Perspectives on the Implementation of Screening and Treatment for Depression and Alcohol Use Disorder in Primary Care in Colombia.

Depression and alcohol use disorder (AUD) greatly contribute to the burden of disease worldwide, and have large impact on Colombia's population. In this study, a qualitative analysis evaluates the implementation of a technology-supported model for screening, decision support, and digital therapy for depression and AUD in Colombian primary care clinics. Patient, provider, and administrator interviews were conducted, exploring attitudes towards depression and AUD, attitudes towards technology, and implementation successes and challenges. Researchers used qualitative methods to analyze interview themes. Despite stigma around depression and AUD, the model improved provider capacity to diagnose and manage patients, helped patients feel supported, and provided useful prevalence data for administrators. Challenges included limited provider time and questions about sustainability. The implementation facilitated the identification, diagnosis, and care of patients with depression and AUD. There is ongoing need to decrease stigma, create stronger networks of mental health professionals, and transition intervention ownership to the healthcare center.

Cardiopulmonary exercise testing in severe osteoarthritis: a crossover comparison of four exercise modalities.

Cardiopulmonary exercise testing is performed increasingly for cardiorespiratory fitness assessment and pre-operative risk stratification. Lower limb osteoarthritis is a common comorbidity in surgical patients, meaning traditional cycle ergometry-based cardiopulmonary exercise testing is difficult. The purpose of this study was to compare cardiopulmonary exercise testing variables and subjective responses in four different exercise modalities. In this crossover study, 15 patients with osteoarthritis scheduled for total hip or knee arthroplasty (mean (SD) age 68 (7) years; body mass index 31.4 (4.1) kg.m-2 ) completed cardiopulmonary exercise testing on a treadmill, elliptical cross-trainer, cycle and arm ergometer. Mean (SD) peak oxygen consumption was 20-30% greater on the lower limb modalities (treadmill 21.5 (4.6) (p < 0.001); elliptical cross-trainer (21.2 (4.1) (p < 0.001); and cycle ergometer (19.4 (4.2) ml.min-1 .kg-1 (p = 0.001), respectively) than on the arm ergometer (15.7 (3.7) ml.min-1 .kg-1 ). Anaerobic threshold was 25-50% greater on the lower limb modalities (treadmill 13.5 (3.1) (p < 0.001); elliptical cross-trainer 14.6 (3.0) (p < 0.001); and cycle ergometer 10.7 (2.9) (p = 0.003)) compared with the arm ergometer (8.4 (1.7) ml.min-1 .kg-1 ). The median (95%CI) difference between pre-exercise and peak-exercise pain scores was greater for tests on the treadmill (2.0 (0.0-5.0) (p = 0.001); elliptical cross-trainer (3.0 (2.0-4.0) (p = 0.001); and cycle ergometer (3.0 (1.0-5.0) (p = 0.001)), compared with the arm ergometer (0.0 (0.0-1.0) (p = 0.406)). Despite greater peak exercise pain, cardiopulmonary exercise testing modalities utilising the lower limbs affected by osteoarthritis elicited higher peak oxygen consumption and anaerobic threshold values compared with arm ergometry.

Generation and characterization of thiol-deficient Mycobacterium tuberculosis mutants.

Mycothiol (MSH) and ergothioneine (ERG) are thiols able to compensate for each other to protect mycobacteria against oxidative stress. Gamma-glutamylcysteine (GGC), another thiol and an intermediate in ERG biosynthesis has detoxification abilities. Five enzymes are involved in ERG biosynthesis, namely EgtA, EgtB, EgtC, EgtD and EgtE. The role of these enzymes in the production of ERG had been unclear. On the other hand, the enzyme MshA is known to be essential for MSH biosynthesis. In this manuscript, we describe the raw data of the generation and characterization of Mycobacterium tuberculosis (M.tb) mutants harbouring a deletion of the gene coding for each of these enzymes, and the raw data of the phenotypic characterization of the obtained thiol-deficient M.tb mutants. High throughput screening (HTS) of off-patent drugs and natural compounds revealed few compounds that displayed a higher activity against the thiol-deficient mutants relative to the wild-type strain. The mode of action of these drugs was further investigated. Raw data displaying these results are described here.

The functional interplay of low molecular weight thiols in Mycobacterium tuberculosis.

BACKGROUND: Three low molecular weight thiols are synthesized by Mycobacterium tuberculosis (M.tb), namely ergothioneine (ERG), mycothiol (MSH) and gamma-glutamylcysteine (GGC). They are able to counteract reactive oxygen species (ROS) and/or reactive nitrogen species (RNS). In addition, the production of ERG is elevated in the MSH-deficient M.tb mutant, while the production of MSH is elevated in the ERG-deficient mutants. Furthermore, the production of GGC is elevated in the MSH-deficient mutant and the ERG-deficient mutants. The propensity of one thiol to be elevated in the absence of the other prompted further investigations into their interplay in M.tb. METHODS: To achieve that, we generated two M.tb mutants that are unable to produce ERG nor MSH but are able to produce a moderate (ΔegtD-mshA) or significantly high (ΔegtB-mshA) amount of GGC relative to the wild-type strain. In addition, we generated an M.tb mutant that is unable to produce GGC nor MSH but is able to produce a significantly low level of ERG (ΔegtA-mshA) relative to the wild-type strain. The susceptibilities of these mutants to various in vitro and ex vivo stress conditions were investigated and compared. RESULTS: The ΔegtA-mshA mutant was the most susceptible to cellular stress relative to its parent single mutant strains (ΔegtA and ∆mshA) and the other double mutants. In addition, it displayed a growth-defect in vitro, in mouse and human macrophages suggesting; that the complete inhibition of ERG, MSH and GGC biosynthesis is deleterious for the growth of M.tb. CONCLUSIONS: This study indicates that ERG, MSH and GGC are able to compensate for each other to maximize the protection and ensure the fitness of M.tb. This study therefore suggests that the most effective strategy to target thiol biosynthesis for anti-tuberculosis drug development would be the simultaneous inhibition of the biosynthesis of ERG, MSH and GGC.

Compounds with Potential Activity against Mycobacterium tuberculosis.

The high acquisition rate of drug resistance by Mycobacterium tuberculosis necessitates the ongoing search for new drugs to be incorporated in the tuberculosis (TB) regimen. Compounds used for the treatment of other diseases have the potential to be repurposed for the treatment of TB. In this study, a high-throughput screening of compounds against thiol-deficient Mycobacterium smegmatis strains and subsequent validation with thiol-deficient M. tuberculosis strains revealed that ΔegtA and ΔmshA mutants had increased susceptibility to azaguanine (Aza) and sulfaguanidine (Su); ΔegtB and ΔegtE mutants had increased susceptibility to bacitracin (Ba); and ΔegtA, ΔmshA, and ΔegtB mutants had increased susceptibility to fusaric acid (Fu). Further analyses revealed that some of these compounds were able to modulate the levels of thiols and oxidative stress in M. tuberculosis This study reports the activities of Aza, Su, Fu, and Ba against M. tuberculosis and provides a rationale for further investigations.

Gamma-glutamylcysteine protects ergothioneine-deficient Mycobacterium tuberculosis mutants against oxidative and nitrosative stress.

Mycobacterium tuberculosis (M.tb.), the causative agent of tuberculosis (TB), cannot synthesize GSH, but synthesizes two major low molecular weight thiols namely mycothiol (MSH) and ergothioneine (ERG). Gamma-glutamylcysteine (GGC), an intermediate in GSH synthesis, has been implicated in the protection of lactic acid bacteria from oxidative stress in the absence of GSH. In mycobacteria, GGC is an intermediate in ERG biosynthesis, and its formation is catalysed by EgtA (GshA). GGC is subsequently used by EgtB in the formation of hercynine-sulphoxide-GGC. In this study, M.tb. mutants harbouring unmarked, in-frame deletions in each of the fives genes involved in ERG biosynthesis (egtA, egtB, egtC, egtD and egtE) or a marked deletion of the mshA gene (required for MSH biosynthesis) were generated. Liquid chromatography tandem mass spectrometry analyses (LC-MS) revealed that the production of GGC was elevated in the MSH-deficient and the ERG-deficient mutants. The ERG-deficient ΔegtB mutant which accumulated GGC was more resistant to oxidative and nitrosative stress than the ERG-deficient, GGC-deficient ΔegtA mutant. This implicates GGC in the detoxification of reactive oxygen and nitrogen species in M.tb.

The Kenya cancer research and control stakeholder program: Evaluating a bilateral partnership to strengthen national cancer efforts.

Background: In response to a growing cancer burden and need for improved coordination among stakeholders in Kenya, the US National Cancer Institute and the Kenya Ministry of Health collaboratively hosted a stakeholder meeting in 2014 which identified four priority areas of need (research capacity building, pathology and cancer registries, cancer awareness and education, and health system strengthening) and developed corresponding action plans. Methods: Surveys were conducted with participants to collect input on the progress and impact of the 2014 stakeholder meeting. Findings: Of 69 eligible participants, 45 responded from academia, healthcare institutions, civil society, government, and international agencies. Of the four technical focus areas, three have continued to conduct working group meetings and two have conducted in-person meetings to review and update their respective action plans. Accomplishments linked to or enhanced by t meeting include: Kenyan and international support for expansion of population-based cancer registries, increased availability of prioritized diagnostic tests in selected regional referral hospitals, a greater focus on development of a national cancer research agenda, strategic planning for a community education strategy for cancer awareness, and improved coordination of partners through in-country technical assistance. Interpretation: The Stakeholder Program has successfully united individuals and organizations to improve cancer control planning in Kenya, and has enhanced existing efforts and programs across the country. This model of partners working in parallel on prioritized track activities has supported development of long term coordination of cancer research and control activities sustainable by the Kenyan government and Kenyan institutions.

Childhood body mass index and endothelial dysfunction evaluated by peripheral arterial tonometry in early midlife.

BACKGROUND/OBJECTIVES: Endothelial dysfunction predicts mortality but it is unknown whether childhood obesity predicts adult endothelial dysfunction. The aim of this study was to determine whether anthropometric indices of body fat in childhood, adolescence and early midlife are associated with endothelial dysfunction in early midlife. SUBJECTS/METHODS: Participants belonged to a representative birth cohort of 1037 individuals born in Dunedin, New Zealand in 1972 and 1973 and followed to age 38 years, with 95% retention (the Dunedin Multidisciplinary Health and Development Study). We assessed anthropometric indices of obesity at ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32 and 38 years. We tested associations between endothelial function assessed by peripheral arterial tonometry (PAT) at age 38 and; age 38 cardiovascular risk factors; age 3 body mass index (BMI); and four BMI trajectory groups from childhood to early midlife. RESULTS: Early midlife endothelial dysfunction was associated with BMI, large waist circumference, low high-density lipoprotein cholesterol, low cardiorespiratory fitness and increased high-sensitivity C-reactive protein. After adjustment for sex and childhood socioeconomic status, 3-year-olds with BMI 1 s.d. above the mean had Framingham-reactive hyperemia index (F-RHI) ratios that were 0.10 below those with normal BMI (ß=-0.10, 95% confidence interval (CI) -0.17 to -0.03, P=0.007) at age 38. Cohort members in the 'overweight', 'obese' and 'morbidly obese' trajectories had F-RHI ratios that were 0.08 (ß=-0.08, 95% CI -0.14 to -0.03, P=0.003), 0.13 (ß=-0.13, 95% CI -0.21 to -0.06, P<0.001) and 0.17 (ß=-0.17, 95% CI -0.33 to -0.01, P=0.033), respectively, below age-peers in the 'normal' trajectory. CONCLUSIONS: Childhood BMI and the trajectories of BMI from childhood to early midlife predict endothelial dysfunction evaluated by PAT in early midlife.

Influence of cow breed type, age and previous lactation status on cow height, calf growth, and patterns of body weight, condition, and blood metabolites for cows grazing bahiagrass pastures.

This study was initiated to evaluate performance and patterns of cow traits and blood metabolites of 3 breeds of cows grazing bahiagrass (Paspalum notatum Flügge) pastures in central Florida. Purebred cows (n = 411) of either Angus (Bos taurus), Brahman (Bos indicus), or Romosinuano (Bos taurus) breeding, rotationally grazed (moved twice weekly) bahiagrass pastures year-round, and received bahiagrass hay supplemented with molasses and soyhulls or legume hay supplemented with unfortified molasses from October to June each production year. At monthly intervals, all cows were weighed, measured at the hip (HH), scored for BCS, and blood samples collected by jugular puncture from 10 cows per cow breed/block group for plasma urea N (PUN), glucose and non-esterified fatty acids (NEFA). Data were analyzed on cows that calved with a statistical model that included fixed effects of year, cowage, cow breed, month, block, supplement group (n = 2, but not presented), and whether the cow weaned a calf the previous year. Cow was a repeated observation over mo. Three-way interactions involving monthly patterns for cowage x year, year x lactation status the previous year, cowage × cow breed, year × cow breed, and cow breed × lactation status the previous year were significant (P < 0.001) for BW and BCS. The interaction for cowage × month was also significant (P < 0.05) for glucose, and cow breed × month was important (P < 0.01) for PUN, glucose, and NEFA. Important differences included: 1) greater BW and BCS for older cows compared to 3-yr old cows; 2) greater BW and BCS before calving for cows that did not lactate the previous year; 3) PUN levels were above 11 mg/dl except for February, August and September, and was generally greater in tropically adapted breeds; 4) GLU was greatest in Brahman, lowest in Angus, and intermediate in Romosinuano cows; and 5) plasma levels of NEFA escalated at calving and then declined, but Brahman cows maintained greater (P < 0.05) levels from calving until weaning than the other breeds. Cows that lactated the previous year had less NEFA than those that did not lactate. Brahman cows were less fertile than Bos taurus breeds, and weaned heavier calves.

A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score.

Genome-wide association studies have identified a number of single-nucleotide polymorphisms (SNPs) that are associated with psychiatric diseases. Increasing body of evidence suggests a complex connection of SNPs and the transcriptional and epigenetic regulation of gene expression, which is poorly understood. In the current study, we investigated the interplay between genetic risk variants, shifts in methylation and mRNA levels in whole blood from 223 adolescents distinguished by a risk for developing psychiatric disorders. We analyzed 37 SNPs previously associated with psychiatric diseases in relation to genome-wide DNA methylation levels using linear models, with Bonferroni correction and adjusting for cell-type composition. Associations between DNA methylation, mRNA levels and psychiatric disease risk evaluated by the Development and Well-Being Assessment (DAWBA) score were identified by robust linear models, Pearson's correlations and binary regression models. We detected five SNPs (in HCRTR1, GAD1, HADC3 and FKBP5) that were associated with eight CpG sites, validating five of these SNP-CpG pairs. Three of these CpG sites, that is, cg01089319 (GAD1), cg01089249 (GAD1) and cg24137543 (DIAPH1), manifest in significant gene expression changes and overlap with active regulatory regions in chromatin states of brain tissues. Importantly, methylation levels at cg01089319 were associated with the DAWBA score in the discovery group. These results show how distinct SNPs linked with psychiatric diseases are associated with epigenetic shifts with relevance for gene expression. Our findings give a novel insight on how genetic variants may modulate risks for the development of psychiatric diseases.

Comparison of three targeted approaches to screening for abdominal aortic aneurysm based on cardiovascular risk.

BACKGROUND: Abdominal aortic aneurysm (AAA) continues to be a significant health burden yet few countries have implemented a comprehensive screening programme. Screening typically places emphasis on men aged over 65 years; however, there is concern that other at-risk groups may be underidentified. The present study examined three potential screening strategies based on cardiovascular risk. METHODS: The prevalence of AAA was determined by abdominal ultrasound imaging in over 50-year-olds of either sex undergoing coronary angiography, vascular laboratory assessment of peripheral arterial disease, or community-based cardiovascular disease (CVD) event risk assessment. A fourth group, consisting of volunteers aged over 60 years who had no symptoms or signs of cardiovascular disease, was used as a comparator group. RESULTS: A total AAA prevalence of 4·4 per cent was detected across all three strategies (137 of 3142 individuals), compared with 1·0 per cent in the CVD-free group. Male sex, age and smoking were all associated with greater AAA prevalence. Although AAA prevalence was lowest using the community-based strategy, those with an AAA detected were on average 7 years younger than those with AAAs detected with the other two strategies (P < 0·001). CONCLUSION: Different strategies, based on CVD risk, resulted in AAA prevalence rates that were significantly greater than that in CVD-free individuals. This may provide opportunities for a targeted approach to community AAA screening in parts of the world where more sophisticated national screening programmes do not exist.

Variation in Arterial Access for Invasive Coronary Procedures in New Zealand: A National Analysis (ANZACS-QI 5).

BACKGROUND: Radial arterial access (RA) and femoral arterial access (FA) rates for invasive coronary angiography (ICA) vary widely internationally. The European Society of Cardiology (ESC) suggests default RA is feasible. We aim to investigate the variation in RA rates across all New Zealand public hospitals. METHODS AND RESULTS: Patient characteristics, procedural details, and inpatient outcome data were collected in the All New Zealand Acute Coronary Syndrome - Quality Improvement (ANZACS-QI) registry on consecutive patients undergoing ICA over five months. Of the 5894 ICAs 81% were via RA. Hospitals averaged 25 - 176 procedures/month (46.5% - 96.4% via RA). Operators averaged 17 procedures/month. Those performing more than 20 ICAs/month had RA rates between 61% - 99%. Of the 75 operators, 69% met the ESC recommendation. After multivariable adjustment higher operator (RR 1.12, CI 1.09 - 1.30) and hospital (RR 1.21, CI 1.15 - 1.28) volume were independent predictors of RA. Those with prior CABG (RR 0.51, CI 0.45 - 0.57), STEMI <12h (RR 0.91, CI 0.87 - 0.96), and female sex (RR 0.96, CI 0.94 - 0.99) were less likely to receive RA. CONCLUSIONS: New Zealand has a high RA rate for ICAs. Rates vary substantially between both operators and centres. Radial arterial was highest amongst the highest volume operators and centres.

Prevalence of abdominal aortic aneurysm in patients referred for transthoracic echocardiography.

BACKGROUND: Previous studies have documented the prevalence of abdominal aortic aneurysm (AAA) during transthoracic echocardiography, but the effect of such screening on subsequent vascular interventions remains unclear. AIM: This study aimed to determine the utility of opportunistic selective screening for AAA in a contemporary large series of patients having transthoracic echocardiography. METHODS: Subjects aged 50 years or older having transthoracic echocardiography had scanning of the infrarenal aorta in a consecutive series of 10 403 men and women. RESULTS: The study subjects had a mean age of 70.2 ± 10.7 years, and 54.1% were men. There was a 3.5% (95% confidence interval (CI) 3.2-3.9%) prevalence of AAA with a median diameter of 39 mm (interquartile range 32 mm-48 mm). In males ≥ 65 years the prevalence of newly diagnosed AAA was 6.2% (95% CI 5.5-7.0%). Of those with newly diagnosed AAA, 39.7% underwent AAA repair. Age and male gender were associated with AAA prevalence. After adjustment for age and gender, echocardiographic variables associated with AAA were left ventricular end diastolic dimension (odds ratio (OR) 1.02, 95%CI 1.01-1.04), interventricular septum thickness (OR 1.11, 95% CI 1.06-1.17), left ventricular posterior wall thickness (OR 1.09, 95% CI 1.03-1.15), left atrial diameter (OR 1.04, 95% CI 1.02-1.07) and aortic root diameter (OR 1.09, 95% CI 1.06-1.11). CONCLUSIONS: This study revealed a high prevalence of newly diagnosed AAA in a group of older men having cardiac evaluation. There was a relationship of increasing age with AAA, and a significant proportion of newly diagnosed subjects were not suitable for AAA repair.

Storm-induced sea-ice breakup and the implications for ice extent.

The propagation of large, storm-generated waves through sea ice has so far not been measured, limiting our understanding of how ocean waves break sea ice. Without improved knowledge of ice breakup, we are unable to understand recent changes, or predict future changes, in Arctic and Antarctic sea ice. Here we show that storm-generated ocean waves propagating through Antarctic sea ice are able to transport enough energy to break sea ice hundreds of kilometres from the ice edge. Our results, which are based on concurrent observations at multiple locations, establish that large waves break sea ice much farther from the ice edge than would be predicted by the commonly assumed exponential decay. We observed the wave height decay to be almost linear for large waves--those with a significant wave height greater than three metres--and to be exponential only for small waves. This implies a more prominent role for large ocean waves in sea-ice breakup and retreat than previously thought. We examine the wider relevance of this by comparing observed Antarctic sea-ice edge positions with changes in modelled significant wave heights for the Southern Ocean between 1997 and 2009, and find that the retreat and expansion of the sea-ice edge correlate with mean significant wave height increases and decreases, respectively. This includes capturing the spatial variability in sea-ice trends found in the Ross and Amundsen-Bellingshausen seas. Climate models fail to capture recent changes in sea ice in both polar regions. Our results suggest that the incorporation of explicit or parameterized interactions between ocean waves and sea ice may resolve this problem.

Intra-individual changes of active matrix metalloproteinase-9 are associated with clinical in-stent restenosis of bare metal stents.

OBJECTIVES: Increased chronic postprocedural levels of active matrix metalloproteinase-9 (MMP-9) have been associated retrospectively with a history of in-stent restenosis (ISR). This study aimed to determine whether index or post-percutaneous coronary intervention (PCI) plasma levels of active MMP-9 are a predictor of subsequent clinical ISR, in a standard population of patients treated with bare metal coronary stents. METHODS: Four hundred thirty-two patients were prospectively recruited and sampled at index and 3 and 6 months after PCI. Those who developed symptomatic angiographically confirmed ISR were compared to randomly selected, asymptomatic controls, stratified by index presentation in a nested case-control design. Plasma samples were analyzed for the active form of MMP-9. RESULTS: In all, 35 patients (8.1%) developed ISR, and these were compared to 98 controls. The increase in active MMP-9 over 3 months was significantly greater in the ISR group (p = 0.030) and independent of the established risk factors. Index clinical presentation was not associated with acute changes in active MMP-9; however, patients with ST-elevation myocardial infarction had greater increases in active MMP-9 at 3 months. CONCLUSIONS: The change in active MMP-9 over 3 months after bare metal coronary stent placement appears to be independently associated with the development of ISR in a standard PCI population.

Pro-MMP-9/TIMP-1 ratio correlates poorly with a direct assessment of MMP-9 activity.

OBJECTIVE: To determine if the pro-MMP-9/TIMP-1 ratio is an accurate surrogate for endogenously active MMP-9 levels. METHODS: Plasma active MMP-9, pro-MMP-9 and TIMP-1 were measured in 295 patients. RESULTS: There was a weak negative correlation between the pro-MMP-9/TIMP-1 ratio and active MMP-9. TIMP-1 was more closely correlated with active MMP-9 than pro-MMP-9. CONCLUSION: Pro-MMP-9/TIMP-1 ratio measured with ELISA is not a good surrogate measure for active MMP-9, and direct measurements of active MMP-9 are therefore recommended.

Seasonal variation and stability of matrix metalloproteinase-9 activity and tissue inhibitor of matrix metalloproteinase-1 with storage at -80°C.

OBJECTIVE: To determine whether active matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 displayed seasonal variation and were stable in storage. METHODS: Plasma active MMP-9 and TIMP-1 were measured at three time-points in 163 individuals. RESULT: There was no evidence for seasonal variation or declining levels for up to three years of storage at -80°C. CONCLUSION: Active MMP-9 and TIMP-1 appear to be stable seasonally, and in storage for at least three years.