein disaggregation by tugging and releasing exposed tails or loops.