From data to decisions? Exploring how healthcare payers respond to the NHS Atlas of Variation in Healthcare in England.
Although information on variations in health service performance is now more widely available, relatively little is known about how healthcare payers use this information to improve resource allocation. We explore to what extent and how Primary Care Trusts (PCTs) in England have used the NHS Atlas of Variation in Healthcare, which has highlighted small area variation in rates of expenditure, activity and outcome. Data collection involved an email survey among PCT Chief Executives and a telephone follow-up to reach non-respondents (total response: 53 of 151 of PCTs, 35%). 45 senior to mid-level staff were interviewed to probe themes emerging from the survey. The data were analysed using a matrix-based Framework approach. Just under half of the respondents (25 of 53 PCTs) reported not using the Atlas, either because they had not been aware of it, lacked staff capacity to analyse it, or did not perceive it as applicable to local decision-making. Among the 28 users, the Atlas served as a prompt to understand variations and as a visual tool to facilitate communication with clinicians. Achieving clarity on which variations are unwarranted and agreeing on responsibilities for action appeared to be important factors in moving beyond initial information gathering towards decisions about resource allocation and behaviour change. Many payers were unable to use information on small area variations in expenditure, activity and outcome. To change this what is additionally required are appropriate tools to understand causes of unexplained variation, in particular unwarranted variation, and enable remedial actions to be prioritised in terms of their contribution to population health.


Tumor-specific recombinant idiotype immunisation after chemotherapy as initial treatment for follicular non-Hodgkin lymphoma.
Tumor-specific variable regions of the clonal immunoglobulin (idiotype, Id) expressed by B cell non-Hodgkin lymphoma (NHL) can be targeted by active immunotherapy. We conducted a phase I/II trial to determine the safety and immunogenicity of a patient-specific, recombinant, mammalian cell-derived Id protein conjugated to keyhole limpet hemocyanin (Id-KLH; MyVax personalised immunotherapy) in 22 patients with follicular NHL in first remission after chemotherapy. Subjects received five subcutaneous immunisations with MyVax plus locally administered granulocyte-macrophage colony-stimulating factor (GM-CSF). Among 21 evaluable patients, 62% mounted Id-specific immune responses. Evoked anti-Id antibodies recognised both recombinant Id and native Id, and could specifically stain autologous tumor cells. At median follow-up of more than 6 years, median progression-free survival is 38 months. Immunisation of follicular lymphoma patients with MyVax Id-KLH is safe and patients often mount tumor-specific immune responses. These results form the basis of a pivotal phase 3 trial of MyVax in follicular NHL.


Prognostic factors for predicting health-related quality of life after intramedullary nailing of tibial fractures: a randomized controlled trial.
Using tibial shaft fracture participants from a large, multicentre randomized controlled trial, we investigated if patient and surgical factors were associated with health-related quality of life (HRQoL) at one year post-surgery. The Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures (SPRINT) trial examined adults with an open or closed tibial shaft fracture who were treated with either reamed or unreamed intramedullary nails. HRQoL was assessed at hospital discharge (for pre-injury level) and at 12 months post-fracture using the Short Musculoskeletal Functional Assessment (SMFA) Dysfunction, SMFA Bother, 36-Item Short Form 36 (SF-36) Physical, and SF-36 Mental Component scores. We used multiple linear regression analysis to determine if baseline and surgical factors, as well as post-intervention procedures within one year of fracture, were associated with these HRQoL outcomes. Significance was set at p < 0.01. We hypothesize that, irrespective of the four measures used, prognosis is guided by both modifiable and non-modifiable factors and that patients do not return to their pre-injury level of function, nor HRQoL. For patient and surgical factors, only pre-injury quality of life and isolated fracture showed a statistical effect on all four HRQoL outcomes, while high-energy injury mechanism, smoking, and race or ethnicity, demonstrated statistical significance for three of the four HRQoL outcomes. Patients who did not require reoperation in response to infection, the need for bone grafts, and/or the need for implant exchanges had statistically superior HRQoL outcomes than those who did require intervention within one year after initial tibial fracture nailing. We identified several baseline patient factors, surgical factors, and post-intervention procedures within one year after intramedullary nailing of a tibial shaft fracture that may influence a patient's HRQoL.Cite this article: Bone Jt Open 2021;2(1):22-32.


Cottonseed meal (gossypol) toxicosis in a swine herd.
Cottonseed meal (CSM) that contained a high concentration of free gossypol was inadvertently used as a protein supplement, without appropriate iron supplementation, for a swine herd in Illinois. Fifty percent of 300 grower and finishing swine died, and an additional 20% became ill during a 4- to 6-week period. Clinical signs included respiratory distress and abdominal distention. At necropsy, the hearts were diffusely pale, flaccid, and rounded because of dilatation of all 4 chambers, the livers were large and congested, and hydropericardium, hydrothorax, and ascites were evident. Histologic changes consisted of diffuse myocardial fiber atropy with perinuclear vacuolation, and multifocal myocardial and skeletal muscle necrosis. Changes in the liver included marked centrilobular congestion, loss of hepatocytes, and fatty degeneration. Differential diagnoses included monensin, selenium, and gossypol toxicoses, and vitamin E/selenium deficiency. Analyzed feed samples did not contain monensin. Feed selenium concentrations ranged from 428 to 1,513 micrograms/kg, and iron concentrations from 160 to 180 mg/kg. Cottonseed meal (3 to 10%) was detected by feed microscopy. A sample of the 40% protein supplement contained 19% CSM and 1,300 mg of free gossypol/kg, whereas feed samples contained 200 to 400 mg of free gossypol/kg. The history, clinical signs, pathologic findings, and feed analyses were compatible with a diagnosis of gossypol toxicosis. Cottonseed meal, a high-protein supplement used widely in southern United States, may contain gossypol (a polyphenolic binaphthalene pigment), which in its free form is especially toxic to simple-stomached animals. If CSM is used, supplementation with ferrous sulfate is recommended at a 1:1 weight ratio with free gossypol, up to 400 mg of FeSO4/kg.


Genome-Wide Natural Selection Signatures Are Linked to Genetic Risk of Modern Phenotypes in the Japanese Population.
Elucidation of natural selection signatures and relationships with phenotype spectra is important to understand adaptive evolution of modern humans. Here, we conducted a genome-wide scan of selection signatures of the Japanese population by estimating locus-specific time to the most recent common ancestor using the ascertained sequentially Markovian coalescent (ASMC), from the biobank-based large-scale genome-wide association study data of 170,882 subjects. We identified 29 genetic loci with selection signatures satisfying the genome-wide significance. The signatures were most evident at the alcohol dehydrogenase (ADH) gene cluster locus at 4q23 (PASMC = 2.2 × 10-36), followed by relatively strong selection at the FAM96A (15q22), MYOF (10q23), 13q21, GRIA2 (4q32), and ASAP2 (2p25) loci (PASMC < 1.0 × 10-10). The additional analysis interrogating extended haplotypes (integrated haplotype score) showed robust concordance of the detected signatures, contributing to fine-mapping of the genes, and provided allelic directional insights into selection pressure (e.g., positive selection for ADH1B-Arg48His and HLA-DPB1*04:01). The phenome-wide selection enrichment analysis with the trait-associated variants identified a variety of the modern human phenotypes involved in the adaptation of Japanese. We observed population-specific evidence of enrichment with the alcohol-related phenotypes, anthropometric and biochemical clinical measurements, and immune-related diseases, differently from the findings in Europeans using the UK Biobank resource. Our study demonstrated population-specific features of the selection signatures in Japanese, highlighting a value of the natural selection study using the nation-wide biobank-scale genome and phenotype data.


Arap1 Deficiency Causes Photoreceptor Degeneration in Mice.
Small guanosine triphosphatase (GTPase) ADP-ribosylation factors (Arfs) regulate membrane traffic and actin reorganization under the control of GTPase-activating proteins (GAPs). Arap1 is an Arf-directed GAP that inhibits the trafficking of epidermal growth factor receptor (EGFR) to the early endosome, but the diversity of its functions is incompletely understood. The aim of this study was to determine the role of Arap1 in the mammalian retina. Genetically engineered Arap1 knockout mice were screened for ocular abnormalities in the National Institutes of Health Knockout Mouse Production and Phenotyping (KOMP2) Project. Arap1 knockout and wild-type eyes were imaged using optical coherence tomography and fundus photography, and analyzed by immunohistochemistry. Arap1-/- mice develop a normal appearing retina, but undergo photoreceptor degeneration starting at 4 weeks postnatal age. The fundus appearance of mutants is notable for pigmentary changes, optic nerve pallor, vascular attenuation, and outer retinal thinning, reminiscent of retinitis pigmentosa in humans. Immunohistochemical studies suggest the cell death is predominantly in the outer nuclear layer. Functional evaluation of the retina by electroretinography reveals amplitudes are reduced. Arap1 is detected most notably in Müller glia, and not in photoreceptors, implicating a role for Müller glia in photoreceptor survival. Arap1 is necessary for normal photoreceptor survival in mice, and may be a novel gene relevant to human retinal degenerative processes, although its mechanism is unknown. Further studies in this mouse model of retinal degeneration will give insights into the cellular functions and signaling pathways in which Arap1 participates.


Electrically induced static exercise elicits a pressor response in the decerebrate rat.
1. The purpose of this investigation was to determine if activation of the exercise pressor reflex in the decerebrate rat induced circulatory responses comparable to those reported in large mammalian species. 2. To activate both mechanically and metabolically sensitive afferent fibres, static hindlimb contractions were induced by stimulating the cut ends of L4 and L5 spinal ventral roots in Sprague-Dawley rats (300-400 g). To selectively stimulate mechanically sensitive receptors, hindlimb muscles were passively stretched. 3. In intact halothane-anaesthetized animals (n = 10), static contraction and passive stretch induced a decrease in mean arterial pressure (Delta MAP = -17 +/- 3 and -8 +/- 1 mmHg for contraction and stretch, respectively) and heart rate (HR). In contrast, MAP increased 23 +/- 2 mmHg during contraction and 19 +/- 3 mmHg during stretch in decerebrate rats (n = 10). These pressor responses were accompanied by a significant tachycardia. In decerebrate animals, the reintroduction of halothane attenuated the increase in MAP and HR caused by both contraction and stretch. 4. In both anaesthetized and decerebrate rats, sectioning the spinal dorsal roots innervating the activated skeletal muscle eliminated responses to contraction and stretch. This finding indicated that an intramuscular neural reflex mediated the response to each stimulus. 5. The results demonstrate that a decerebrate preparation in the rat is a reliable model for the study of the exercise pressor reflex. Development of the model would enable the study of this reflex in a variety of pathological conditions and allow investigation of the mechanisms controlling cardiovascular responses to exercise in health and disease.


Social determinants of mental disorders and the Sustainable Development Goals: a systematic review of reviews.
Mental health has been included in the UN Sustainable Development Goals. However, uncertainty exists about the extent to which the major social determinants of mental disorders are addressed by these goals. The aim of this study was to develop a conceptual framework for the social determinants of mental disorders that is aligned with the Sustainable Development Goals, to use this framework to systematically review evidence regarding these social determinants, and to identify potential mechanisms and targets for interventions. We did a systematic review of reviews using a conceptual framework comprising demographic, economic, neighbourhood, environmental events, and social and culture domains. We included 289 articles in the final Review. This study sheds new light on how the Sustainable Development Goals are relevant for addressing the social determinants of mental disorders, and how these goals could be optimised to prevent mental disorders.


Lipodystrophy, insulin resistance, and adiponectin concentration in HIV-infected children and adolescents.
Alterations of fat distribution and insulin resistance are associated with increased risk of metabolic derangements and cardiovascular disease. HIV-infected adult patients on antiretroviral treatment often show lipodystrophy, insulin resistance and hypoadiponectinemia, but data in children are controversial. We investigated serum adiponectin concentration in a cohort of HIV-infected youths, and we assessed the relationships with lipodystrophy and insulin resistance. We studied 36 HIV-infected patients (aged 5.0 - 19.4 years), and 171 healthy subjects (aged 4.9 - 17.9 years) for adiponectin measurements. All patients underwent body composition assessment by dual-energy x-ray absorptiometry, and an oral glucose tolerance test to determine the fasting insulin concentration, the insulin area under the curve (AUC), and the HOMA index. Adiponectin serum concentration was measured by an immunoenzymatic assay. Sixteen patients had central fat accumulation, 6 had peripheral lipoatrophy, 5 had a mixed phenotype, and the remaining 9 were non-lipodystrophic. Fasting insulin, insulin AUC, and HOMA index were significantly higher in patients with central fat adiposity and mixed phenotype than in the other two groups. The patients of the former two groups had adiponectin concentration much lower than healthy controls, and patients with peripheral lipoatrophy or normal phenotype had normal concentration. Low adiponectin concentration is associated to central fat and mixed lipohypertrophy, and to signs of insulin resistance in HIV-infected youths. Strict monitoring of metabolic and cardiovascular evolution should be performed in these patients.


Functional characterization of E. coli LptC: interaction with LPS and a synthetic ligand.
Lipopolysaccharide (LPS), the main cell-surface molecular constituent of Gram-negative bacteria, is synthesized in the inner membrane (IM) and transported to the outer membrane (OM) by the Lpt (lipopolysaccharide transport) machinery. Neosynthesized LPS is first flipped by MsbA across the IM, then transported to the OM by seven Lpt proteins located in the IM (LptBCFG), in the periplasm (LptA), and in the OM (LptDE). A functional OM is essential to bacterial viability and requires correct placement of LPS in the outer leaflet. Therefore, LPS biogenesis represents an ideal target for the development of novel antibiotics against Gram-negative bacteria. Although the structures of Lpt proteins have been elucidated, little is known about the mechanism of LPS transport, and few data are available on Lpt–LPS binding. We report here the first determination of the thermodynamic and kinetic parameters of the interaction between LptC and a fluorescent lipo-oligosaccharide (fLOS) in vitro. The apparent dissociation constant (Kd) of the fLOS–LptC interaction was evaluated by two independent methods. The first was based on fLOS capture by resin-immobilized LptC; the second used quenching of LptC intrinsic fluorescence by fLOS in solution. The Kd values by the two methods (71.4 and 28.8 μm, respectively) are very similar, and are of the same order of magnitude as that of the affinity of LOS for the upstream transporter, MsbA. Interestingly, both methods showed that fLOS binding to LptC is mostly irreversible, thus reflecting the fact that LPS can be released from LptC only when energy is supplied by ATP or in the presence of a higher-affinity LptA protein. A fluorescent glycolipid was synthesized: this also interacted irreversibly with LptC, but with lower affinity (apparent Kd=221 μM). This compound binds LptC at the LPS binding site and is a prototype for the development of new antibiotics targeting LPS transport in Gram-negative bacteria.


KIM-1-mediated phagocytosis reduces acute injury to the kidney.
Kidney injury molecule 1 (KIM-1, also known as TIM-1) is markedly upregulated in the proximal tubule after injury and is maladaptive when chronically expressed. Here, we determined that early in the injury process, however, KIM-1 expression is antiinflammatory due to its mediation of phagocytic processes in tubule cells. Using various models of acute kidney injury (AKI) and mice expressing mutant forms of KIM-1, we demonstrated a mucin domain-dependent protective effect of epithelial KIM-1 expression that involves downregulation of innate immunity. Deletion of the mucin domain markedly impaired KIM-1-mediated phagocytic function, resulting in increased proinflammatory cytokine production, decreased antiinflammatory growth factor secretion by proximal epithelial cells, and a subsequent increase in tissue macrophages. Mice expressing KIM-1Δmucin had greater functional impairment, inflammatory responses, and mortality in response to ischemia- and cisplatin-induced AKI. Compared with primary renal proximal tubule cells isolated from KIM-1Δmucin mice, those from WT mice had reduced proinflammatory cytokine secretion and impaired macrophage activation. The antiinflammatory effect of KIM-1 expression was due to the interaction of KIM-1 with p85 and subsequent PI3K-dependent downmodulation of NF-κB. Hence, KIM-1-mediated epithelial cell phagocytosis of apoptotic cells protects the kidney after acute injury by downregulating innate immunity and inflammation.


Effects of five days of bed rest with intermittent centrifugation on neurovestibular function.
We tested whether intermittent short-radius centrifugation was effective for mitigating alteration in balance and gait following bed rest. Ten male subjects were exposed to 5 days of 6° head-down tilt bed rest with: (a) no countermeasure; (b) daily 1-g centrifugation for a continuous 30-min period; and (c) daily 1-g centrifugation for six periods of 5 min. During and after the bed rest, subjects were asked to scale the severity of neurovestibular symptoms that followed centrifugation or 80° head-up tilt. Following the bed rest, equilibrium scores were derived from anterior-posterior sway while standing on a foam pad with the eyes open or closed while making pitch head movements, and gait was evaluated by grading subjects' performance during various locomotion tasks. At the beginning of bed rest, one single 30-min period of centrifugation induced more severe neurovestibular symptoms than six periods of 5-min centrifugation. After bed rest, although equilibrium scores and gait performance were not significantly altered, subjects felt less neurovestibular dysfunction with orthostatic stress when centrifugation was used. Centrifugation was effective at reducing the severity of neurovestibular symptoms after bed rest, but this decrease was not different between one or multiple daily sessions.


Peripheral quantitative computed tomography measures are associated with adult fracture risk: the Hertfordshire Cohort Study.
Peripheral quantitative computed tomography (pQCT) captures novel aspects of bone geometry that may contribute to fracture risk and offers the ability to measure both volumetric bone mineral density (vBMD) and a separation of trabecular and cortical compartments of bone, but longitudinal data relating measures obtained from this technique to incident fractures are lacking. Here we report an analysis from the Hertfordshire Cohort Study, where we were able to study associations between measures obtained from pQCT and DXA in 182 men and 202 women aged 60-75 years at baseline with incident fractures over 6 years later. Among women, radial cortical thickness (HR 1.72, 95% CI 1.16, 2.54, p=0.007) and cortical area (HR 1.91, 95% CI 1.27, 2.85, p=0.002) at the 66% slice were both associated with incident fractures; these results remained significant after adjustment for confounders (age, BMI, social class, cigarette smoking and alcohol consumption, physical activity, dietary calcium, HRT and years since menopause). Further adjustment for aBMD made a little difference to the results. At the tibia, cortical area (HR 1.58, 95% CI 1.10, 2.28, p=0.01), thickness (HR 1.49, 95% CI 1.08, 2.07, p=0.02) and density (HR 1.64, 95% CI 1.18, 2.26, p=0.003) at the 38% site were all associated with incident fractures with the cortical area and density relationships remaining robust to adjustment for the confounders listed above. Further adjustment for aBMD at this site did lead to attenuation of relationships. Among men, tibial stress-strain index (SSI) was predictive of incident fractures (HR 2.30, 95% CI 1.28, 4.13, p=0.005). Adjustment for confounding variables and aBMD did not render this association non-significant. In conclusion, we have demonstrated relationships between measures of bone size, density and strength obtained by pQCT and incident fracture. These relationships were attenuated but in some cases remained significant after adjustment for BMD measures obtained by DXA, suggesting that some additional information may be conferred by this assessment.


Prevalence of Impaired Kidney Function in the German Elderly: Results from the Berlin Aging Study II (BASE-II).
In aging populations with an ever-growing burden of risk factors such as obesity, diabetes, and hypertension, chronic kidney disease (CKD) is on the rise. However, little is known about its exact prevalence among elderly adults, and often albuminuria is not included in the definition of CKD. Moreover, novel equations for the estimated glomerular filtration rate (eGFR) have recently emerged, which have not been applied comprehensively to older adults. Data on CKD awareness among the elderly are sparse. To determine the prevalence of CKD among older adults by eGFR and albumin/creatinine ratio (ACR), compare the performance of 6 established and novel eGFR formulas, explore risk factors, and determine the awareness of CKD in a large cohort of community-dwelling elderly from Germany. A total of 1,628 subjects from the Berlin Aging Study II (BASE-II) were included in this analysis (mean age 68.7 years; 51.2% female). Extensive cross-sectional data on sociodemographics, lifestyle, medication, and diagnoses were inquired during structured interviews and a medical examination, and blood and urine parameters were measured. In all, 77.1% of the subjects had hypertension, 12.4% had diabetes, and 18.3% were obese. The prevalence of CKD strongly depended on the eGFR equations used: 25.4% (full age spectrum [FAS] equation), 24.6% (Berlin Initiative Study), 23.1% (Lund-Malmö revised), 19.3% (Cockcroft-Gault), 16.4% (Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI]), and 14.7% (Modification of Diet in Renal Disease [MDRD]). Of the subjects with an eGFRFAS <60 mL/min/1.73 m2 and/or an ACR >30 mg/g, only 3.9% were aware of having CKD. Polypharmacy, age, BMI, coronary artery disease, non-HDL cholesterol, and female sex were independently associated with CKD. CKD is prevalent among older adults in Germany, but awareness is low. The FAS equation detects higher rates of CKD than MDRD and CKD-EPI, which are most widely used at present. Also, when CKD is defined based on eGFR and albuminuria, considerably more people are identified than by eGFR alone. Finally, polypharmacy is associated with an increased risk for CKD in the elderly.


Association of the tyrosine kinase LCK with phospholipase C-gamma 1 after stimulation of the T cell antigen receptor.
Stimulation of the T cell antigen receptor (TCR) activates a protein tyrosine kinase and leads to the tyrosine phosphorylation of phosphoinositide-specific phospholipase C-gamma 1 (PLC gamma 1). The molecular interactions involved in this phosphorylation are not known. After stimulation of the TCR on Jurkat T cells, tyrosine-phosphorylated proteins of 36, 38, 58, and 63 kD coprecipitate with PLC gamma 1. An identical pattern of proteins precipitate with TrpE fusion proteins that contain the Src homology (SH) 2 domains of PLC gamma 1, indicating that these regions of PLC gamma 1 are responsible for binding. TCR stimulation leads to an association between the SH2 domains of PLC gamma 1 and a protein tyrosine kinase, which, by peptide mapping, is identical to p56lck. These studies establish that p56lck associates with PLC gamma 1 as a result of TCR stimulation of Jurkat cells, suggesting that p56lck plays a central role in coupling the TCR to the activation of PLC gamma 1.


Tailored DVDs: a novel strategy for educating racially and ethnically diverse older adults about their medicines.
The availability of comprehensive and accurate medication history information in electronic medical records and through electronic prescribing provides the opportunity to create tailored interventions based on individuals' particular medication information needs. To meet the challenges of providing medication information to low-literate English and Spanish speaking older adults, we sought to create individualized, culturally and linguistically inclusive medication education materials for older adults from diverse backgrounds. We used a mixed-method design including a systematic review, analysis of existing data, a telephone survey (n=326), and exploratory focus groups stratified by race/ethnicity and language spoken (11 focus groups; n=106) to identify what information about medications older adults need, want to learn, and in what format. We evaluated reactions to three DVDs at low-income senior community centers (2 focus groups; n=16). Exploratory focus groups provided insights on areas for improvement in patient-provider communication, and suggested use of vignettes and testimonials. Upon viewing, participants could relate to the testimonials in which actors portrayed people who have problems with their medications and were interested in the medication advice presented, especially when it was presented by a healthcare professional. Tailored medication education materials in English and Spanish DVD and print material format are suitable for low-literate audiences, acceptable to older adults, and feasible to implement using health IT. Virtually all households in the United States have a television, with most having a DVD player. DVD segments can be used in Internet links, physician office-based television, and consumer health IT applications.


Optical trapping of a spherically symmetric sphere in the ray-optics regime: a model for optical tweezers upon cells.
Since their invention in 1986, optical tweezers have become a popular manipulation and force measurement tool in cellular and molecular biology. However, until recently there has not been a sophisticated model for optical tweezers on trapping cells in the ray-optics regime. We present a model for optical tweezers to calculate the optical force upon a spherically symmetric multilayer sphere representing a common biological cell. A numerical simulation of this model shows that not only is the magnitude of the optical force upon a Chinese hamster ovary cell significantly three times smaller than that upon a polystyrene bead of the same size, but the distribution of the optical force upon a cell is also much different from that upon a uniform particle, and there is a 30% difference in the optical trapping stiffness of these two cases. Furthermore, under a small variant condition for the refractive indices of any adjacent layers of the sphere, this model provides a simple approximation to calculate the optical force and the stiffness of an optical tweezers system.


Reconciliation and interpretation of Big Bend National Park particulate sulfur source apportionment: results from the Big Bend Regional Aerosol and Visibility Observational Study--part I.
The Big Bend Regional Aerosol and Visibility Observational (BRAVO) study was an intensive monitoring study from July through October 1999 followed by extensive assessments to determine the causes and sources of haze in Big Bend National Park, located in Southwestern Texas. Particulate sulfate compounds are the largest contributor of haze at Big Bend, and chemical transport models (CTMs) and receptor models were used to apportion the sulfate concentrations at Big Bend to North American source regions and the Carbón power plants, located 225 km southeast of Big Bend in Mexico. Initial source attribution methods had contributions that varied by a factor of > or =2. The evaluation and comparison of methods identified opposing biases between the CTMs and receptor models, indicating that the ensemble of results bounds the true source attribution results. The reconciliation of these differences led to the development of a hybrid receptor model merging the CTM results and air quality data, which allowed a nearly daily source apportionment of the sulfate at Big Bend during the BRAVO study. The best estimates from the reconciliation process resulted in sulfur dioxide (SO2) emissions from U.S. and Mexican sources contributing approximately 55% and 38%, respectively, of sulfate at Big Bend. The distribution among U.S. source regions was Texas, 16%; the Eastern United States, 30%; and the Western United States, 9%. The Carbón facilities contributed 19%, making them the largest single contributing facility. Sources in Mexico contributed to the sulfate at Big Bend on most days, whereas contributions from Texas and Eastern U.S. sources were episodic, with their largest contributions during Big Bend sulfate episodes. On the 20% of the days with the highest sulfate concentrations, U.S. and Mexican sources contributed approximately 71% and 26% of the sulfate, respectively. However, on the 20% of days with the lowest sulfate concentrations, Mexico contributed 48% compared with 40% for the United States.


Leader β-cells coordinate Ca2+ dynamics across pancreatic islets in vivo.
Pancreatic β-cells form highly connected networks within isolated islets. Whether this behaviour pertains to the situation in vivo, after innervation and during continuous perfusion with blood, is unclear. In the present study, we used the recombinant Ca2+ sensor GCaMP6 to assess glucose-regulated connectivity in living zebrafish Danio rerio, and in murine or human islets transplanted into the anterior eye chamber. In each setting, Ca2+ waves emanated from temporally defined leader β-cells, and three-dimensional connectivity across the islet increased with glucose stimulation. Photoablation of zebrafish leader cells disrupted pan-islet signalling, identifying these as likely pacemakers. Correspondingly, in engrafted mouse islets, connectivity was sustained during prolonged glucose exposure, and super-connected 'hub' cells were identified. Granger causality analysis revealed a controlling role for temporally defined leaders, and transcriptomic analyses revealed a discrete hub cell fingerprint. We thus define a population of regulatory β-cells within coordinated islet networks in vivo. This population may drive Ca2+ dynamics and pulsatile insulin secretion.


Collaboration of midwives in primary care midwifery practices with other maternity care providers.
Inter-professional collaboration is considered essential in effective maternity care. National projects are being undertaken to enhance inter-professional relationships and improve communication between all maternity care providers in order to improve the quality of maternity care in the Netherlands. However, little is known about primary care midwives' satisfaction with collaboration with other maternity care providers, such as general practitioners, maternity care assistance organisations (MCAO), maternity care assistants (MCA), obstetricians, clinical midwives and paediatricians. More insight is needed into the professional working relations of primary care midwives in the Netherlands before major changes are made OBJECTIVE: To assess how satisfied primary care midwives are with collaboration with other maternity care providers and to assess the relationship between their 'satisfaction with collaboration' and personal and work-related characteristics of the midwives, their attitudes towards their work and collaboration characteristics (accessibility). The aim of this study was to provide insight into the professional working relations of primary care midwives in the Netherlands. Our descriptive cross-sectional study is part of the DELIVER study. Ninety nine midwives completed a written questionnaire in May 2010. A Friedman ANOVA test assessed differences in satisfaction with collaboration with six groups of maternity care providers. Bivariate analyses were carried out to assess the relationship between satisfaction with collaboration and personal and work-related characteristics of the midwives, their attitudes towards their work and collaboration characteristics. Satisfaction experienced by primary care midwives when collaborating with the different maternity care providers varies within and between primary and secondary/tertiary care. Interactions with non-physicians (clinical midwives and MCA(O)) are ranked consistently higher on satisfaction compared with interactions with physicians (GPs, obstetricians and paediatricians). Midwives with more work experience were more satisfied with their collaboration with GPs. Midwives from the southern region of the Netherlands were more satisfied with collaboration with GPs and obstetricians. Compared to the urban areas, in the rural or mixed areas the midwives were more satisfied regarding their collaboration with MCA(O)s and clinical midwives. Midwives from non-Dutch origin were less satisfied with the collaboration with paediatricians. No relations were found between the overall mean satisfaction of collaboration and work-related and personal characteristics and attitude towards work. Inter-professionals relations in maternity care in the Netherlands can be enhanced, especially the primary care midwives' interactions with physicians and with maternity care providers in the northern and central part of the Netherlands, and in urban areas. Future exploratory or deductive research may provide additional insight in the collaborative practice in everyday work setting.


Neurologic complications of scuba diving.
Recreational scuba diving has become a popular sport in the United States, with almost 9 million certified divers. When severe diving injury occurs, the nervous system is frequently involved. In dive-related barotrauma, compressed or expanding gas within the ears, sinuses and lungs causes various forms of neurologic injury. Otic barotrauma often induces pain, vertigo and hearing loss. In pulmonary barotrauma of ascent, lung damage can precipitate arterial gas embolism, causing blockage of cerebral blood vessels and alterations of consciousness, seizures and focal neurologic deficits. In patients with decompression sickness, the vestibular system, spinal cord and brain are affected by the formation of nitrogen bubbles. Common signs and symptoms include vertigo, thoracic myelopathy with leg weakness, confusion, headache and hemiparesis. Other diving-related neurologic complications include headache and oxygen toxicity.


Increased receptor for advanced glycation end product expression in the human alcoholic prefrontal cortex is linked to adolescent drinking.
Adolescence is characterized behaviorally by increased impulsivity and risk-taking that declines in parallel with maturation of the prefrontal cortex and executive function. In the brain, the receptor for advanced glycation end products (RAGE) is critically involved in neurodevelopment and neuropathology. In humans, the risk of alcoholism is greatly increased in those who begin drinking between 13 and 15years of age, and adolescents binge drink more than any other age group. We have previously found that alcoholism is associated with increased expression of neuroimmune genes. This manuscript tested the hypothesis that adolescent binge drinking upregulates RAGE and Toll-like receptor (TLR) 4 as well as their endogenous agonist, high-mobility group box 1 (HMGB1). Immunohistochemistry, Western blot, and mRNA analyses found that RAGE expression was increased in the human post-mortem alcoholic orbitofrontal cortex (OFC). Further, an earlier age of drinking onset correlated with increased expression of RAGE, TLR4, and HMGB1. To determine if alcohol contributed to these changes, we used an adolescent binge ethanol model in rats (5.0g/kg, i.g., 2-day on/2-day off from postnatal day [P] 25 to P55) and assessed neuroimmune gene expression. We found an age-associated decline of RAGE expression from late adolescence (P56) to young adulthood (P80). Adolescent intermittent ethanol exposure did not alter RAGE expression at P56, but increased RAGE in the young adult PFC (P80). Adolescent intermittent ethanol exposure also increased TLR4 and HMGB1 expression at P56 that persisted into young adulthood (P80). Assessment of young adult frontal cortex mRNA (RT-PCR) found increased expression of proinflammatory cytokines, oxidases, and neuroimmune agonists at P80, 25days after ethanol treatment. Together, these human and animal data support the hypothesis that an early age of drinking onset upregulates RAGE/TLR4-HMGB1 and other neuroimmune genes that persist into young adulthood and could contribute to risk of alcoholism or other brain diseases associated with neuroinflammation.


Embryonic origins of ZebrinII parasagittal stripes and establishment of topographic Purkinje cell projections.
The establishment of neural circuits involves both the precise positioning of cells within brain regions and projection of axons to specific target cells. In the cerebellum (Cb), the medial-lateral (M-L) and anterior-posterior (A-P) position of each Purkinje cell (PC) and the topography of its axon can be defined with respect to two coordinate systems within the Cb; one based on the pattern of lobules and the other on PC gene expression in parasagittal clusters in the embryo (e.g. Pcp2) and stripes in the adult (e.g. ZebrinII). The relationship between the embryonic clusters of molecularly defined PCs and particular adult PC stripes is not clear. Using a mouse genetic inducible fate mapping (GIFM) approach and a Pcp2-CreER-IRES-hAP transgene, we marked three bilateral clusters of PC clusters with myristolated green fluorescent protein (mGfp) on approximately embryonic day (E) 15 and followed their fate into adulthood. We found that these three clusters contributed specifically to ZebrinII-expressing PCs, including nine of the adult stripes. This result suggests that embryonic PCs maintain a particular molecular identity, and that each embryonic cluster can contribute PCs to more than one adult M-L stripe. Each PC projects a primary axon to one of the deep cerebellar nuclei (DCN) or the vestibular nuclei in the brainstem in an organized fashion that relates to the position of the PCs along the M-L axis. We characterized when PC axons from the three M-L clusters acquire topographic projections. Using a combination of GIFM to mark the PC clusters with mGfp and staining for human placental alkaline phosphatase (hAP) in Pcp2-CreER-IRES-hAP transgenic embryos we found that axons from each embryonic PC cluster intermingled with neurons within particular DCN or projected out of the Cb toward the vestibular nuclei by E14.5. These studies show that PC molecular patterning, efferent circuitry, and DCN nucleogenesis occur simultaneously, suggesting a link between these processes.


What can we learn from the hair of the dog? Complex effects of endogenous and exogenous stressors on canine hair cortisol.
Hair is an emerging biological matrix in which to measure chronic HPA axis activity, offering a longer term view into an animal's life. We explored effects of exogenous (e.g. lifestyle, medications, social environment) and endogenous (e.g. disease, behaviour) stressors on hair cortisol concentration (HCC) in a population of Border Collies (BCs). Owners of BCs were recruited and reported their dog's lifestyle, clinical history, anxiety-related behaviour, and collected a white hair sample from their dog's dorsal neck region. HCC was determined using established methods with a commercial cortisol assay kit. Samples from 135 BCs were analysed, with 91 healthy controls and 44 diagnosed with epilepsy as a model disease. Factors associated with higher HCC included psychosocial stressors (living with three or more other dogs) and lifestyle (engaging in competitive flyball); while factors associated with lower HCC included anxiety (stranger-directed and non-social), health (epilepsy diagnosis, with number of seizures to date negatively correlated with HCC) and medication (certain anti-epileptic drugs were associated with elevated or reduced HCC). These novel results highlight the potential of chronic stress with frequent or persisting HPA-axis hyperactivity leading to a state of hypocortisolism, and the need to consider stressor recency and recurrence when interpreting HCC data.


Small-molecule FRET probes for protein kinase activity monitoring in living cells.
In this study, the applicability of fluorescently labeled adenosine analogue-oligoarginine conjugates (ARC-Photo probes) for monitoring of protein kinase A (PKA) activity in living cells was demonstrated. ARC-Photo probes possessing subnanomolar affinity towards the catalytic subunit of PKA (PKAc) and competitive with the regulatory subunit (PKAr), penetrate cell plasma membrane and associate with PKAc fused with yellow fluorescent protein (PKAc-YFP). Detection of inter-molecular Förster resonance energy transfer (FRET) efficiency between the fluorophores of the fusion protein and ARC-Photo probe can be used for both the evaluation of non-labeled inhibitors of PKAc and for monitoring of cAMP signaling via detection of changes in the activity of PKA as a cAMP downstream effector.


Sexual health care in family medicine.
Although patients frequently present with sexual concerns, family doctors generally do not handle them well. Sexual issues may present in many ways: as specific concerns; as a component of non-sexual complaints or as a factor in relationship or marital problems. The family doctor must include sexual enquiry and counselling as part of overall health care, and in the management of illnesses. In order to be effective counsellors, physicians must examine their own attitudes, and become knowledgeable about sexuality and myths influencing sexual behavior, and skillful at interviewing and sexual history-taking. The family doctor can become adept at giving patients permission to discuss their sexuality, and at providing information and strategies to enhance sensual enjoyment and communication with partners. Small group training sessions incorporating discussion and role-playing effectively teach physicians skills and strategies in sexual counselling.


Reproductive resilience to food shortage in a small heterothermic primate.
The massive energetic costs entailed by reproduction in most mammalian females may increase the vulnerability of reproductive success to food shortage. Unexpected events of unfavorable climatic conditions are expected to rise in frequency and intensity as climate changes. The extent to which physiological flexibility allows organisms to maintain reproductive output constant despite energetic bottlenecks has been poorly investigated. In mammals, reproductive resilience is predicted to be maximal during early stages of reproduction, due to the moderate energetic costs of ovulation and gestation relative to lactation. We experimentally tested the consequences of chronic-moderate and short-acute food shortages on the reproductive output of a small seasonally breeding primate, the grey mouse lemur (Microcebus murinus) under thermo-neutral conditions. These two food treatments were respectively designed to simulate the energetic constraints imposed by a lean year (40% caloric restriction over eight months) or by a sudden, severe climatic event occurring shortly before reproduction (80% caloric restriction over a month). Grey mouse lemurs evolved under the harsh, unpredictable climate of the dry forest of Madagascar and should thus display great potential for physiological adjustments to energetic bottlenecks. We assessed the resilience of the early stages of reproduction (mating success, fertility, and gestation) to these contrasted food treatments, and on the later stages (lactation and offspring growth) in response to the chronic food shortage only. Food deprived mouse lemurs managed to maintain constant most reproductive parameters, including oestrus timing, estrogenization level at oestrus, mating success, litter size, and litter mass as well as their overall number of surviving offspring at weaning. However, offspring growth was delayed in food restricted mothers. These results suggest that heterothermic, fattening-prone mammals display important reproductive resilience to energetic bottlenecks. More generally, species living in variable and unpredictable habitats may have evolved a flexible reproductive physiology that helps buffer environmental fluctuations.


Phylogeographic, genomic, and meropenem susceptibility analysis of Burkholderia ubonensis.
The bacterium Burkholderia ubonensis is commonly co-isolated from environmental specimens harbouring the melioidosis pathogen, Burkholderia pseudomallei. B. ubonensis has been reported in northern Australia and Thailand but not North America, suggesting similar geographic distribution to B. pseudomallei. Unlike most other Burkholderia cepacia complex (Bcc) species, B. ubonensis is considered non-pathogenic, although its virulence potential has not been tested. Antibiotic resistance in B. ubonensis, particularly towards drugs used to treat the most severe B. pseudomallei infections, has also been poorly characterised. This study examined the population biology of B. ubonensis, and includes the first reported isolates from the Caribbean. Phylogenomic analysis of 264 B. ubonensis genomes identified distinct clades that corresponded with geographic origin, similar to B. pseudomallei. A small proportion (4%) of strains lacked the 920kb chromosome III replicon, with discordance of presence/absence amongst genetically highly related strains, demonstrating that the third chromosome of B. ubonensis, like other Bcc species, probably encodes for a nonessential pC3 megaplasmid. Multilocus sequence typing using the B. pseudomallei scheme revealed that one-third of strains lack the "housekeeping" narK locus. In comparison, all strains could be genotyped using the Bcc scheme. Several strains possessed high-level meropenem resistance (≥32 μg/mL), a concern due to potential transmission of this phenotype to B. pseudomallei. In silico analysis uncovered a high degree of heterogeneity among the lipopolysaccharide O-antigen cluster loci, with at least 35 different variants identified. Finally, we show that Asian B. ubonensis isolate RF23-BP41 is avirulent in the BALB/c mouse model via a subcutaneous route of infection. Our results provide several new insights into the biology of this understudied species.


Antiproliferative and antiviral activity of methanolic extracts from Sardinian Maltese Mushroom (Cynomorium coccineum L.).
Cynomorium coccineum is a non-photosynthetic plant that grows in Mediterranean countries and that is amply used in the traditional medicine. The aim of this study was to extend previous studies on the chemical and biological properties of C. coccineum, evaluating the potential antiviral and antiproliferative activity of the methanolic extract. The MTT assay was used for the in vitro cytotoxic studies against human cancer-derived cell lines, while both MTT and plaque reduction (PRT) methods were used to evaluate the potential inhibitory effect of the extract against a panel of mammal viruses. The results obtained showed no selective activity against any DNA and RNA virus but revealed an interesting antiproliferative activity against human leukaemia-derived cell lines.


Synergy of β-Lactams with Vancomycin against Methicillin-Resistant Staphylococcus aureus: Correlation of Disk Diffusion and Checkerboard Methods.
Modified disk diffusion (MDD) and checkerboard tests were employed to assess the synergy of combinations of vancomycin and β-lactam antibiotics for 59 clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Mu50 (ATCC 700699). Bacterial inocula equivalent to 0.5 and 2.0 McFarland standard were inoculated on agar plates containing 0, 0.5, 1, and 2 μg/ml of vancomycin. Oxacillin-, cefazolin-, and cefoxitin-impregnated disks were applied to the surface, and the zones of inhibition were measured at 24 h. The CLSI-recommended checkerboard method was used as a reference to detect synergy. The MICs for vancomycin were determined using the Etest method, broth microdilution, and the Vitek 2 automated system. Synergy was observed with the checkerboard method in 51% to 60% of the isolates when vancomycin was combined with any β-lactam. The fractional inhibitory concentration indices were significantly lower in MRSA isolates with higher vancomycin MIC combinations (P < 0.05). The overall agreement between the MDD and checkerboard methods to detect synergy in MRSA isolates with bacterial inocula equivalent to McFarland standard 0.5 were 33.0% and 62.5% for oxacillin, 45.1% and 52.4% for cefazolin, and 43.1% and 52.4% for cefoxitin when combined with 0.5 and 2 μg/ml of vancomycin, respectively. Based on our study, the simple MDD method is not recommended as a replacement for the checkerboard method to detect synergy. However, it may serve as an initial screening method for the detection of potential synergy when it is not feasible to perform other labor-intensive synergy tests.


Depletion of zebrafish titin reduces cardiac contractility by disrupting the assembly of Z-discs and A-bands.
The genetic study of titin has been notoriously difficult because of its size and complicated alternative splicing routes. Here, we have used zebrafish as an animal model to investigate the functions of individual titin isoforms. We identified 2 titin orthologs in zebrafish, ttna and ttnb, and annotated the full-length genomic sequences for both genes. We found that ttna, but not ttnb, is required for sarcomere assembly in the heart as well as the subsequent establishment of cardiac contractility. In fact, ttna is the earliest sarcomeric mRNA that is expressed in the heart, which makes it an early molecular marker for cardiomyocyte differentiation. Surprisingly, ttna is required for later steps of sarcomere assembly, including the assembly of Z-discs and A-bands, but not for early steps such as the assembly of Z-bodies and nonstriated myosin filaments. Reduction of individual titin isoforms in vivo using morpholino-modified antisense oligonucleotides indicated that (1) both N2B exon-containing and N2A exon-containing isoforms of ttna are required for sarcomere assembly in the heart; (2) N2A exon-containing isoforms of both ttna and ttnb are required for sarcomere assembly in the somites; and (3) the N2B exon-containing isoforms of ttnb are expressed later than other titin isoforms and are probably involved in modulating their expression; however, these isoforms of ttnb are not required for sarcomere assembly. Collectively, our results reveal distinct functions of different titin isoforms and suggest that various phenotypes in "titinopathies" may be attributable to the disruption of different titin isoforms.


The seasonal feeding ecology of the javan slow loris (nycticebus javanicus).
To describe the strategy employed by exudativorous primates during seasonal shifts in food abundance using the Javan slow loris as a model. Males and females may cope differently as well as exploit fallback foods in different proportions. Observing 15 free ranging Javan slow lorises over a year, we quantified their seasonal diet and nutrient intake using intake rates. For gum intake rates, we conducted a trial with 10 captive Javan slow lorises measuring the length of time it took for them to ingest 10 g of gum. We monitored phenology in our field site over five plots that were assessed monthly. We weighed our free-ranging animals every six months. We analyzed all food items slow lorises ingested for macronutrients using the nutritional geometry framework. The slow loris diet consisted of eight food categories, with gum and insects being the major food sources in terms of wet weight intake. The captive gum trials resulted in an intake rate of 0.021 g/s. All food items eaten by wild Javan slow lorises were available in the wet season and were restricted in the dry season. Males and females reacted differently to seasonal abundances with females ingesting more protein, gum, fruits and flowers and males ingesting more fiber. The strategy used by the Javan slow lorises during periods of lower food availability were similar to folivorous primates and included increased dependence on lower quality foods. The reproductive costs of gestation and lactation may place a burden on females that requires them to alter their foraging strategy during the dry season to ensure enough protein and overall energy is ingested. The overall strategy used by these exudativorous primates is one of nutrient maximization as no nutrient was clearly preferred over another.


Evidence for a Link Between Fkbp5/FKBP5, Early Life Social Relations and Alcohol Drinking in Young Adult Rats and Humans.
Alcohol misuse has been linked to dysregulation of stress, emotion, and reward brain circuitries. A candidate key mediator of this association is the FK506-binding protein (FKBP5), a negative regulator of the glucocorticoid receptor. The aim of the present study was to further understand the Fkbp5/FKBP5-related genetic underpinnings underlying the relationship between early life social relations and alcohol drinking. The effect of maternal separation and voluntary alcohol drinking on Fkbp5 expression was investigated in the brain of young adult rats, whereas the interaction effect of the functional FKBP5 single nucleotide polymorphism rs1360780 genotype and parent-child relationship on problematic drinking was examined in young adult humans. In rats, Fkbp5 expression in the nucleus accumbens and ventral tegmental area, core regions of the reward system, was affected in a region-dependent manner and in opposite direction by maternal separation and alcohol drinking. Fkbp5 expression in the cingulate cortex was affected by the combined effect of maternal separation and alcohol drinking. In humans, the TT genotype, in the presence of a poor relationship between the child and parents, was associated with problematic drinking behavior. The present findings suggest that Fkbp5 expression in mesocorticolimbic dopaminergic regions associates with early life stress-mediated sensitivity to alcohol drinking and that FKBP5 genotype interacts with parent-child relationship to influence alcohol drinking. These findings are the first to point to a role of FKBP5 in propensity to alcohol misuse and call for studies of the underlying molecular mechanisms to identify potential drug targets.


Structural determinants of reductive terpene cyclization in iridoid biosynthesis.
The carbon skeleton of ecologically and pharmacologically important iridoid monoterpenes is formed in a reductive cyclization reaction unrelated to canonical terpene cyclization. Here we report the crystal structure of the recently discovered iridoid cyclase (from Catharanthus roseus) bound to a mechanism-inspired inhibitor that illuminates substrate binding and catalytic function of the enzyme. Key features that distinguish iridoid synthase from its close homolog progesterone 5β-reductase are highlighted.


Tumour lineage-homing cell-penetrating peptides as anticancer molecular delivery systems.
Cell-penetrating peptides have gained attention owing to their promise in noninvasive delivery systems. Among the identified cell-penetrating peptides, the TAT peptide has been preferentially used for transduction into cells of diverse origins. However, this activity is nonselective between neoplastic and non-neoplastic cells. Here we describe artificial cell-penetrating peptides that are selectively and efficiently incorporated into human tumour cells, according to their lineage. Ten representative tumour lineage-homing cell-penetrating peptides were obtained by screening of a random peptide library constructed using messenger RNA display technology, and some of the isolates were further modified by amino-acid substitution. Their advantageous tumour cell-targeting ability is corroborated in an in vivo mouse model for imaging and growth suppression of metastatic xenoplant tumours. These cell-penetrating peptides are potentially useful for the efficient targeting of human neoplasms in a tumour origin-dependent manner, and provide a framework for the development of peptide-based anti-tumour technologies.


Glucose lowering and anti-atherogenic effects of incretin-based therapies: GLP-1 analogues and DPP-4-inhibitors.
Type 2 diabetes is a chronic, progressive disease with a multi-faceted pathophysiology. Beyond the known defects of insulin resistance and beta-cell insufficiency, derangement of incretin hormones normally produced from the gut wall in response to food intake play an important role. In recent years, the 'incretin-based' therapies (IBTs) have been developed to address hyperglycemia through either mimicking the action of the endogenous incretin glucagon-like polypeptide (GLP-1) (GLP-1 receptor agonists) or by inhibiting the activity of the enzyme that degrades GLP-1 (the dipeptyl peptidase-4 inhibitors). We reviewed available evidence on the glucose lowering and anti-atherogenic effects of IBT. In addition to their glucose-lowering and weight-neutral or weight-reducing actions, IBT decrease systolic blood pressure and improve fasting and postprandial lipid parameters by reducing total-cholesterol, low-density lipoprotein-cholesterol and triglycerides concentrations, and increasing high-density lipoprotein-cholesterol values. Reduced high-sensitivity C-reactive protein levels and improved endothelial dysfunction have been reported too. IBT have several beneficial effects on cardiovascular risk factors and, for this reason, it has been recently suggested to extend the use of these drugs in diabetic patients with cardiovascular complications. Yet, the long-term effects of IBT on subclinical or clinical atherosclerosis remain to be established by future studies.


Geography and Environment Shape Landscape Genetics of Mediterranean Alpine Species Silene ciliata Poiret. (Caryophyllaceae).
The study of the drivers that shape spatial genetic structure across heterogeneous landscapes is one of the main approaches used to understand population dynamics and responses in changing environments. While the Isolation-by-Distance model (IBD) assumes that genetic differentiation increases among populations with geographical distance, the Isolation-by-Resistance model (IBR) also considers geographical barriers and other landscape features that impede gene flow. On the other hand, the Isolation-by-Environment model (IBE) explains genetic differentiation through environmental differences between populations. Although spatial genetic studies have increased significantly in recent years, plants from alpine ecosystems are highly underrepresented, even though they are great suitable systems to disentangle the role of the different factors that structure genetic variation across environmental gradients. Here, we studied the spatial genetic structure of the Mediterranean alpine specialist Silene ciliata across its southernmost distribution limit. We sampled three populations across an altitudinal gradient from 1850 to 2400 m, and we replicated this sample over three mountain ranges aligned across an E-W axis in the central part of the Iberian Peninsula. We genotyped 20 individuals per population based on eight microsatellite markers and used different landscape genetic tools to infer the role of topographic and environmental factors in shaping observed patterns along the altitudinal gradient. We found a significant genetic structure among the studied Silene ciliata populations which was related to the orography and E-W configuration of the mountain ranges. IBD pattern arose as the main factor shaping population genetic differentiation. Geographical barriers between mountain ranges also affected the spatial genetic structure (IBR pattern). Although environmental variables had a significant effect on population genetic diversity parameters, no IBE pattern was found on genetic structure. Our study reveals that IBD was the driver that best explained the genetic structure, whereas environmental factors also played a role in determining genetic diversity values of this dominant plant of Mediterranean alpine environments.


Does Closing the Eyes Enhance Auditory Attention? Eye Closure Increases Attentional Alpha-Power Modulation but Not Listening Performance.
In challenging listening conditions, closing the eyes is a strategy with intuitive appeal to improve auditory attention and perception. On the neural level, closing the eyes increases the power of alpha oscillations (∼10 Hz), which are a prime signature of auditory attention. Here, we test whether eye closure benefits neural and behavioral signatures of auditory attention and perception. Participants (n = 22) attended to one of two alternating streams of spoken numbers with open or closed eyes in a darkened chamber. After each trial, participants indicated whether probes had been among the to-be-attended or to-be-ignored numbers. In the EEG, states of relative high versus low alpha power accompanied the presentation of attended versus ignored numbers. Importantly, eye closure did not only increase the overall level of absolute alpha power but also the attentional modulation thereof. Behaviorally, however, neither perceptual sensitivity nor response criterion was affected by eye closure. To further examine whether this behavioral null result would conceptually replicate in a simple auditory detection task, a follow-up experiment was conducted that required participants (n = 19) to detect a near-threshold target tone in noise. As in the main experiment, our results provide evidence for the absence of any difference in perceptual sensitivity and criterion for open versus closed eyes. In summary, we demonstrate here that the modulation of the human alpha rhythm by auditory attention is increased when participants close their eyes. However, our results speak against the widely held belief that eye closure per se improves listening behavior.


Long-term assessment of an innovative mangrove rehabilitation project: case study on Carey Island, Malaysia.
Wave energy and storm surges threaten coastal ecology and nearshore infrastructures. Although coastal structures are conventionally constructed to dampen the wave energy, they introduce tremendous damage to the ecology of the coast. To minimize environmental impact, ecofriendly coastal protection schemes should be introduced. In this paper, we discuss an example of an innovative mangrove rehabilitation attempt to restore the endangered mangroves on Carey Island, Malaysia. A submerged detached breakwater system was constructed to dampen the energy of wave and trap the sediments behind the structure. Further, a large number of mangrove seedlings were planted using different techniques. Further, we assess the possibility of success for a future mangrove rehabilitation project at the site in the context of sedimentology, bathymetry, and hydrogeochemistry. The assessment showed an increase in the amount of silt and clay, and the seabed was noticeably elevated. The nutrient concentration, the pH value, and the salinity index demonstrate that the site is conducive in establishing mangrove seedlings. As a result, we conclude that the site is now ready for attempts to rehabilitate the lost mangrove forest.


BARD1 reads H2A lysine 15 ubiquitination to direct homologous recombination.
Protein ubiquitination at sites of DNA double-strand breaks (DSBs) by RNF168 recruits BRCA1 and 53BP11,2, which are mediators of the homologous recombination and non-homologous end joining DSB repair pathways, respectively3. Non-homologous end joining relies on 53BP1 binding directly to ubiquitinated lysine 15 on H2A-type histones (H2AK15ub)4,5 (which is an RNF168-dependent modification6), but how RNF168 promotes BRCA1 recruitment and function remains unclear. Here we identify a tandem BRCT-domain-associated ubiquitin-dependent recruitment motif (BUDR) in BRCA1-associated RING domain protein 1 (BARD1) (the obligate partner protein of BRCA1) that, by engaging H2AK15ub, recruits BRCA1 to DSBs. Disruption of the BUDR of BARD1 compromises homologous recombination and renders cells hypersensitive to PARP inhibition and cisplatin. We further show that BARD1 binds nucleosomes through multivalent interactions: coordinated binding of H2AK15ub and unmethylated H4 lysine 20 by its adjacent BUDR and ankyrin repeat domains, respectively, provides high-affinity recognition of DNA lesions in replicated chromatin and promotes the homologous recombination activities of the BRCA1-BARD1 complex. Finally, our genetic epistasis experiments confirm that the need for BARD1 chromatin-binding activities can be entirely relieved upon deletion of RNF168 or 53BP1. Thus, our results demonstrate that by sensing DNA-damage-dependent and post-replication histone post-translation modification states, BRCA1-BARD1 complexes coordinate the antagonization of the 53BP1 pathway with promotion of homologous recombination, establishing a simple paradigm for the governance of the choice of DSB repair pathway.


Structural design and molecular evolution of a cytokine receptor superfamily.
A family of cytokine receptors comprising molecules specific for a diverse group of hematopoietic factors and growth hormones has been principally defined by a striking homology of binding domains. This work proposes that the approximately 200-residue binding segment of the canonical cytokine receptor is composed of two discrete folding domains that share a significant sequence and structural resemblance. Analogous motifs are found in tandem approximately 100-amino acid domains in the extracellular segments of a receptor family formed by the interferon-alpha/beta and -gamma receptors and tissue factor, a membrane tether for a coagulation protease. Domains from the receptor supergroup reveal clear evolutionary links to fibronectin type III structures, approximately 90-amino acid modules that are typically found in cell surface molecules with adhesive functions. Predictive structural analysis of the shared receptor and fibronectin domains locates seven beta-strands in conserved regions of the chain; these strands are modeled to fold into antiparallel beta-sandwiches with a topology that is similar to immunoglobulin constant domains. These findings have strong implications for understanding the evolutionary emergence of an important class of regulatory molecules from primitive adhesive modules. In addition, the resulting double-barrel design of the receptors and the spatial clustering of conserved residues suggest a likely binding site for cytokine ligands.


Amplification and noise properties of an erbium-doped multicore fiber amplifier.
A multicore erbium-doped fiber (MC-EDF) amplifier for simultaneous amplification in the 7-cores has been developed, and the gain and noise properties of individual cores have been studied. The pump and signal radiation were coupled to individual cores of MC-EDF using two tapered fiber bundled (TFB) couplers with low insertion loss. For a pump power of 146 mW, the average gain achieved in the MC-EDF fiber was 30 dB, and noise figure was less than 4 dB. The net useful gain from the multicore-amplifier, after taking into consideration of all the passive losses, was about 23-27 dB. Pump induced ASE noise transfer between the neighboring channel was negligible.


The nocturnal leopard gecko (Eublepharis macularius) uses UVb radiation for vitamin D3 synthesis.
Vitamin D is an important regulator of calcium and phosphorus homeostasis in animals. It can be acquired from the diet or synthesised de novo when skin is exposed to UVb. Vitamin D deficiency can lead to a complex of diseases collectively called metabolic bone disease (MBD). Diurnal lizards without access to UVb are prone to develop vitamin D deficiency, even when dietary vitamin D3 is provided. A trial was conducted to determine whether juvenile nocturnal lizards require access to UVb to prevent vitamin D deficiency. All leopard geckos (Eublepharis macularius) were supplemented with dietary vitamin D3. One group was exposed to low level UVb radiation (33-51 μW/cm2) from hatching until 6 months of age and a second group remained unexposed. Animals were fed ad libitum and their growth and weight gain compared with non-exposed controls. At the end of the trial, blood samples were analysed for vitamin D3 metabolites. The concentration of the vitamin D3 metabolite, 25(OH)D3, was higher in UVb exposed animals (61 ± 20 vs. 38 ± 8 nmol/L), confirming cutaneous synthesis with UVb exposure. Growth and weight gain were similar in both groups, and this, together with the absence of clinical symptoms, suggests that dietary vitamin D3 alone can meet the vitamin D requirements for growth of this nocturnal gecko, during the first six months of life. It remains to be investigated whether the higher vitamin D metabolite levels holds other health benefits for this species, such as improved bone density or immune response.


Lactic Acid Bacteria in Durum Wheat Flour Are Endophytic Components of the Plant during Its Entire Life Cycle.
This study aimed at assessing the dynamics of lactic acid bacteria and other Firmicutes associated with durum wheat organs and processed products. 16S rRNA gene-based high-throughput sequencing showed that Lactobacillus, Streptococcus, Enterococcus, and Lactococcus were the main epiphytic and endophytic genera among lactic acid bacteria. Bacillus, Exiguobacterium, Paenibacillus, and Staphylococcus completed the picture of the core genus microbiome. The relative abundance of each lactic acid bacterium genus was affected by cultivars, phenological stages, other Firmicutes genera, environmental temperature, and water activity (aw) of plant organs. Lactobacilli, showing the highest sensitivity to aw, markedly decreased during milk development (Odisseo) and physiological maturity (Saragolla). At these stages, Lactobacillus was mainly replaced by Streptococcus, Lactococcus, and Enterococcus. However, a key sourdough species, Lactobacillus plantarum, was associated with plant organs during the life cycle of Odisseo and Saragolla wheat. The composition of the sourdough microbiota and the overall quality of leavened baked goods are also determined throughout the phenological stages of wheat cultivation, with variations depending on environmental and agronomic factors.


A focus of endemic malaria in central Java.
This report describes one of the few remaining foci of endemic malaria on the island of Java, the Kokap subdistrict, near the Southcentral coast. Kokap was hypoendemic in June 1994 with prevalence of parasitemia at 0.98% (n = 10,606 of 40,246 residents). Plasmodium vivax comprised 63% of infections and P. falciparum all others. The incidence of indigenous infection during 1993 was 48 cases/1,000 person-years (p-yr), and it was relatively uniform among age groups (38 to 53/1,000 p-yr). Nine deaths due to malaria had been recorded in the past three years (8.3 deaths per 100,000 p-yr); the case fatality rate was 0.17%. Subdistricts adjoining Kokap to the north, east, and south reported incidence rates of < 2 cases/1,000 p-yr. To the west, Purworejo District had a high case incidence (11 cases/1,000 p-yr) but other districts to the west did not (< 1.2 cases/1,000 p-yr). The highest case incidence village area within Kokap (169 cases/1,000 p-yr) bordered the district of Purworejo to the west. Endemic malaria in Kokap and Purworejo coincided with where steep hills and narrow valleys dominated the terrain.


The global distribution of Crimean-Congo hemorrhagic fever.
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne infection caused by a virus (CCHFV) from the Bunyaviridae family. Domestic and wild vertebrates are asymptomatic reservoirs for the virus, putting animal handlers, slaughter-house workers and agricultural labourers at highest risk in endemic areas, with secondary transmission possible through contact with infected blood and other bodily fluids. Human infection is characterized by severe symptoms that often result in death. While it is known that CCHFV transmission is limited to Africa, Asia and Europe, definitive global extents and risk patterns within these limits have not been well described. We used an exhaustive database of human CCHF occurrence records and a niche modeling framework to map the global distribution of risk for human CCHF occurrence. A greater proportion of shrub or grass land cover was the most important contributor to our model, which predicts highest levels of risk around the Black Sea, Turkey, and some parts of central Asia. Sub-Saharan Africa shows more focalized areas of risk throughout the Sahel and the Cape region. These new risk maps provide a valuable starting point for understanding the zoonotic niche of CCHF, its extent and the risk it poses to humans.


Inherited causes of clonal haematopoiesis in 97,691 whole genomes.
Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.


Exact geodesics and shortest paths on polyhedral surfaces.
We present two algorithms for computing distances along convex and non-convex polyhedral surfaces. The first algorithm computes exact minimal-geodesic distances and the second algorithm combines these distances to compute exact shortest-path distances along the surface. Both algorithms have been extended to compute the exact minimal-geodesic paths and shortest paths. These algorithms have been implemented and validated on surfaces for which the correct solutions are known, in order to verify the accuracy and to measure the run-time performance, which is cubic or less for each algorithm. The exact-distance computations carried out by these algorithms are feasible for large-scale surfaces containing tens of thousands of vertices, and are a necessary component of near-isometric surface flattening methods that accurately transform curved manifolds into flat representations.


The changes of cerebral morphology related to aging in Taiwanese population.
A cross-sectional study with the 3-dimensional (3D) MRI reconstruction technique was conducted to investigate cerebral complexity changes related to age differences in native Taiwanese population. In our sample of 85 participants aged between 25 and 81, age was associated with gradual ventricular expansion. A nonlinear quadratic relationship between white matter volume and age was found overall in the brain. Widespread age-related reduction in white matter was detected from late adulthood onwards. However, no significant age-related changes in the cortex and whole brain volume were determined throughout adulthood. These findings provided information in describing brain structural complexity, which might in the future serve as an objective diagnostic index or as a predictive parameter for neurological diseases. Our method then may be used for cross-cultural longitudinal studies to evaluate the effect of disease, environment and aging on the brain.


Online exports and the skilled-unskilled wage gap.
The development of the Internet is often seen as a source of demand for skilled workers and therefore a potential driver of the wage gap between skilled and unskilled workers. This paper focuses on the impact that international trade in online platforms has on the skilled-unskilled wage gap. Because online trade allows smaller firms with relatively more unskilled workers to access world markets, one can expect an expansion of online exports to reduce the wage gap. After correcting for potential endogeneity bias in a sample of 22 developing countries for which online trade and wage gap data can be matched, we find that a 1 percent increase in the share of online exports over GDP leads to a 0.01 percent decline in the skilled-unskilled wage gap.


Lateral regionalization and diffusion of a maturation-dependent antigen in the ram sperm plasma membrane.
We have used a monoclonal antibody ESA 152 in fluorescence recovery after photobleaching (FPR) studies of a maturation-dependent surface antigen of ram sperm. The antibody is an immunoglobulin G secreted by a hybridoma derived from NS1 mouse myeloma cells. The ESA 152 antigen is not detectable in testicular sperm. It is localized on the surface of ejaculated sperm where it is present on all regions of the surface, but tends to be concentrated on the posterior region of the head. The ESA 152 antigen can be extracted by detergents or chloroform-methanol. The extracted antigen is sensitive to proteases and migrates with an apparent Mr approximately 30,000 in SDS-containing 10-20% polyacrylamide gradient gels. FPR measurements of ESA 152 lateral mobility in the membrane yield diffusion coefficients in the range 10(-9)-10(-8) cm2/s, values typical of lipids but observed for proteins only at the fluid dynamic limit where diffusion is controlled by lipid fluidity. Immobile fractions, typical of membrane proteins, are observed on all regions. When the antigen is stained by a fluoresceinated Fab fragment of the ESA 152 antibody, the diffusibility is highly regionalized, with particularly low, but rapid, recovery on the midpiece. Cross-linking of the antigen with the intact ESA 152 antibody induces a redistribution in which the antigen is excluded from the posterior head region. This cross-linking is accompanied by increases in ESA 152 diffusibility on both the anterior head and the midpiece.


Epidemiology, outcome, and risk factors for infectious complications in myelofibrosis patients receiving ruxolitinib: A multicenter study on 446 patients.
Infections represent one of the major concerns regarding the utilization of ruxolitinib (RUX) in patients with myelofibrosis. With the aim to investigate epidemiology, outcome and risk factors for infections in RUX-exposed patients, we collected clinical and laboratory data of 446 myelofibrosis patients treated with RUX between June 2011 and November 2016 in 23 European Hematology Centers. After a median RUX exposure of 23.5 months (range, 1-56), 123 patients (28%) experienced 161 infectious events (grades 3-4 32%, fatal 9%), for an incidence rate of 17 cases per 100 pts/y. The rate of infections tended to decrease over time: 14% of patients developed the first infection within 6 months, 5% between 6 and 12 months, 3.7% between 12 and 18 months, 3.4% between 18 and 24 months, and 7.9% thereafter (P < .0001). Respiratory tract infections were more frequently observed (81 events, 50%), and bacteria were the most frequent etiological agents (68.9%). However, also viral (14.9%) and fungal infections (2.5%) were observed. In multivariate analysis, previous infectious event (HR 2.54; 95% CI, 1.51-4.28; P = .0005) and high international prognostic score system category (IPSS) (HR 1.53; 95% CI, 1.07-2.20; P = .021) significantly correlated with higher infectious risk. On the contrary, spleen reduction ≥50% from baseline after 3 months of treatment (P = .02) was associated with better infection-free survival. Taken together, these findings reinforce the concept of disease severity as the most important risk factor for infections, and describe, for the first time, that a positive therapeutic effect in reducing splenomegaly may also reduce subsequent infectious complications.


Insomnia, immunity, and infections in cancer patients: Results from a longitudinal study.
Insomnia is very common in cancer patients receiving chemotherapy. Poor sleep is associated with immune alterations but the actual impact on health resulting from such immune changes has rarely been studied. The aim of this study was to evaluate, in women treated with chemotherapy for breast or gynecological cancer, the relationships between insomnia, immunity, and the occurrence of infections. Fifty-two patients were assessed before chemotherapy (Time [T]1), on 4 occasions during the first 2 cycles of chemotherapy (i.e., on immunosuppression and recovery weeks; T2-T5), at posttreatment (T6), and at 3-month (T7) and 6-month (T8) follow-ups. A clinical interview was administered to assess insomnia (Insomnia Interview Schedule) and the occurrence of infections. Patients were categorized into 1 of these 3 subgroups on the basis of the insomnia interview at T1: good sleepers (GS), insomnia symptoms (SX), and insomnia syndrome (SYN). Finally, blood samples were collected at each time point (T1-T8) to measure several immune parameters (e.g., neutrophils, lymphocytes). Mixed-model analyses of covariance revealed that SYN patients at T1 had significantly lower counts of some blood cells after chemotherapy (T6) as compared to GS (i.e., total white blood cells and neutrophils) and as compared to GS and SX patients (i.e., total lymphocytes, CD3+ and CD4+ cells). At T8, SYN patients at T1 showed significantly lower lymphocytes, CD3+ and CD4+ counts as compared to SX patients. Finally, SYN patients at T1 were at a significantly higher risk of reporting infectious episodes at T5 as compared to SX patients. Although replication is warranted, these results suggest that prechemotherapy insomnia may potentiate the vulnerability to show immune alterations and develop infections due to chemotherapy during the cancer care trajectory. Overall, they further emphasize the need to provide effective treatments for sleep difficulties in patients undergoing chemotherapy. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


The process of NCCN guidelines adaptation to the Middle East and North Africa region.
The NCCN developed clinical practice guidelines for oncology that set the standard of cancer care in the United States. Because of wide acceptance of, need for, and interest in standardized treatment practices across the world, NCCN launched initiatives to help international groups adapt these guidelines. This article describes the initiative in the Middle East and North Africa (MENA) region. A group of oncology experts and key opinion leaders were assembled into 7 specific committees to develop treatment guidelines for breast cancer, lung cancer, colon cancer, prostate cancer, hepatobiliary cancer, lymphoma, and palliative care. The committees reviewed the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to identify any modifications required for them to be more applicable to the MENA region based on available evidence and regional experience. These modifications were discussed with NCCN experts and summarized for each specific area. The development of these guidelines generated a strong interest in the region to develop more evidence-based practice and create further networking and collaboration.


Genetic variants in the TEP1 gene are associated with prostate cancer risk and recurrence.
Telomere-related genes play an important role in carcinogenesis and progression of prostate cancer (PCa). It is not fully understood whether genetic variations in telomere-related genes are associated with development and progression in PCa patients. Six potentially functional single-nucleotide polymorphisms (SNPs) of three key telomere-related genes were evaluated in 1015 PCa cases and 1052 cancer-free controls, to test their associations with risk of PCa. Among 426 PCa patients who underwent radical prostatectomy (RP), the prognostic significance of the studied SNPs on biochemical recurrence (BCR) was also assessed using the Kaplan-Meier analysis and Cox proportional hazards regression model. The relative telomere lengths (RTLs) were measured in peripheral blood leukocytes using real-time PCR in the RP patients. TEP1 rs1760904 AG/AA genotypes were significantly associated with a decreased risk of PCa (odds ratio (OR): 0.77, 95% confidence interval (CI): 0.64-0.93, P=0.005) compared with the GG genotype. By using median RTL as a cutoff level, RP patients with TEP1 rs1760904 AG/AA genotypes tended to have a longer RTL than those with the GG genotype (OR: 1.55, 95% CI: 1.04-2.30, P=0.031). A significant interaction between TEP1 rs1713418 and age in modifying PCa risk was observed (P=0.005). After adjustment for clinicopathologic risk factors, the presence of heterozygotes or rare homozygotes of TEP1 rs1760904 and TNKS2 rs1539042 were associated with BCR in the RP cohorts (hazard ratio: 0.53, 95% CI: 0.36-0.79, P=0.002 and hazard ratio: 1.67, 95% CI: 1.07-2.48, P=0.017, respectively). These data suggest that genetic variations in the TEP1 gene may be biomarkers for risk of PCa and BCR after RP.


Libraries for each human chromosome, constructed from sorter-enriched chromosomes by using linker-adaptor PCR.
We describe here the production of complex libraries enriched in sequences from each human chromosome type, starting with only a few thousand sorter-purified chromosomes. In this procedure, DNA is extracted from the sorted chromosomes, digested to completion by using the frequently cutting restriction endonuclease Sau3A1, and ligated, on each end, to an adaptor oligonucleotide. These fragments are then amplified using PCR with a sequence homologous to the adaptor oligonucleotide as a primer. We have used this procedure to produce PCR libraries for each of the 24 human chromosomes. These libraries were characterized by gel electrophoresis and found to be composed of a continuum of sequences ranging in size from a few hundred to approximately 1,000 bp. The libraries, when used as probes for fluorescence in situ hybridization, stained the target chromosomes more or less continuously, even after PCR amplification for more than 200 cycles. These libraries are useful as hybridization probes to facilitate molecular cytogenetic studies and as sources of probes either for identification of polymorphic short tandemly repeated sequences or for development of sequence-tagged sites.


Anti-inflammatory effects of atorvastatin on peripheral blood mononuclear cells and synovial fibroblasts in rheumatoid arthritis.
Statins, such as atorvastatin (ATV), are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors known to exert lipid-lowering but also anti-inflammatory, effects. In this study, we analysed the in vitro effects of ATV on peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA), a chronic inflammatory joint disease. PBMCs isolated from 25 RA patients and 20 healthy blood donors were stimulated in vitro with 0.1 microM ATV for 24 h. PBMC cultures were analysed for cell surface markers to characterize T-cell subtypes (CD4, CD8, CD69, HLA-DR) by flow cytometry and for T helper cell type 1 (Th1) and type 2 (Th2) cytokines [interferon-gamma (IFN-gamma), interleukin-4 (IL-4), IL-10] in culture supernatants by enzyme-linked immunosorbent assay (ELISA). Furthermore, RNA isolated from ATV-stimulated RA-FLS pre- and post-ATV stimulation was analysed by microarray and quantitative reverse transcription polymerase chain reaction (RT-PCR). Flow cytometric analysis of T-cell subsets revealed no significant differences for CD4, CD8, CD69, and HLA-DR surface marker expression of PBMCs in RA patients and healthy controls after ATV stimulation. However, the proportion of IFN-gamma expressing CD4+ T cells and the IFN-gamma cytokine concentrations in culture supernatants were significantly reduced in T-cell cultures from RA patients. In ATV-stimulated FLS a significant downregulation of proinflammatory cytokine (IL-6) and chemokine (IL-8) expression was detected (p<0.001). Our study demonstrates a marked in vitro anti-inflammatory activity of ATV in RA including a systemic effect on a pathogenic CD4+ T-cell population (Th1) and a local effect on FLS. These findings may provide a scientific rationale for statins as add-on therapy in RA.


Millennium development health metrics: where do Africa's children and women of childbearing age live?
The Millennium Development Goals (MDGs) have prompted an expansion in approaches to deriving health metrics to measure progress toward their achievement. Accurate measurements should take into account the high degrees of spatial heterogeneity in health risks across countries, and this has prompted the development of sophisticated cartographic techniques for mapping and modeling risks. Conversion of these risks to relevant population-based metrics requires equally detailed information on the spatial distribution and attributes of the denominator populations. However, spatial information on age and sex composition over large areas is lacking, prompting many influential studies that have rigorously accounted for health risk heterogeneities to overlook the substantial demographic variations that exist subnationally and merely apply national-level adjustments.Here we outline the development of high resolution age- and sex-structured spatial population datasets for Africa in 2000-2015 built from over a million measurements from more than 20,000 subnational units, increasing input data detail from previous studies by over 400-fold. We analyze the large spatial variations seen within countries and across the continent for key MDG indicator groups, focusing on children under 5 and women of childbearing age, and find that substantial differences in health and development indicators can result through using only national level statistics, compared to accounting for subnational variation.Progress toward meeting the MDGs will be measured through national-level indicators that mask substantial inequalities and heterogeneities across nations. Cartographic approaches are providing opportunities for quantitative assessments of these inequalities and the targeting of interventions, but demographic spatial datasets to support such efforts remain reliant on coarse and outdated input data for accurately locating risk groups. We have shown here that sufficient data exist to map the distribution of key vulnerable groups, and that doing so has substantial impacts on derived metrics through accounting for spatial demographic heterogeneities that exist within nations across Africa.


Implication of a Chromosome 15q15.2 Locus in Regulating UBR1 and Predisposing Smokers to MGMT Methylation in Lung.
O(6)-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that protects cells from carcinogenic effects of alkylating agents; however, MGMT is silenced by promoter hypermethylation during carcinogenesis. A single-nucleotide polymorphism (SNP) in an enhancer in the MGMT promoter was previously identified to be highly significantly associated with risk for MGMT methylation in lung cancer and sputum from smokers. To further genetic investigations, a genome-wide association and replication study was conducted in two smoker cohorts to identify novel loci for MGMT methylation in sputum that were independent of the MGMT enhancer polymorphism. Two novel trans-acting loci (15q15.2 and 17q24.3) that were identified acted together with the enhancer SNP to empower risk prediction for MGMT methylation. We found that the predisposition to MGMT methylation arising from the 15q15.2 locus involved regulation of the ubiquitin protein ligase E3 component UBR1. UBR1 attenuation reduced turnover of MGMT protein and increased repair of O6-methylguanine in nitrosomethylurea-treated human bronchial epithelial cells, while also reducing MGMT promoter activity and abolishing MGMT induction. Overall, our results substantiate reduced gene transcription as a major mechanism for predisposition to MGMT methylation in the lungs of smokers, and support the importance of UBR1 in regulating MGMT homeostasis and DNA repair of alkylated DNA adducts in cells.


Priorities for improved management of acute rheumatic fever and rheumatic heart disease: analysis of cross-sectional continuous quality improvement data in Aboriginal primary healthcare centres in Australia.
Objective This study investigated the delivery of guideline-recommended services for the management of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) in Australian primary healthcare centres participating in the Audit and Best Practice for Chronic Disease (ABCD) National Research Partnership project. Methods ARF and RHD clinical audit data were collected from 63 Aboriginal centres in four Australian jurisdictions using the ABCD ARF/RHD audit tool. Records of up to 30 patients treated for ARF and/or RHD were analysed per centre from the most recent audit conducted between 2009 and 2014. The main outcome measure was a quality of ARF and RHD care composite indicator consisting of nine best-practice service items. Results Of 1081 patients, most were Indigenous (96%), female (61%), from the Northern Territory and Queensland (97%) and <25 years of age (49%). The composite indicator was highest in the 0-14 year age group (77% vs 65-67% in other age groups). Timely injections and provision of client education are important specific areas for improvement. Multiple regression showed age >15 years to be a significant negative factor for several care indicators, particularly for the delivery of long-acting antibiotic injections and specialist services in the 15-24 year age group. Conclusions The results suggest that timely injection and patient education are priorities for managing ARF and RHD, particularly focusing on child-to-adult transition care. What is known about the topic? The burden of rheumatic fever and RHD in some Aboriginal communities is among the highest documented globally. Guideline-adherent RHD prevention and management in primary health care (PHC) settings are critically important to reduce this burden. Continuous quality improvement (CQI) is a proven strategy to improve guideline adherence, using audit cycles and proactive engagement of PHC end users with their own data. Previously, such CQI strategies using a systems approach were shown to improve delivery of ARF and RHD care in six Aboriginal health services (three government and three community controlled). What does this paper add? This paper focuses on the variation across age groups in the quality of ARF and/or RHD care according to nine quality of care indicators across 63 PHC centres serving the Aboriginal population in the Northern Territory, Queensland, South Australia and Western Australia. These new findings provide insight into difference in quality of care by life stage, indicating particular areas for improvement of the management of ARF and RHD at the PHC level, and can act as a baseline for monitoring of care quality for ARF and RHD into the future. What are the implications for practitioners? Management plans and innovative strategies or systems for improving adherence need to be developed as a matter of urgency. PHC professionals need to closely monitor adherence to secondary prophylaxis at both the clinic and individual level. RHD priority status needs to be assigned and recorded as a tool to guide management. Systems strengthening needs to particularly target child-to-adult transition care. Practitioners are urged to keep a quick link to the RHDAustralia website to access resources and guidelines pertaining to ARF and RHD (https://www.rhdaustralia.org.au/arf-rhd-guideline, accessed 3 October 2019). CQI strategies can assist PHC centres to improve the care they provide to patients.