Use of point-of-care C-reactive protein testing for screening of tuberculosis in the community in high-burden settings: a prospective, cross-sectional study in Zambia and South Africa.

BACKGROUND: WHO recommends community-wide, systematic tuberculosis screening in high-prevalence settings. C-reactive protein has been proposed as a tuberculosis screening tool for people living with HIV. We aimed to assess the performance of a point-of-care C-reactive protein test for tuberculosis screening in the community in two countries with a high tuberculosis burden. METHODS: We conducted a prospective, cross-sectional study in four communities in Zambia and South Africa, nested in a tuberculosis prevalence survey. We included adults (aged ≥15 years) who were sputum-eligible (tuberculosis-suggestive symptoms or computer-aided-detection score ≥40 on chest x-ray) and whose sputum was tested with Xpert Ultra and liquid culture. A 5% random sample of individuals who were non-sputum-eligible was also included. We calculated sensitivity and specificity of point-of-care C-reactive protein testing, alone and combined with symptom screening, to detect tuberculosis in participants who were sputum-eligible, compared with a microbiological reference standard (positive result in Xpert Ultra, culture, or both). FINDINGS: Between Feb 19 and Aug 11, 2019, 9588 participants were enrolled in the tuberculosis prevalence study, 1588 of whom had C-reactive protein testing and received results (875 [55·1%] were women and girls, 713 [44·9%] were men and boys, 1317 [82·9%] were sputum-eligible, and 271 [17·1%] were non-sputum-eligible). Among participants who were sputum-eligible, we identified 76 individuals with tuberculosis, of whom 25 were living with HIV. Sensitivity of point-of-care C-reactive protein testing with a cutoff point of 5 mg/L or more was 50·0% (38/76, 95% CI 38·3-61·7) and specificity was 72·3% (890/1231, 69·7-74·8). Point-of-care C-reactive protein combined in parallel with symptom screening had higher sensitivity than symptom screening alone (60·5% [46/76, 95% CI 48·6-71·6] vs 34·2% [26/76, 23·7-46·0]). Specificity of point-of-care C-reactive protein combined in parallel with symptom screening was 51·7% (636/1231, 95% CI 48·8-54·5) versus 70·5% (868/1231, 67·9-73·0) with symptom screening alone. Similarly, in people living with HIV, sensitivity of point-of-care C-reactive protein combined with symptom screening was 72·0% (18/25, 95% CI 50·6-87·9) and that of symptom screening alone was 36·0% (9/25, 18·0-57·5). Specificity of point-of-care C-reactive protein testing combined in parallel with symptom screening in people living with HIV was 47·0% (118/251, 95% CI 40·7-53·4) versus 72·1% (181/251, 66·1-77·6) with symptom screening alone. INTERPRETATION: Point-of-care C-reactive protein testing alone does not meet the 90% sensitivity stipulated by WHO's target product profile for desirable characteristics for screening tests for detecting tuberculosis. However, combined with symptom screening, it might improve identification of individuals with tuberculosis in communities with high prevalence, and might be particularly useful where other recommended tools, such as chest x-ray, might not be readily available. FUNDING: European and Developing Countries Clinical Trials Partnership.

Optimising Xpert-Ultra and culture testing to reliably measure tuberculosis prevalence in the community: findings from surveys in Zambia and South Africa.

OBJECTIVES: Prevalence surveys remain the best way to assess the national tuberculosis (TB) burden in many countries. Challenges with using culture (the reference standard) for TB diagnosis in prevalence surveys have led to increasing use of molecular tests (Xpert assays), but discordance between these two tests has created problems for deciding which individuals have TB. We aimed to design an accurate diagnostic algorithm for TB prevalence surveys (TBPS) that limits the use of culture. DESIGN: TBPS in four communities, conducted during 2019. SETTING: Three Zambian communities and one South-African community included in the TBPS of the Tuberculosis Reduction through Expanded Anti-retroviral Treatment and Screening study. PARTICIPANTS: Randomly sampled individuals aged ≥15 years. Among those who screened positive on chest X-ray or symptoms, two sputum samples were collected for field Xpert-Ultra testing and a third for laboratory liquid-culture testing. Clinicians reviewed screening and test results; in Zambia, participants with Mycobacterium tuberculosis-positive results were followed up 6-13 months later. Among 10 984 participants, 2092 screened positive, 1852 provided two samples for Xpert-Ultra testing, and 1009 had valid culture results. OUTCOMES: Culture and Xpert-Ultra test results. RESULTS: Among 946 culture-negative individuals, 917 were Xpert-negative, 12 Xpert-trace-positive and 17 Xpert-positive (grade very low, low, medium or high), with Xpert categorised as the highest grade of the two sample results. Among 63 culture-positive individuals, 8 were Xpert-negative, 9 Xpert-trace-positive and 46 Xpert-positive. Counting trace-positive results as positive, the sensitivity of Xpert-Ultra compared with culture was 87% (95% CI 76% to 94%) using two samples compared with 76% (95% CI 64% to 86%) using one. Specificity was 97% when trace-positive results were counted as positive and 98% when trace-positive results were counted as negative. Most Xpert-Ultra-positive/culture-negative discordance was among individuals whose Xpert-positive results were trace-positive or very low grade or they reported previous TB treatment. Among individuals with both Xpert-Ultra results grade low or above, the positive-predictive-value was 90% (27/30); 3/30 were plausibly false-negative culture results. CONCLUSION: Using Xpert-Ultra as the primary diagnostic test in TBPS, with culture only for confirmatory testing, would identify a high proportion of TB cases while massively reducing survey culture requirements. TRIAL REGISTRATION NUMBER: NCT03739736.

Foliar ẟ15N patterns in legumes and non-N fixers across a climate gradient, Hawai'i Island, USA.

Recent studies from the Hawaiian Islands showed that pedogenic thresholds demarcate domains in which rock-derived nutrient dynamics remain similar across wide variations in rainfall. These thresholds appear related to certain aspects of N cycling, but the degree to which they correspond to patterns of biological N fixation (BNF)-the dominant input of N into less-managed ecosystems-remains unclear. We measured aboveground plant biomass, foliar nutrient concentrations, and foliar δ15N along a climate gradient on ~ 150,000-year-old basaltic substrate to characterize foliar N sources and spatially relate them to soil nutrients. Patterns in legume δ15N correspond to known pedogenic thresholds along the rainfall gradient, with low δ15N values (~ 0 to - 2‰) occurring in the dry, biologically inactive domain and the wet, highly weathered domain. Elevated δ15N in the middle, fertile domain suggests a greater reliance of legumes on soil N where it has accumulated over time. Non-legume face N deficiencies throughout most of the gradient while legumes maintain low C:N ratios via symbiotic BNF. However, legume abundance declines outside the fertile domain, limiting ecosystem N inputs. Breakpoints in legume δ15N data suggest that P (and potentially other nutrients) limits BNF and, by extension, legume abundance in wet region. Nutrients may also constrain legume abundance in the dry domain, but pedogenic effects could not be isolated from climatic constraints at the dry sites. We conclude that pedogenic thresholds defined by climate can be informative of foliar δ15N patterns in cases where legumes are not directly constrained by climate, land use, or other external factors.

Global patterns and climatic controls of forest structural complexity.

The complexity of forest structures plays a crucial role in regulating forest ecosystem functions and strongly influences biodiversity. Yet, knowledge of the global patterns and determinants of forest structural complexity remains scarce. Using a stand structural complexity index based on terrestrial laser scanning, we quantify the structural complexity of boreal, temperate, subtropical and tropical primary forests. We find that the global variation of forest structural complexity is largely explained by annual precipitation and precipitation seasonality (R² = 0.89). Using the structural complexity of primary forests as benchmark, we model the potential structural complexity across biomes and present a global map of the potential structural complexity of the earth´s forest ecoregions. Our analyses reveal distinct latitudinal patterns of forest structure and show that hotspots of high structural complexity coincide with hotspots of plant diversity. Considering the mechanistic underpinnings of forest structural complexity, our results suggest spatially contrasting changes of forest structure with climate change within and across biomes.

Allosteric "beta-blocker" isolated from a DNA-encoded small molecule library.

The ß2-adrenergic receptor (ß2AR) has been a model system for understanding regulatory mechanisms of G-protein-coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known ß-adrenergic receptor drugs target the orthosteric binding site of the receptor, we set out to isolate allosteric ligands for this receptor by panning DNA-encoded small-molecule libraries comprising 190 million distinct compounds against purified human ß2AR. Here, we report the discovery of a small-molecule negative allosteric modulator (antagonist), compound 15 [([4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide], exhibiting a unique chemotype and low micromolar affinity for the ß2AR. Binding of 15 to the receptor cooperatively enhances orthosteric inverse agonist binding while negatively modulating binding of orthosteric agonists. Studies with a specific antibody that binds to an intracellular region of the ß2AR suggest that 15 binds in proximity to the G-protein binding site on the cytosolic surface of the ß2AR. In cell-signaling studies, 15 inhibits cAMP production through the ß2AR, but not that mediated by other Gs-coupled receptors. Compound 15 also similarly inhibits ß-arrestin recruitment to the activated ß2AR. This study presents an allosteric small-molecule ligand for the ß2AR and introduces a broadly applicable method for screening DNA-encoded small-molecule libraries against purified GPCR targets. Importantly, such an approach could facilitate the discovery of GPCR drugs with tailored allosteric effects.

Modular Chemical Descriptor Language (MCDL): Stereochemical modules.

BACKGROUND: In our previous papers we introduced the Modular Chemical Descriptor Language (MCDL) for providing a linear representation of chemical information. A subsequent development was the MCDL Java Chemical Structure Editor which is capable of drawing chemical structures from linear representations and generating MCDL descriptors from structures. RESULTS: In this paper we present MCDL modules and accompanying software that incorporate unique representation of molecular stereochemistry based on Cahn-Ingold-Prelog and Fischer ideas in constructing stereoisomer descriptors. The paper also contains additional discussions regarding canonical representation of stereochemical isomers, and brief algorithm descriptions of the open source LINDES, Java applet, and Open Babel MCDL processing module software packages. CONCLUSIONS: Testing of the upgraded MCDL Java Chemical Structure Editor on compounds taken from several large and diverse chemical databases demonstrated satisfactory performance for storage and processing of stereochemical information in MCDL format.

Changes in regional brain volumes in social anxiety disorder following 12 weeks of treatment with escitalopram.

It has been suggested that antidepressants, including the selective serotonin reuptake inhibitors have neurotrophic effects. Nevertheless, the impact of treatment with a selective serotonin re-uptake inhibitor on regional brain volumes in social anxiety disorder has not been studied. 11 subjects with social anxiety disorder completed magnetic resonance imaging both before and after 12-weeks of treatment with 20 mg/day escitalopram. No increases in structural grey matter were found, but there were decreases in bilateral superior temporal cortex, vermis and the left cerebellum volumes following 12 weeks of treatment with escitalopram. These preliminary findings require replication to determine their reliability, and extension to determine whether or not they are disorder specific.

The importance of instruction on mass casualty incidents in baccalaureate nursing programs: perceptions of nursing faculty.

This study examined whether a relationship exists between mass casualty incident knowledge and perceived importance of incorporating competencies regarding mass casualty incidents into baccalaureate nursing programs by faculty in Louisiana. A total of 285 educators in baccalaureate nursing programs in Louisiana were asked to complete the survey instrument; usable surveys was collected from 166 participants (58%). Results indicated participants had limited training and life experiences regarding mass casualty incidents, as well as limited knowledge of mass casualty incidents. However, participants perceived mass casualty incident instruction as important for inclusion in nursing curricula. There was a positive relationship between self-perceived knowledge of mass casualty incidents and perceived importance of including these competencies into the nursing curriculum. These findings suggest schools of nursing take steps to identify or train a pool of educators who can teach mass casualty incident preparation.

Large-scale gene trapping in C57BL/6N mouse embryonic stem cells.

We report the construction and analysis of a mouse gene trap mutant resource created in the C57BL/6N genetic background containing more than 350,000 sequence-tagged embryonic stem (ES) cell clones. We also demonstrate the ability of these ES cell clones to contribute to the germline and produce knockout mice. Each mutant clone is identified by a genomic sequence tag representing the exact insertion location, allowing accurate prediction of mutagenicity and enabling direct genotyping of mutant alleles. Mutations have been identified in more than 10,000 genes and show a bias toward the first intron. The trapped ES cell lines, which can be requested from the Texas A&M Institute for Genomic Medicine, are readily available to the scientific community.

Odor analysis of decomposing buried human remains.

This study, conducted at the University of Tennessee's Anthropological Research Facility (ARF), lists and ranks the primary chemical constituents which define the odor of decomposition of human remains as detected at the soil surface of shallow burial sites. Triple sorbent traps were used to collect air samples in the field and revealed eight major classes of chemicals which now contain 478 specific volatile compounds associated with burial decomposition. Samples were analyzed using gas chromatography-mass spectrometry (GC-MS) and were collected below and above the body, and at the soil surface of 1.5-3.5 ft. (0.46-1.07 m) deep burial sites of four individuals over a 4-year time span. New data were incorporated into the previously established Decompositional Odor Analysis (DOA) Database providing identification, chemical trends, and semi-quantitation of chemicals for evaluation. This research identifies the "odor signatures" unique to the decomposition of buried human remains with projected ramifications on human remains detection canine training procedures and in the development of field portable analytical instruments which can be used to locate human remains in shallow burial sites.

Clinical research trials: factors that influence and hinder participation.

The objective of this study was to examine factors that influence and hinder participation of African Americans in clinical research trials. Specifically, we examined and compared the perceived advantages and disadvantages to participation in clinical research trials, exposure to selected experiences prior to participation (i.e., who and what influenced the decision to participate or not), and perceptions regarding necessary preparation for participation in clinical research trials. Three hundred eighty six African Americans responded to the questionnaire that was administered in the study. As expected, African Americans who had previously participated in a clinical research trial agreed with factors perceived as advantages to participation, while respondents who had not previously participated endorsed factors perceived as potential disadvantages to participation in clinical research trials.

Cultural competence of baccalaureate nursing faculty: are we up to the task?

Reported low levels of cultural competence among baccalaureate nursing students, as well as professional nurses, have raised questions about nursing faculty's readiness to prepare culturally competent graduates. This study examined cultural competence among faculty of baccalaureate nursing programs in Louisiana. Using a five-point Likert-type scale, the respondents were asked to express their level of agreement with statements addressing the components of cultural competence. The data analysis revealed the respondents' rating of their cultural awareness (4.14), desire (3.67) knowledge (3.65), skills (3.65), and encounters (3.56). Overall cultural competence was rated as 3.73. When the overall cultural competence index was regressed on the index of each subscale, the cultural knowledge index and the cultural encounter index significantly explained 87% of the variance in the model. These findings suggest that faculty should be encouraged to attend continuing education programs on cultural competence to improve their knowledge in this area. This continuing education, coupled with more local and/or international cross-cultural encounters should significantly improve the overall cultural competence of the respondents.

Further safety enhancement of a specialized power assisted tricycle for a child with osteogenesis imperfecta type III and design of an adjustble hand power tricycle.

Several tricycles, one a customized power assisted tricycle, and the second a hand powered tricycle were developed, which offered a unique opportunity to serve multiple purposes in several children's development throughout Wyoming. In Both cases these tricycles provide the children with the opportunity to gain muscle mass, strength, coordination, and confidence. The power assisted tricycle was completed as a senior design project in 2002, and over time safety enhancements have been completed to make the tricycle safer for operation. Unfortunately, the safety system enhancements were not acceptable for it to be released for use. For this reason the tricycle was further redesigned to include more redundant safety systems which will allow the tricycle to be safe for the child's use. The second tricycle was designed to allow for a group of children who have limited use of their legs, to be able to use the same tricycle to give them more upper body strength. A gear system using multiple gear sprockets was adapted to a preexisting tricycle to provide hand power rather than foot power. Without these improvements, the children would not have the opportunity to use these tricycles to help with their development.

Decompositional odor analysis database.

This study, conducted at the University of Tennessee's Anthropological Research Facility (ARF), describes the establishment of the Decompositional Odor Analysis (DOA) Database for the purpose of developing a man-portable, chemical sensor capable of detecting clandestine burial sites of human remains, thereby mimicking canine olfaction. This "living" database currently spans the first year and a half of burial, providing identification, chemical trends and semi-quantitation of chemicals liberated below, above and at the surface of graves 1.5 to 3.5 ft deep (0.45 to 1.0 m) for four individuals. Triple sorbent traps (TSTs) were used to collect air samples in the field and revealed eight major classes of chemicals containing 424 specific volatile compounds associated with burial decomposition. This research is the first step toward identification of an "odor signature" unique to human decomposition with projected ramifications on cadaver dog training procedures and in the development of field portable analytical instruments which can be used to locate human remains buried in shallow graves.

Effect of shear on concentrated hydrous ferric floc rheology.

The primary interest of this work is to determine the effect of continuous shear, variable shear rate, and shear history on concentrated hydrous ferric floc rheology. The floc suspensions are strongly shear degrading with the behaviour being adequately described by a power law model. This is supported by images of the floc particles, which indicate a breakdown in floc structure, with the release of water and formation of smaller particles, after the application of shear. A shear rate sweep of the sample produces a hysteresis loop due to the time dependency of the samples. Higher shear rates are shown to destroy more structure, resulting in an overall decrease in floc viscosity. This is irreversible, and occurs due to a breakdown in floc structure to release trapped water and produce smaller floc particles. Shear also causes an instantaneous reduction in viscosity. This effect is instantaneously recoverable, and is due to a decrease in floc particle aggregation. Floc behaviour within the shear rate range 20-250 s(-1) is also adequately modelled by the Sisko model.

Effect of freeze-thaw process on partitioning of contaminants in ferric precipitate.

The primary interest of this work was to determine the processing conditions which will provide the most water removal from the precipitate after freezing and thawing. The work examined the effect of variables such as freezing time, freezing temperature, and pre-treatment steps, e.g. agitation or concentration, on the freeze thaw process of ferric precipitates. The extent of dewatering of freeze thawed samples was not significantly affected by freezing rate or curing time, provided the floc was completely frozen. However, a pre-concentration step was found to produce a more concentrated residual. The relatively low degree of structure within the ferric flocs makes them particularly suitable for freeze-thaw conditioning. Only a slight increase in leach out of contaminant from the floc was observed. Thus, the experiments indicate that this is a very simple and effective method of dewatering precipitates, which does not require the use of additional additives.

Clinical research trials: a comparison of African Americans who have and have not participated.

The purpose of this is study was to gain an understanding of the knowledge and perceptions African Americans have that influence decisions to participate or not participate in clinical research trials. A survey instrument designed to measure the key variables; knowledge and perceptions of clinical research processes, and selected demographic characteristics were utilized in this study. The major finding suggests that African Americans who have been participants in a clinical trial are more likely to participate in future clinical trials if details are provided in advance concerning the requirements and criteria for their participation.