Children with disorders of sex development: A qualitative study of early parental experience

<p>Abstract</p> <p>Background</p> <p>Clinical research on psychological aspects of disorders of sex development (DSD) has focused on psychosexual differentiation with relatively little attention directed toward parents' experiences of early clinical management and their influence on patient and family psychosocial adaptation.</p> <p>Objectives</p> <p>To characterize parental experiences in the early clinical care of children born with DSD.</p> <p>Study Design</p> <p>Content analysis of interviews with parents (n = 41) of 28 children, newborn to 6 years, with DSD.</p> <p>Results</p> <p>Four major domains emerged as salient to parents: (1) the gender assignment process, (2) decisions regarding genital surgery, (3) disclosing information about their child's DSD, and (4) interacting with healthcare providers. Findings suggested discordance between scientific and parental understandings of the determinants of "sex" and "gender." Parents' expectations regarding the benefits of genital surgery appear largely met; however, parents still had concerns about their child's future physical, social and sexual development. Two areas experienced by many parents as particularly stressful were: (1) uncertainties regarding diagnosis and optimal management, and (2) conflicts between maintaining privacy versus disclosing the condition to access social support.</p> <p>Conclusions</p> <p>Parents' experiences and gaps in understanding can be used to inform the clinical care of patients with DSD and their families. Improving communication between parents and providers (and between parents and their support providers) throughout the early clinical management process may be important in decreasing stress and improving outcomes for families of children with DSD.</p

Effects of human anti-spike protein receptor binding domain antibodies on severe acute respiratory syndrome coronavirus neutralization escape and fitness

The receptor binding domain (RBD) of the spike (S) glycoprotein of severe acute respiratory syndrome coronavirus (SARS-CoV) is a major target of protective immunity in vivo. Although a large number of neutralizing antibodies (nAbs) have been developed, it remains unclear if a single RBD-targeting nAb or two in combination can prevent neutralization escape and, if not, attenuate viral virulence in vivo. In this study, we used a large panel of human nAbs against an epitope that overlaps the interface between the RBD and its receptor, angiotensin-converting enzyme 2 (ACE2), to assess their cross-neutralization activities against a panel of human and zoonotic SARS-CoVs and neutralization escape mutants. We also investigated the neutralization escape profiles of these nAbs and evaluated their effects on receptor binding and virus fitness in vitro and in mice. We found that some nAbs had great potency and breadth in neutralizing multiple viral strains, including neutralization escape viruses derived from other nAbs; however, no single nAb or combination of two blocked neutralization escape. Interestingly, in mice the neutralization escape mutant viruses showed either attenuation (Urbani background) or increased virulence (GD03 background) consistent with the different binding affinities between their RBDs and the mouse ACE2. We conclude that using either single nAbs or dual nAb combinations to target a SARS-CoV RBD epitope that shows plasticity may have limitations for preventing neutralization escape during in vivo immunotherapy. However, RBD-directed nAbs may be useful for providing broad neutralization and prevention of escape variants when combined with other nAbs that target a second conserved epitope with less plasticity and more structural constraint

A therapeutic vaccine prototype induces protective immunity and reduces cardiac fibrosis in a mouse model of chronic Trypanosoma cruzi infection.

Chagas disease, caused by the parasite Trypanosoma cruzi, develops into chronic Chagas' cardiomyopathy in ~30% of infected individuals, characterized by conduction disorders, arrhythmias, heart failure, and even sudden cardiac death. Current anti-parasitic treatments are plagued by significant side effects and poor efficacy in the chronic phase of disease; thus, there is a pressing need for new treatment options. A therapeutic vaccine could bolster the protective TH1-mediated immune response, thereby slowing or halting the progression of chronic Chagas' cardiomyopathy. Prior work in mice has demonstrated therapeutic efficacy of a Tc24 recombinant protein vaccine in the acute phase of Chagas disease. However, it is anticipated that humans will be vaccinated therapeutically when in the chronic phase of disease. This study investigates the therapeutic efficacy of a vaccine prototype containing recombinant protein Tc24, formulated with an emulsion containing the Toll-like receptor 4 agonist E6020 as an immunomodulatory adjuvant in a mouse model of chronic T. cruzi infection. Among outbred ICR mice vaccinated during chronic T. cruzi infection, there is a significant increase in the number of animals with undetectable systemic parasitemia (60% of vaccinated mice compared to 0% in the sham vaccine control group), and a two-fold reduction in cardiac fibrosis over the control group. The vaccinated mice produce a robust protective TH1-biased immune response to the vaccine, as demonstrated by a significant increase in antigen-specific IFNγ-production, the number of antigen-specific IFNγ-producing cells, and IgG2a antibody titers. Importantly, therapeutic vaccination significantly reduced cardiac fibrosis in chronically infected mice. This is a first study demonstrating therapeutic efficacy of the prototype Tc24 recombinant protein and E6020 stable emulsion vaccine against cardiac fibrosis in a mouse model of chronic T. cruzi infection

Derivation of the first clinical diagnostic models for dehydration severity in patients over five years with acute diarrhea.

Diarrheal diseases lead to an estimated 1.3 million deaths each year, with the majority of those deaths occurring in patients over five years of age. As the severity of diarrheal disease can vary widely, accurately assessing dehydration status remains the most critical step in acute diarrhea management. The objective of this study is to empirically derive clinical diagnostic models for assessing dehydration severity in patients over five years with acute diarrhea in low resource settings. We enrolled a random sample of patients over five years with acute diarrhea presenting to the icddr,b Dhaka Hospital. Two blinded nurses independently assessed patients for symptoms/signs of dehydration on arrival. Afterward, consecutive weights were obtained to determine the percent weight change with rehydration, our criterion standard for dehydration severity. Full and simplified ordinal logistic regression models were derived to predict the outcome of none (9%) dehydration. The reliability and accuracy of each model were assessed. Bootstrapping was used to correct for over-optimism and compare each model's performance to the current World Health Organization (WHO) algorithm. 2,172 patients were enrolled, of which 2,139 (98.5%) had complete data for analysis. The Inter-Class Correlation Coefficient (reliability) was 0.90 (95% CI = 0.87, 0.91) for the full model and 0.82 (95% CI = 0.77, 0.86) for the simplified model. The area under the Receiver-Operator Characteristic curve (accuracy) for severe dehydration was 0.79 (95% CI: 0.76-0.82) for the full model and 0.73 (95% CI: 0.70, 0.76) for the simplified model. The accuracy for both the full and simplified models were significantly better than the WHO algorithm (p<0.001). This is the first study to empirically derive clinical diagnostic models for dehydration severity in patients over five years. Once prospectively validated, the models may improve management of patients with acute diarrhea in low resource settings

Impact of emergency medicine training implementation on mortality outcomes in Kigali, Rwanda: An interrupted time-series study

Introduction: Although emergency medicine (EM) training programmes have begun to be introduced in low- and middle-income countries (LMICs), minimal data exist on their effects on patient-centered outcomes in such settings. This study evaluated the impact of EM training and associated systems implementation on mortality among patients treated at the University Teaching Hospital-Kigali (UTH-K). Methods: At UTH-K an EM post-graduate diploma programme was initiated in October 2013, followed by a residency-training programme in August 2015. Prior to October 2013, care was provided exclusively by general practice physicians (GPs); subsequently, care has been provided through mutually exclusive shifts allocated between GPs and EM trainees. Patients seeking Emergency Centre (EC) care during November 2012–October 2013 (pre-training) and August 2015–July 2016 (post-training) were eligible for inclusion. Data were abstracted from a random sample of records using a structured protocol. The primary outcomes were EC and overall hospital mortality. Mortality prevalence and risk differences (RD) were compared pre- and post-training. Magnitudes of effects were quantified using regression models to yield adjusted odds ratios (aOR) with 95% confidence intervals (CI). Results: From 43,213 encounters, 3609 cases were assessed. The median age was 32 years with a male predominance (60.7%). Pre-training EC mortality was 6.3% (95% CI 5.3–7.5%), while post-training EC mortality was 1.2% (95% CI 0.7–1.8%), constituting a significant decrease in adjusted analysis (aOR = 0.07, 95% CI 0.03–0.17; p < 0.001). Pre-training overall hospital mortality was 12.2% (95% CI 10.9–13.8%). Post-training overall hospital mortality was 8.2% (95% CI 6.9–9.6%), resulting in a 43% reduction in mortality likelihood (aOR = 0.57, 95% CI 0.36–0.94; p = 0.016). Discussion: In the studied population, EM training and systems implementation was associated with significant mortality reductions demonstrating the potential patient-centered benefits of EM development in resource-limited settings. Keywords: Emergency medicine, Training, Mortality, Rwanda, Afric

Recipient Pretransplant Inosine Monophosphate Dehydrogenase Activity in Nonmyeloablative Hematopoietic Cell Transplantation

AbstractMycophenolic acid, the active metabolite of mycophenolate mofetil (MMF), inhibits inosine monophosphate dehydrogenase (IMPDH) activity. IMPDH is the rate-limiting enzyme involved in de novo synthesis of guanosine nucleotides and catalyzes the oxidation of inosine 5′-monophosphate to xanthosine 5′-monophosphate (XMP). We developed a highly sensitive liquid chromatography–mass spectrometry method to quantitate XMP concentrations in peripheral blood mononuclear cells (PMNCs) isolated from the recipient pretransplant and used this method to determine IMPDH activity in 86 nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) patients. The incubation procedure and analytical method yielded acceptable within-sample and within-individual variability. Considerable between-individual variability was observed (12.2-fold). Low recipient pretransplant IMPDH activity was associated with increased day +28 donor T cell chimerism, more acute graft-versus-host disease (GVHD), lower neutrophil nadirs, and more cytomegalovirus reactivation but not with chronic GVHD, relapse, nonrelapse mortality, or overall mortality. We conclude that quantitation of the recipient's pretransplant IMPDH activity in PMNC lysate could provide a useful biomarker to evaluate a recipient's sensitivity to MMF. Further trials should be conducted to confirm our findings and to optimize postgrafting immunosuppression in nonmyeloablative HCT recipients

Mobile Universal Lexicon Evaluation System in MS: A New Visual Test of Rapid Picture Naming

Vision-based measures of rapid number naming (King-Devick [K-D]) have improved the sensitivity of sports-related concussion screening and also demonstrate slower testing times in patients with multiple sclerosis (MS). K-D requires saccades and vergence, measuring aspects of frontal, parietal and brainstem centers. We developed the Mobile Universal Lexicon Evaluation System (MULES) to capture a more extensive vision network, integrating saccades, color perception, and object identification. This study introduces MULES, a new vision-based test of rapid picture naming, to the visual assessment of patients with MS