Facilitators and barriers to adolescent participation in a TB clinical trial.

The inclusion of adolescents in TB drug trials is essential for the development of safe, child-friendly regimens for the prevention and treatment of TB. TB Trials Consortium Study 31/AIDS Clinical Trials Group A5349 (S31/A5349) enrolled adolescents as young as 12 years old. We assessed investigator and coordinator described facilitators and barriers to adolescent recruitment, enrollment, and retention.Interviews were conducted with six investigators from sites that enrolled adolescent participants and six investigators from non-enrolling sites. Additionally, two focus groups were conducted with study coordinators from enrolling sites and two focus groups with non-enrolling sites. Discussions were transcribed, analyzed, summarized, and summaries were reviewed by Community Research Advisors Group members and research group representatives for content validity.Investigators and coordinators attributed the successful enrollment of adolescents to the establishment and cultivation of external partnerships, flexibility to accommodate adolescents' schedules, staff engagement, recruitment from multiple locations, dedicated recruitment staff working onsite to access potential participants, creation of youth-friendly environments, and effective communications. Non-enrolling sites were mainly hindered by regulations. Suggestions for improvement in future trials focused on study planning and site preparations.Proactive partnerships and collaboration with institutions serving adolescents helped identify and reduce barriers to their inclusion in this trial..

Addressing the needs of people with extensively drug-resistant TB through pre-approval access to drugs and research.

Multiple therapeutic options exist for people with drug-resistant TB (DR-TB), but there is an urgent need to improve access to novel compounds and regimens for people with difficult to treat forms of TB. In additional to formal research studies and clinical trials, other mechanisms of accessing promising new TB compounds need to be introduced as soon as these drugs have shown efficacy and safety in phase II trials. Pre-approval access programs for newer TB drugs such as bedaquiline, delamanid, and pretomanid all suffered from shortcomings. These can be addressed for the next generation of new TB drugs through a series of concerted actions by stakeholders at multiple levels. In this viewpoint, we advocate for transparent, accessible pre-approval access as a core element of person-centered care for DR-TB.

Il existe de nombreuses options thérapeutiques pour les personnes atteintes de TB résistante aux médicaments (DR-TB), mais il est urgent d'améliorer l'accès aux nouvelles molécules et aux nouveaux schémas thérapeutiques pour les personnes atteintes de formes de TB difficiles à traiter. Outre les études de recherche formelles et les essais cliniques, d'autres mécanismes d'accès aux nouvelles molécules prometteuses contre la TB doivent être mis en place dès que ces médicaments ont démontré leur efficacité et leur innocuité lors des essais de phase II. Les programmes d'accès avant approbation pour les nouveaux médicaments contre la TB tels que la bédaquiline, le delamanid et le pretomanid ont tous souffert de lacunes. Ces problèmes peuvent être résolus pour la prochaine génération de nouveaux médicaments contre la TB grâce à une série d'actions concertées entre les parties prenantes à différents niveaux. Dans cette optique, nous préconisons un accès transparent et accessible avant approbation, en tant qu'élément central des soins centrés sur la personne pour la DR-TB.

One size does not fit all: community views on choices for TB treatment and prevention.

Treatment and prevention paradigms in TB have been dominated by a 'one-size-fits-all' approach, in which all persons are given the same treatment regimens. This stands in contrast to other health conditions, where differentiated models of care have been shown to be effective. In this Viewpoint, we make the case for considering multiple factors when deciding which regimens should be offered to people with TB infection and disease. Choice about which regimens to use should be made in conjunction with people who have TB and consider efficacy, safety, duration, pill burden, formulation, drug interactions, time spent in monitoring, drug susceptibility, compatibility with other areas of life, and availability of support services. Ideally, these choices should be considered within an equity framework with the most intensified services being offered to those considered most vulnerable.

Les paradigmes de traitement et de prévention de la TB ont été dominés par une approche « unique ¼, dans laquelle toutes les personnes reçoivent les mêmes schémas thérapeutiques. Cette approche contraste avec d'autres problèmes de santé, pour lesquels des modèles de soins différenciés se sont avérés efficaces. Dans ce point de vue, nous plaidons en faveur de la prise en compte de multiples facteurs au moment de décider des schémas thérapeutiques à proposer aux personnes atteintes de infection tuberculeuse et de TB maladie. Le choix des traitements doit être fait en collaboration avec les personnes atteintes de TB et tenir compte de l'efficacité, de l'innocuité, de la durée, du nombre de comprimés, de la formulation, des interactions médicamenteuses, du temps consacré à la surveillance, de la sensibilité aux médicaments, de la compatibilité avec d'autres domaines de la vie et de la disponibilité des services d'aide. Idéalement, ces choix devraient être envisagés dans un cadre d'équité, les services les plus intensifs étant proposés aux personnes considérées comme les plus vulnérables.

Delayed cognitive impairments in a rat model of Gulf War Illness are stimulus-dependent.

Gulf War Illness (GWI) collectively describes the multitude of central and peripheral disturbances affecting soldiers who served in the 1990-1991 Gulf War. While the mechanisms responsible for GWI remain elusive, the prophylactic use of the reversible acetylcholinesterase inhibitor, pyridostigmine bromide (PB), and war-related stress have been identified as chief factors in GWI pathology. Post-deployment stress is a common challenge faced by veterans, and aberrant cholinergic and/or immune responses to these psychological stressors may play an important role in GWI pathology, especially the cognitive impairments experienced by many GWI patients. Therefore, the current study investigated if an immobilization stress challenge would produce abnormal responses in PB-treated rats three months later. Results indicate that hippocampal cholinergic responses to an immobilization stress challenge are impaired three months after PB administration. We also assessed if an immune or stress challenge reveals deficits in PB-treated animals during hippocampal-dependent learning and memory tasks at this delayed timepoint. Novel object recognition (NOR) testing paired with either acute saline or lipopolysaccharide (LPS, 30 µg/kg, i.p.), as well as Morris water maze (MWM) testing was conducted approximately three months after PB administration and/or repeated restraint stress. Rats with a history of PB treatment exhibited 24-hour hippocampal-dependent memory deficits when challenged with LPS, but not saline, in the NOR task. Similarly, in the same cohort, PB-treated rats showed 24-hour memory deficits in the MWM task. Ultimately, these studies highlight the long-term effects of PB treatment on hippocampal function and provide insight into the progressive cognitive deficits observed in veterans with GWI.

Cognitive Development in Single-Suture Craniosynostosis - A Systematic Review.

There is conflicting evidence whether single-suture craniosynostosis (SSC), is linked to adversities of cognitive development. To assess the evidence for a link between SSC and cognition, a systematic literature search was conducted and eligible studies assessed for inclusion by two independent readers. Forty-eight studies met inclusion criteria. Small to medium but persistent effects on both general and some specific cognitive functions across age bands were found in higher quality studies for SSC overall. There was limited evidence for effects related to surgical correction. Methodologies varied substantially and there was a lack of longitudinal studies using broad assessment batteries.

Value of prolonged scrotal drainage after penile prosthesis implantation: a multicenter prospective nonrandomized pilot study.

We aimed to understand the risks and benefits of post-inflatable penile prosthesis (IPP) implantation drainage and optimal duration. Our patients were divided into 3 groups: Group 1 (n = 114) had no drain placed, Group 2 had a drain placed for 24 h (n = 114) and Group 3 had a drain placed for 72 h (n = 117). Postoperative scrotal hematoma and prosthesis infection rates were compared between the groups. The patients from Group 3 demonstrated a statistically significant lower incidence of hematoma on the 10th postoperative day: (n = 1, 0.9%) compared to Group 2: (n = 11, 9.6%) and Group 1: (n = 8, 7%), (p = 0.013). However, on the 3rd postoperative day, there was a statistically significant lower incidence of hematoma in both Groups 3 and 2: (0.9% and 6.1%, respectively) vs. Group 1: (11.4%), (p = 0.004). Hematoma rates followed the same group order after the first day of surgery: 1.7% (n = 2), 5.3% (n = 6), and 8.8% (n = 10), respectively, (p = 0.05). Five patients (4.4%) in Group 1 and four patients (3.5%) in Group 2 developed an IPP associated infection, opposed to only a single patient (0.85%) in Group 3, (p = 0.210). We concluded that prolonged scrotal drainage for 72 h after virgin IPP implantation significantly reduces hematoma and infection rates.

High-speed running density in collegiate women's lacrosse.

High-speed running density (HSRd) is the ratio of high-speed efforts and distance covered. This study aimed to evaluate differences in HSRd between training, games, and among positions in collegiate women's lacrosse, and correlate HSRd with other training metrics. Data were collected during a collegiate training year (practices n = 162, games n = 14) through players (n = 25) wearing microtechnology. HSRd differed between training sessions and games (p < .001, d = .281) and by position (p < .001, d = .005-.712). Games (14.7 ± 13.8%) had a higher HSRd than training sessions (13.1 ± 13.7%), and goalies had higher HSRd during games than the other positions. HSRd was moderately inversely correlated (p < .001) with max speed (r = -.395-.543) and had low inverse correlations (p < .001) with distance (r = -.134-.225), accelerations (r = -217-.233), and decelerations (r = -.195-.268). Training did not mimic the HSRd of games. Defenders and goalies perform intense reactionary movements to make a defensive play, resulting in higher HSRd.

Mortality in Perinatally HIV-infected Adolescents After Transition to Adult Care in Spain.

INTRODUCTION: After the introduction of combination antiretroviral treatment, (ART) mortality in HIV-infected patients has dramatically decreased. However, it is still high in patients at risk, as adolescents transitioning to adult care (AC) without virologic control. The aim of this study was to characterize mortality and comorbidities of perinatally infected HIV (PHIV) patients after transition to AC. METHODS: A multicenter retrospective study from patients included in the CoRISpe-FARO Spanish cohort was conducted. PHIV patients who died after transition to AC between 2009 and 2019 were included. Clinical, immunovirologic characteristics, treatments received, comorbidities and causes of death were described. RESULTS: Among 401 PHIV patients, 14 died (3.5%). All were Spanish, 11/14 (78.6%) women. The median age at diagnosis was 1.5 years (interquartile range [IQR] 0.5-3.9), at transfer to AC was 18 years [16.1-19.9] and at death was 25.8 years [23.6-27.1]. In pediatric units [pediatric care (PC)], CD4+ nadir was 85 cells/µL [IQR 9.7-248.5] and 6/14 patients were classified as C-clinical stage. During AC, all patients were on C-clinical stage and CD4+ nadir dropped to 11.5 cells/µL [4.5-43.3]. cART adherence was extremely poor: in PC, 8/14 patients registered voluntary treatment interruptions; only one had undetectable VL at transition. In AC, 12/14 patients stopped treatment 2 or more periods of time. All deaths were related to advanced HIV disease. Mental health disorders were observed in 7/14 (50%). Main complications described: recurrent bacterial infections (57.1%), wasting syndrome (42.9%), esophageal candidiasis (28.6%) and Pneumocystis jirovecii pneumonia (28.6%). Four women had 11 pregnancies; 5 children were born (none infected). CONCLUSIONS: Young adults PHIV infected who transition to AC without virologic suppression or proven ability to adhere to ART are at high risk of mortality. Mortality was noted as a consequence of advanced HIV disease, frequent mental health problems and poor adherence to ART.

WHO ethics guidance on TB care and migration: challenges to the implementation process.

We summarise the current ethical guidance on tuberculosis (TB) care and migration, as set out in the WHO "Ethics Guidance for the Implementation of the End TB Strategy." Among other aspects, the Ethics Guidance states that there should be firm legal principles in place that ensure the enforcement of migration law on the one hand and the protection of human rights, including the right to health, on the other are separated from one another. As a challenge to the Ethics Guidance and its implementation, we describe two cases, each of which typifies particular problems. Case one describes the experience of a migrant worker in the United Arab Emirates who is deported when mandatory medical exams show evidence of current or prior TB. Case two raises the issue of providing more than TB care, which may also be needed for holistic care. The paper concludes with our suggestions for ways in which we could make progress towards ethically optimal TB care for migrants.

Upholding ethical values and human rights at the frontier of TB research.

Until recently, human rights have played a minor role in the fight against tuberculosis (TB), even less so in TB research. This is changing, however. The WHO's End TB Strategy and Ethics Guidance stress respect for human rights and ethical principles in every area of TB care, including research. The desired reductions in TB incidence and mortality are impossible without new tools and strategies to fight the disease. Yet, little suggests that the current state of TB research-including funding levels, evidence being produced, and community involvement-will alleviate concerns related to the availability, accessibility, and acceptability of TB diagnostics, drugs, and prevention in the near future. In this article, we consider these ethics concerns in relation to the right to enjoy the benefits of scientific progress and the right to health. We also reflect on community involvement in research and offer recommendations in the spirit of the rights to health and science, such as involving affected communities in all aspects of research planning, execution, and dissemination. Finally, we argue that states have a responsibility under international law for the continued realization of the right to health. This realization rests, in part, on the realization of the right to science.

Tuberculosis in a Spanish cohort of children living with HIV: the CHOTIS study (Childhood HIV & TB study).

BACKGROUND: Tuberculosis (TB) is the leading opportunistic infection in children with human immunodeficiency virus (HIV), but is uncommon in low prevalence regions. We aim to describe the changing epidemiology and clinical presentation of TB-HIV co-infection in a cohort of HIV-infected children in Spain.METHODS: Children diagnosed with TB between 1995 and 2016 in the paediatric HIV cohort were identified. The incidence and clinical presentation were compared in three periods: 1995-1999 (P1, before initiation of combined antiretroviral therapy, cART), 2000-2009 (P2, increase in immigration), and 2010-2016 (P3, decrease in immigration).RESULTS: We included 29 TB cases among 1183 children aged <18 years (2.4%, 243/100 000 person-years). The proportion was stable in P1 and P2 (1.3%), but decreased in P3 (0.8%). The median age at TB diagnosis was 6.4 years (IQR 4-10.6); most children in P3 were aged >10 years (20% vs. 23.1% vs. 83.3%, P = 0.01). TB was diagnosed at HIV presentation in 11/29 children (37.9%). Foreign-born children accounted for respectively 0%, 8% and 67% of the total number of children in each period (P ≤ 0.0001). One third had extrapulmonary TB; four children died (13.8%).CONCLUSION: In our cohort, the incidence of TB-HIV co-infection decreased with decline in immigration. In regions with adequate cART coverage and low TB transmission, paediatric TB-HIV coinfection is uncommon, but associated with significant morbidity. Strategies for TB surveillance, diagnosis and treatment in this vulnerable population should be reinforced.

High-submuscular vs. space of Retzius reservoir placement during implantation of inflatable penile implants.

We have evaluated the data of patients who underwent ectopic high submuscular reservoir placement during implantation of inflatable penile prostheses and compared them to those of patients who underwent to traditional reservoir placement in the space of Retzius (SR). The main focus was on evaluating complications and patient satisfaction rates in both methods of RP. One hundred and forty-two patients underwent implantation of the Coloplast Titan OTR prosthesis with exclusive use of the "Clover Leaf" reservoir. We performed a retrospective evaluation, analyzing the treatment-associated complications by means of the Clavien-Dindo classification. All patients as well as their partners received questionnaires with validated scores. Group I: 70 (49.3%) patients who underwent HSM RP. Group II: 72 (50.7%) patients who underwent SR RP. Neither grade IV nor grade V Clavien-Dindo complications were documented. In total, we observed 4 (3.3%) cases grade III b complications, which resulted in revision. Distribution was as follows: infected device (n = 4), scrotal hematoma (n = 2), scrotal seroma (n = 1), and scrotal skin fistula (n = 1). 88% of the patients with ectopic HSM RP and 81% with traditional SR RP were satisfied with their implant. Of the patients with HSM RP, 64.3% (n = 45; BMI range: 18.5-28.8) reported that they were able to feel their reservoir by palpation immediately after surgery. Palpability disappeared in 80% of the patients in this group (BMI > 26.5) after capsule formation at 3 months post-surgery. Only one patient (1.4%; BMI 20.5) reported that he was able to see the reservoir. Our findings suggest that the novel reservoir placement is safe, efficient and results in excellent patient satisfaction, even if the reservoir is initially palpable or visible.

Growth Patterns in Children With Congenital Cytomegalovirus Infection.

BACKGROUND: Congenital cytomegalovirus infection (CMVc) affects 0.7%-6% of recent births. Among its clinical manifestations are low weight and length at birth. OBJECTIVE: Describe the growth patterns of children with CMVc in their early years. METHODS: Observational, multicenter study of patients with CMVc. Anthropometric data were collected during the first 2 years of life and compared with World Health Organization standards. RESULTS: Anthropometric characteristics of 383 children with CMVc were studied, of which 198 (51%) were symptomatic at birth. At birth, 9% were small for gestational age (SGA) in terms of their weight and length and 17% had microcephaly. At 24 ± 3 months, 10% had a weight and length ≤2 SD, and 13% a head circumference ≤2 SD. Of those who were SGA at birth, at 24 ± 3 months >20% remained at ≤2 SD of their weight and length. Conversely, 75% of children with low weight or length at 24 ± 3 had not been SGA at birth. 20% of infants with microcephaly at birth remained with microcephaly, and 10% of those without microcephaly developed it at 24 ± 3 months. The average growth rate in length and weight was normal. Patients who were symptomatic at birth, premature and with motor and neurocognitive impairment had a significantly higher risk of low weight and length at 24 ± 3 months. CONCLUSION: Around 10% of children with CMVc are at ≤2 SD in weight, length and head circumference at 24 ± 3 months. The lack of adequate growth is associated with symptoms at birth, prematurity and motor and neurocognitive impairment. Growth impairment could be incorporated into the symptomatic spectrum of CMVc.

Sociodemographic changes and trends in the rates of new perinatal HIV diagnoses and transmission in Spain from 1997 to 2015.

BACKGROUND: There are not enough nationwide studies on perinatal HIV transmission in connection with a combination of antiretroviral treatments in Spain. Our objectives were to study sociodemographic changes and trends in the rates of HIV diagnoses and perinatal transmission in Spain from 1997 to 2015. METHODS: A retrospective study using data from Spanish Paediatric HIV Network (CoRISpe) and Spanish Minimum Basic Data Set (MDBS) was performed. HIV- diagnosed children between 1997 and 2015 were selected. Sociodemographic, clinical and immunovirological data of HIV-infected children and their mothers were studied in four calendar periods (P1: 1997-2000; P2: 2001-2005; P3: 2006-2010; P4: 2011-2015). Rates of perinatal HIV diagnoses and transmission from 1997 to 2015 were calculated. RESULTS: A total of 532 HIV-infected children were included in this study. Of these children, 406 were Spanish (76.3%) and 126 immigrants (23.7%). A decrease in the number of HIV diagnoses, 203 (38.2%) children in the first (P1), 149 (28%) in the second (P2), 130 (24.4%) in the third (P3) and 50 (9.4%) in the fourth (P4) calendar periods was studied. The same decrease in the Spanish HIV-infected children (P1, 174 (46.6%), P2, 115 (30.8%), P3, 65 (17.4%) and P4, 19 (5.1%)) was monitored. However, an increase in the number of HIV diagnoses by sexual contact (P1: 0%; P2: 1.3%; P3: 4.6%; P4: 16%) was observed. The rates of new perinatal HIV diagnoses and perinatal transmission in Spanish children decreased from 0.167 to 0.005 per 100,000 inhabitants and 11.4% to 0.4% between 1997 and 2015, respectively. CONCLUSIONS: A decline of perinatal HIV diagnoses and transmission was observed. However, an increase of teen-agers HIV diagnoses with sexual infection was studied. Public awareness campaigns directed to teen-agers are advisable to prevent HIV infection by sexual contact.

Cells respond to deletion of CAV1 by increasing synthesis of extracellular matrix.

A range of cellular functions have been attributed to caveolae, flask-like invaginations of the plasma membrane. Here, we have used RNA-seq to achieve quantitative transcriptional profiling of primary embryonic fibroblasts from caveolin 1 knockout mice (CAV1-/- MEFs), and thereby to gain hypothesis-free insight into how these cells respond to the absence of caveolae. Components of the extracellular matrix were decisively over-represented within the set of genes displaying altered expression in CAV1-/- MEFs when compared to congenic wild-type controls. This was confirmed biochemically and by imaging for selected examples. Up-regulation of components of the extracellular matrix was also observed in a second cell line, NIH-3T3 cells genome edited to delete CAV1. Up-regulation of components of the extracellular matrix was detected in vivo by assessing collagen deposition and compliance of CAV1-/- lungs. We discuss the implications of these findings in terms of the cellular function of caveolae.

Genetic testing for familial hypercholesterolemia among survivors of acute coronary syndrome.

BACKGROUND: Familial hypercholesterolemia could be prevalent among patients with acute coronary syndrome. OBJECTIVE: To investigate both the frequency of causative mutations for familial hypercholesterolemia (FH) and the optimal selection of patients for genetic testing among patients with an acute coronary syndrome (ACS). METHODS: One hundred and sixteen patients with an ACS during 2009-2015 were identified through the SWEDEHEART registry. Patients who had either a high total cholesterol level ≥7 mmol L-1 combined with a triglyceride level ≤2.6 mmol L-1 , or were treated with lipid-lowering medication and had a total cholesterol level >4.9 mmol L-1 and a triglyceride level ≤2.6 mmol L-1 were included. Genetic testing was performed first with a regionally designed FH mutation panel (118 mutations), followed by testing with a commercially available FH genetic analysis (Progenika Biopharma). RESULTS: A total of 6.9% (8/116) patients had a FH-causative mutation, all in the LDL-receptor. Five patients were detected on the panel, and further testing of the remaining 111 patients detected an additional 3 FH-causative mutations. Baseline characteristics were similar in FH-positive and FH-negative patients with respect to age, gender, prior ACS and diabetes. Patients with a FH-causative mutation had higher Dutch Lipid Clinical Network (DLCN) score (5.5 (5.0-6.5) vs 3.0 (2.0-5.0), P < 0.001) and a higher low-density lipoprotein level (5.7 (4.7-6.5) vs 4.9 (3.5-5.4), P = 0.030). The Dutch Lipid Clinical Network (DLCN) score had a good discrimination with an area under the curve of 0.856 (95% CI 0.763-0.949). CONCLUSION: Genetic testing for FH should be considered in patients with ACS and high DLCN score.

TRPV4 inhibition attenuates stretch-induced inflammatory cellular responses and lung barrier dysfunction during mechanical ventilation.

Mechanical ventilation is an important tool for supporting critically ill patients but may also exert pathological forces on lung cells leading to Ventilator-Induced Lung Injury (VILI). We hypothesised that inhibition of the force-sensitive transient receptor potential vanilloid (TRPV4) ion channel may attenuate the negative effects of mechanical ventilation. Mechanical stretch increased intracellular Ca2+ influx and induced release of pro-inflammatory cytokines in lung epithelial cells that was partially blocked by about 30% with the selective TRPV4 inhibitor GSK2193874, but nearly completely blocked with the pan-calcium channel blocker ruthenium red, suggesting the involvement of more than one calcium channel in the response to mechanical stress. Mechanical stretch also induced the release of pro-inflammatory cytokines from M1 macrophages, but in contrast this was entirely dependent upon TRPV4. In a murine ventilation model, TRPV4 inhibition attenuated both pulmonary barrier permeability increase and pro-inflammatory cytokines release due to high tidal volume ventilation. Taken together, these data suggest TRPV4 inhibitors may have utility as a prophylactic pharmacological treatment to improve the negative pathological stretch-response of lung cells during ventilation and potentially support patients receiving mechanical ventilation.

What we know and what we don't know about perinatal Zika virus infection: a systematic review.

INTRODUCTION: Zika virus (ZIKV) infection has caused the most challenging worldwide infectious epidemic outbreak in recent months. ZIKV causes microcephaly and other congenital malformations. There is a need to perform updated systematic reviews on ZIKV infection periodically because this epidemic is bringing up new evidence with extraordinary speed. Areas covered: Evidence related to ZIKV infection in the gestational, perinatal, and early infant periods covering epidemiology, virology, pathogenesis, risk factors, time of infection during pregnancy, newborn symptoms, treatment, and vaccines. To this end, a search was performed using terms ['Zika'] AND ['Perinatal Infection'] OR ['Congenital Infection'] in the PubMed® international electronic database. Out of a total of 1,538 articles published until 30 November 2017, we finally assessed 106 articles articles that were relevant to the research areas included in this study. Expert commentary: ZIKV is a new teratogenic/neurotropic virus affecting fetuses. Many challenges are still far from being solved regarding the epidemiology, case definition, clinical and laboratory diagnosis, and preventive measures. An approach using 'omics' and new biomarkers for diagnosis, and a ZIKV-vaccine for treatment, might finally give us the tools to solve these challenges.