Complementary Nonsputum Diagnostic Testing for Tuberculosis in People with HIV Using Oral Swab PCR and Urine Lipoarabinomannan Detection.

Testing for mycobacterial lipoarabinomannan (LAM) in urine is a practical but insensitive alternative to sputum testing to diagnose tuberculosis (TB) in people with HIV (PWH). Here, we evaluated urine LAM testing alongside PCR-based tests for Mycobacterium tuberculosis (MTB) DNA in tongue swabs. We hypothesized that the two nonsputum samples would deliver complementary, not redundant, results. The study included 131 South African patients of whom 64 (48.1%) were confirmed to have TB by GeneXpert MTB/RIF Ultra (Xpert Ultra) or culture analysis of sputum. A total of 120 patients (91.6%) were coinfected with HIV and 130 yielded a valid urine LAM result (Alere DETERMINE LAM Ag). Tongue swab samples were tested by IS6110-targeted qPCR with a quantification cycle (Cq) cutoff of 32. Relative to reference sputum testing (TB culture and Xpert Ultra), combined urine LAM and oral swab testing (either sample positive) was significantly more sensitive than either nonsputum sample alone (57% sensitivity for combined testing versus 35% and 39% sensitivity for urine LAM and tongue swabs; P = 0.01 and 0.04, respectively). Specificity of combined testing (neither sample positive) was 97%. On average, tongue swab-positive participants had higher sputum signal strength than urine-LAM positive participants, as measured by sputum Xpert Ultra Cq value (P = 0.037). A subset of tongue swabs (N = 18) was also tested by using Xpert Ultra, which reproduced true positive and true negative IS6110 qPCR results and resolved the two false-positive tongue swabs. With further development, tongue swabs and urine may feasibly serve as complementary nonsputum samples for diagnosis of TB in PWH.

Practice Patterns and Preferences Among Hematopoietic Cell Transplantation Clinicians.

Hematopoietic cell transplantation can cure many high-risk diseases but is associated with complexity, cost, and risk. Several areas in transplantation practice were identified in the 2014 Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium (BMT CTN SOSS) as high priorities for further study. We developed a survey for hematopoietic cell transplantation clinicians to identify current practices in BMT CTN SOSS priority areas and to understand, more generally, the variation in approach to transplantation and estimation of transplantation benefit in current medical practice. Of 1439 transplantation clinicians surveyed, 305 responded (20% response rate). Clinicians were well represented by age, experience, geography, and size of practice. We found that several techniques identified in the BMT CTN SOSS, such as maintenance therapy for acute myeloid leukemia or myelodysplastic syndromes after allogeneic transplantation, were already being utilized in practice on and off study, with higher rates of use in higher-volume centers. There was significant variation among clinicians in use of transplantation technologies and approaches to common transplantation scenarios. Appraisals of risks and benefits of transplantation appeared to converge upon similar estimates despite the presentation of different hypothetical scenarios. These results suggest overall equipoise in several BMT CTN SOSS high-priority areas and support the need for better data to inform clinical practice.

Numerical modeling of internal tides and submesoscale turbulence in the US Caribbean regional ocean.

The US Caribbean ocean circulation is governed by an influx of Atlantic water through the passages between Puerto Rico, Hispaniola and the Virgin Islands, and an interplay of the Caribbean Sea water with the local topography of the region. We present an analysis of the US Caribbean ocean flow simulated by the USCROMS; which is the ROMS AGRIF model configured for the US Caribbean regional ocean at a horizontal resolution of 2 km. Outputs from the USCROMS show a seasonal variability in the strength of submesoscale turbulence within a mixed layer whose depth varies from -70 to -20 m from winter to summer, and internal tides originating from the passages between the islands. Energy spectra of the simulated baroclinic velocity show diurnal and semi-diurnal maxima and several higher-order harmonic frequency maxima associated with non-linear internal waves forming over steep slopes with super-critical topography in the continental shelf. The strongest conversion rates of the depth-averaged barotropic to baroclinic tidal energy occur at localized regions in the continental shelf with super-critical topography. These regions also exhibit enhanced transport and dissipation of the depth-averaged barotropic and baroclinic tidal kinetic energy. The dissipation in these regions is nearly 3 orders of magnitude stronger than the open ocean dissipation. The energy transport terms show a seasonal pattern characterized by stronger variance during summer and reduced variance during the winter. At the benthic regions, the dissipation levels depend on the topographic depth and the tidal steepness parameter. If the benthic region lies within the upper-ocean mixed-layer, the benthic dissipation is enhanced by surface-forced processes like wind forcing, convective mixing, submesoscale turbulence and bottom friction. If the benthic region lies below the mixed-layer, the benthic dissipation is enhanced by the friction between the super-critical topographic slopes and the periodically oscillating baroclinic tidal currents. Due to bottom friction, the tidal oscillation in the lateral currents adjacent to the sloping topography generates cyclonic and anti-cyclonic vortices with O(1) Rossby number depending on the orientation of the flow. While the cyclonic vortices form positive potential vorticity (q) leading to barotropic shear instability, anti-cyclonic vortices form negative q which leads to periodically occurring inertial instability. The lateral and inertial instabilities caused by the baroclinic tidal oscillations act as routes to submesoscale turbulence at the benthic depths of -100 m to -400 m near the super-critical topography of the continental shelf, forming O(10 km) long streaks of turbulent water with dissipation levels that are 3 orders of magnitude stronger than the dissipation in the open ocean at the same depth. The magnitudes of the dissipation and q at the benthic regions over super-critical continental-shelf topography are also modulated by the spring-neap tidal signals.

A pilot study to show that asymptomatic sexually transmitted infections alter the foreskin epithelial proteome.

There is limited data on the role of asymptomatic STIs (aSTIs) on the risk of human immunodeficiency virus (HIV) acquisition in the male genital tract (MGT). The impact of foreskin removal on lowering HIV acquisition is well described, but molecular events leading to HIV acquisition are unclear. Here, in this pilot study, we show that asymptomatic urethral infection with Chlamydia trachomatis (CT) significantly impacts the foreskin proteome composition. We developed and optimized a shotgun liquid chromatography coupled tandem mass spectrometry (MS)-based proteomics approach and utilized this on foreskins collected at medical male circumcision (MMC) from 16 aSTI+ men and 10 age-matched STI- controls. We used a novel bioinformatic metaproteomic pipeline to detect differentially expressed (DE) proteins. Gene enrichment ontology analysis revealed proteins associated with inflammatory and immune activation function in both inner and outer foreskin from men with an aSTI. Neutrophil activation/degranulation and viral-evasion proteins were significantly enriched in foreskins from men with aSTI, whereas homotypic cell-cell adhesion proteins were enriched in foreskin tissue from men without an aSTI. Collectively, our data show that asymptomatic urethral sexually transmitted infections result in profound alterations in epithelial tissue that are associated with depletion of barrier integrity and immune activation.

Combination of EP4 antagonist MF-766 and anti-PD-1 promotes anti-tumor efficacy by modulating both lymphocytes and myeloid cells.

Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP1-4). Specific targeting of EP receptors, as opposed to COX-1/2 inhibition, has been proposed to achieve preferential antagonism of PGE2-mediated immune suppression. Here we describe the anti-tumor activity of MF-766, a potent and highly selective small-molecule inhibitor of the EP4 receptor. EP4 inhibition by MF-766 synergistically improved the efficacy of anti-programmed cell death protein 1 (PD-1) therapy in CT26 and EMT6 syngeneic tumor mouse models. Multiparameter flow cytometry analysis revealed that treatment with MF-766 promoted the infiltration of CD8+ T cells, natural killer (NK) cells and conventional dendritic cells (cDCs), induced M1-like macrophage reprogramming, and reduced granulocytic myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME). In vitro experiments demonstrated that MF-766 restored PGE2-mediated inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in THP-1 cells and human blood, and PGE2-mediated inhibition of interleukin (IL)-2-induced interferon (IFN)-γ production in human NK cells. MF-766 reversed the inhibition of IFN-γ in CD8+ T-cells by PGE2 and impaired suppression of CD8+ T-cells induced by myeloid-derived suppressor cells (MDSC)/PGE2. In translational studies using primary human tumors, MF-766 enhanced anti-CD3-stimulated IFN-γ, IL-2, and TNF-α production in primary histoculture and synergized with pembrolizumab in a PGE2 high TME. Our studies demonstrate that the combination of EP4 blockade with anti-PD-1 therapy enhances antitumor activity by differentially modulating myeloid cell, NK cell, cDC and T-cell infiltration profiles.

Psychological and parental functioning of widowed fathers: The first two years.

Widowed parents play a critical role in promoting family adaptation and facilitating their children's adjustment to the loss of a parent; yet the psychological wellbeing of these parents has received scant attention. In this study we examined depressive symptoms and grief intensity in 252 spousally bereaved men with dependent-age children. Participants learned of the study and completed initial surveys at variable time points during their first 2 years of bereavement. Depressive and grief symptoms remained persistently high, with 45% of the sample exceeding screening thresholds for clinically significant depressive symptoms two years after the death of their spouses. In linear regression models, higher intensity or frequency of depression and grief symptoms were associated with poorer psychological adaptation, lower parenting self-efficacy, and lower parenting satisfaction scores. Relationships between fathers' distress and potentially modifiable end-of-life variables regarding their spouses were examined. Notably, those who reported that their wives were at peace with dying had lower depressive and grief scores at various intervals. Overall, the magnitude and duration of the depressive and grief symptoms suggests that widowed fathers' psychological distress does not quickly abate over the first 2 years of bereavement, which may be attributable to the unique set of bereavement challenges facing widowed parents such as facilitating their children's grief, assuming sole parenting responsibilities, and managing a household on their own. The findings underscore the need to further examine emotional distress in widowed parents and how their wellbeing impacts family functioning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Correspondence of visual evoked potentials with FMRI signals in human visual cortex.

Functional magnetic resonance imaging (FMRI) and event related potentials (ERPs) are tools that can be used to image brain activity with relatively good spatial and temporal resolution, respectively. Utilizing both of these methods is therefore desirable in neuroimaging studies to explore the spatio-temporal characteristics of brain function. While several studies have investigated the relationship between EEG and positive (+) BOLD (activation), little is known about the relationship between EEG signals and negative (-) BOLD (deactivation) responses. In this study, we used a visual stimuli designed to shift cortical activity from anterior to posterior regions of the visual cortex. Using EEG and FMRI, we investigated how shifts in +BOLD and -BOLD location were correlated to shifts in the N75 and P100 visual evoked potential (VEP) dipolar sources. The results show that the N75 dipole along with +BOLD, were indeed shifted from posterior to anterior regions of the visual cortex. The P100 VEP component, along with the -BOLD were not shifted to the same extent, indicating that N75 is better correlated to +BOLD than to -BOLD. These findings indicate how different components of the EEG signal are related to the positive and negative BOLD responses, which may aid in interpreting the relationship between visually evoked EEG and FMRI signals.

A precision therapy against cancers driven by KIT/PDGFRA mutations.

Targeting oncogenic kinase drivers with small-molecule inhibitors can have marked therapeutic benefit, especially when administered to an appropriate genomically defined patient population. Cancer genomics and mechanistic studies have revealed that heterogeneous mutations within a single kinase can result in various mechanisms of kinase activation. Therapeutic benefit to patients can best be optimized through an in-depth understanding of the disease-driving mutations combined with the ability to match these insights to tailored highly selective drugs. This rationale is presented for BLU-285, a clinical stage inhibitor of oncogenic KIT and PDGFRA alterations, including activation loop mutants that are ineffectively treated by current therapies. BLU-285, designed to preferentially interact with the active conformation of KIT and PDGFRA, potently inhibits activation loop mutants KIT D816V and PDGFRA D842V with subnanomolar potency and also inhibits other well-characterized disease-driving KIT mutants both in vitro and in vivo in preclinical models. Early clinical evaluation of BLU-285 in a phase 1 study has demonstrated marked activity in patients with diseases associated with KIT (aggressive systemic mastocytosis and gastrointestinal stromal tumor) and PDGFRA (gastrointestinal stromal tumor) activation loop mutations.

Determinants of health-service use by low-income people.

Poverty influences health status, life expectancy, health behaviours, and use of health services. This study examined factors influencing the use of health-related services by people living in poverty. In the first phase, 199 impoverished users of health-related services in 2 large Canadian cities were interviewed by their peers. In the second phase, group interviews with people living in poverty (n = 52) were conducted. Data were analyzed using thematic content analysis. Diverse health-related services were used to meet basic and health needs, to maintain human contact, and to cope with life's challenges. Use of services depended on proximity, affordability, convenience, information, and providers' attitudes and behaviours. Use was impeded by inequities based on income status. To promote the health of people living in poverty, nurses and other health professionals can enhance the accessibility and quality of services, improve their interactions with people living in poverty, provide information about available programs, offer coordinated community-based services, collaborate with other sectors, and advocate for more equitable services and policies.

Maternal cell contamination of amniotic fluid samples obtained by open needle versus trocar technique of amniocentesis.

OBJECTIVE: To determine the incidence of maternal cell contamination (MCC) in the open-needle amniocentesis sampling technique compared with the trocar-in-place technique. METHODS: A retrospective analysis was conducted on 2,498 mid-trimester amniocenteses performed in two tertiary care centres in Canada. The University of Alberta centre used the open-needle (without the trocar) technique and the University of British Columbia centre used the standard (with the trocar in place) technique. Data were gathered regarding the nature of the amniotic fluid, number of needle passes, amniocentesis results, and the occurrence of maternal cell contamination. The statistical analysis used logistic regression, and controlled for the potential confounders of bloody fluid taps and requirement for more than one needle insertion. RESULTS: The incidence of maternal cell contamination was 1.16% with the open-needle technique and 0.78% with the standard trocar-in-place technique (p < 0.315), with a power of 42%. CONCLUSION: The data suggested there is no significant increase in maternal cell contamination with the open-needle versus trocar-in-place techniques of amniocentesis. However, the small sample size, combined with the low prevalence of the outcome of interest (MCC), provides insufficient power to draw firm conclusions about the difference in MCC between the two techniques.

Short communication: Lower baseline CD4 count is associated with a greater propensity toward virological failure in a cohort of South African HIV patients.

The antiretroviral (ARV) service at Edendale Hospital in Pietermaritzburg, KwaZulu-Natal, South Africa has initiated more than 9,000 adults on therapy since 2004; however, virological outcomes among this patient cohort have not been systematically assessed. We conducted a retrospective chart review of patients initiating ARVs in recent years of the antiretroviral roll-out to determine the efficacy of this program. Clinic records were randomly selected for patients who had initiated ARVs between January 2009 and December 2012. Demographic and virological data were collected. Virological failure was defined as failure to achieve a plasma viral load (VL) <25 copies/ml after 6-12 months of ARV initiation or ≥2 consecutive HIV-RNA VLs ≥400 copies/ml following suppression of <25 copies/ml. Records for 228 individuals were reviewed. Twenty-one (9%) individuals experienced virological failure necessitating a regimen change. The median (interquartile range, IQR) duration of antiretroviral exposure was 19 (11-31) months. Individuals experiencing virological failure did not differ from individuals experiencing success with regards to sex, age, baseline hemoglobin, creatinine, alanine aminotransferase level, or weight (p>0.05) except for having a lower baseline CD4 [median 74 (IQR 31-94) versus 142 (IQR 61-211) cells/µl; p=0.0036 (Mann-Whitney U test)]. No differences were observed between groups in type of ARV regimen, WHO stage at time of ARV initiation, or tuberculosis status. Therefore, using a relatively strict definition of virological failure, we observed that virological success was achievable in over 90% of individuals at the Edendale Hospital ARV clinic. Lower baseline CD4 was associated with greater propensity toward virological failure.

High prevalence of undetected heart failure in long-term care residents: findings from the Heart Failure in Care Homes (HFinCH) study.

AIMS: Diagnosis of heart failure in older people in long-term care is challenging because of co-morbidities, cognitive deficit, polypharmacy, immobility, and poor access to services. This study aimed to ascertain heart failure prevalence and clinical management in this population. METHODS AND RESULTS: A total of 405 residents, aged 65-100 years, in 33 UK care facilities were prospectively enrolled between April 2009 and June 2010. The presence of heart failure was determined using European Society of Cardiology guidelines, modified where necessary for immobility. Evaluation of symptoms and signs, functional capacity, and quality of life, portable on-site echocardiography, and medical record review were completed in 399 cases. The point prevalence of heart failure was 22.8% [n = 91, 95% confidence interval (CI) 18.8-27.2%]; of these, 62.7% (n = 57, 95% CI 59.6-66.5%) had heart failure with preserved ejection fraction and 37.3% had left ventricular systolic dysfunction (n = 34, 95% CI 34.8-40.5%). A total of 76% (n = 61) of previous diagnoses of heart failure were not confirmed, and up to 90% (n = 82) of study cases were new. No symptoms or signs were reliable predictors of heart failure. CONCLUSION: Heart failure was diagnosed in almost a quarter of residents: the prevalence was substantially higher than in other populations. The majority of heart failure cases were undiagnosed, while three-quarters of previously recorded cases were misdiagnosed. Common symptoms and signs appear to have little clinical utility in this population. Early, accurate differential diagnosis is key to the effective management of heart failure; this may be failing in long-term care facilities.

The National Ignition Facility neutron imaging system.

The National Ignition Facility (NIF) is scheduled to begin deuterium-tritium (DT) shots possibly in the next several years. One of the important diagnostics in understanding capsule behavior and to guide changes in Hohlraum illumination, capsule design, and geometry will be neutron imaging of both the primary 14 MeV neutrons and the lower-energy downscattered neutrons in the 6-13 MeV range. The neutron imaging system (NIS) described here, which we are currently building for use on NIF, uses a precisely aligned set of apertures near the target to form the neutron images on a segmented scintillator. The images are recorded on a gated, intensified charge coupled device. Although the aperture set may be as close as 20 cm to the target, the imaging camera system will be located at a distance of 28 m from the target. At 28 m the camera system is outside the NIF building. Because of the distance and shielding, the imager will be able to obtain images with little background noise. The imager will be capable of imaging downscattered neutrons from failed capsules with yields Y(n)>10(14) neutrons. The shielding will also permit the NIS to function at neutron yields >10(18), which is in contrast to most other diagnostics that may not work at high neutron yields. The following describes the current NIF NIS design and compares the predicted performance with the NIF specifications that must be satisfied to generate images that can be interpreted to understand results of a particular shot. The current design, including the aperture, scintillator, camera system, and reconstruction methods, is briefly described. System modeling of the existing Omega NIS and comparison with the Omega data that guided the NIF design based on our Omega results is described. We will show NIS model calculations of the expected NIF images based on component evaluations at Omega. We will also compare the calculated NIF input images with those unfolded from the NIS images generated from our NIS numerical modeling code.

Challenges to the success of HIV and tuberculosis care and treatment in the public health sector in South Africa.

The escalating human immunodeficiency virus (HIV) and tuberculosis (TB) epidemics have had a significant impact on public health services in resource-limited settings. The province of KwaZulu-Natal in South Africa is estimated to have one of the greatest TB/HIV coinfection burdens on the African continent, coupled with historically low TB treatment success rates. In May 2004, the South African government began providing antiretroviral therapy (ART) for HIV-infected individuals within the public sector. As in many counties, this HIV treatment program was established in parallel with an existing TB treatment service. In 2005, the Integration of TB in Education and Care for HIV/AIDS (iTEACH) Program was launched in KwaZulu-Natal at Edendale Hospital. The goal of iTEACH was to identify barriers to effective treatment and develop support interventions to enable rapid expansion of access to ART and improve ART and TB treatment outcomes within the district served by this facility. In the present article, we discuss challenges to the delivery of TB and HIV care by these separate treatment programs, as well as opportunities to improve both TB treatment and ART outcomes through lessons learned during ART scale-up in the context of the HIV and TB coepidemics.

An enzyme-linked immunosorbent assay to measure insulin receptor dephosphorylation by PTP1B.

Considerable effort exists within drug discovery to develop novel compounds to improve the underlying metabolic defects in type 2 diabetes. One approach is focused on inhibition of the tyrosine phosphatase, PTP1B, an important negative regulator of both insulin and leptin signaling. Historically, tyrosine phosphatase assays have used either small organic phosphates or, alternatively, phosphorylated peptides from the target proteins themselves. In characterizing inhibitors of PTP1B, measuring turnover of small organic phosphates is limited to evaluation of compounds that bind the active site itself. Peptide substrates allow identification of additional subsets of inhibitors (e.g., those that bind the second aryl-phosphate site), but assays of peptide turnover often involve detection steps that then limit full kinetic evaluation of inhibitors. Here we use a polyclonal antibody specific for the phosphorylated insulin receptor to allow much more sensitive detection of peptide phosphorylation. This kinetically robust enzyme-linked immunosorbent assay (ELISA) gives k(cat) and K(m) values for a phosphorylated insulin receptor peptide consistent with values determined by a continuous fluorescence-based assay. Furthermore, IC50 values determined for well-behaved active site inhibitors agree well with values determined for p-nitrophenyl phosphate cleavage. This assay permits full characterization of a larger subset of inhibitors as drug candidates for this promising target.

Intensity noise reduction in a multiwavelength distributed Bragg reflector fiber laser.

Noise reduction in a multiwavelength distributed Bragg reflector fiber laser was demonstrated. A 20 dB reduction of in-phase intensity noise was achieved by using negative feedback to modulate the drive current of the laser pump diode. Strategies for reducing antiphase noise components are discussed.

Organizational capacity for community development in regional health authorities: a conceptual model.

The value of community development (CD) practices is well documented in the health promotion literature; it is a foundational strategy outlined in the Ottawa Charter for Health Promotion. Despite the importance of collaborative action with communities to enhance individual and community health and well-being, there exists a major gap between the evidence for CD and the actual extent to which CD is carried out by health organizations. In this paper it is argued that the gap exists because we have failed to turn the evaluative gaze inward-to examine the capacity of health organizations themselves to facilitate CD processes. This study was designed to explicate key elements that contribute to organizational capacity for community development (OC-CD). Twenty-two front-line CD workers and managers responsible for CD initiatives from five regional health authorities in Alberta, Canada, were interviewed. Based on the study findings, a multidimensional model for conceptualizing OC-CD is presented. Central to the model are four inter-related dimensions: (i) organizational commitment to CD, rooted in particular values and beliefs, leadership and shared understanding of CD; (ii) supportive structures and systems, such as job design, flexible planning processes, evaluation mechanisms and collaborative processes; (iii) allocation of resources for CD; and (iv) working relationships and processes that model CD within the health organization. These four dimensions contribute to successful CD practice in numerous ways, but perhaps most importantly by supporting the empowerment and autonomy of the pivotal organizational player in health promotion practice: the front-line worker.