The SENSE study: Post intervention effects of a randomized controlled trial of a cognitive-behavioral and mindfulness-based group sleep improvement intervention among at-risk adolescents.
Sleep problems are a major risk factor for the emergence of mental health problems in adolescence. The aim of this study was to investigate the post intervention effects of a cognitive-behavioral/mindfulness-based group sleep intervention on sleep and mental health among at-risk adolescents. A randomized controlled trial (RCT) was conducted across High schools in Melbourne, Australia. One hundred forty-four adolescents (aged 12-17 years) with high levels of anxiety and sleeping difficulties, but without past or current depressive disorder, were randomized into either a sleep improvement intervention or an active control 'study skills' intervention. Both programs consisted of 7 90-min-long group sessions delivered over 7 weeks. One hundred twenty-three participants began the interventions (female = 60%; mean age = 14.48, SD = 0.95), with 60 in the sleep condition and 63 in the control condition. All participants were required to complete a battery of mood and sleep questionnaires, 7 days of wrist actigraphy (an objective measure of sleep), and sleep diary entry at pre- and-post intervention. The sleep intervention condition was associated with significantly greater improvements in subjective sleep (global sleep quality [with a medium effect size], sleep onset latency, daytime sleepiness [with small effect sizes]), objective sleep (sleep onset latency [with a medium effect size]), and anxiety (with a small effect size) compared with the control intervention condition. The SENSE study provides evidence that a multicomponent group sleep intervention that includes cognitive-behavioral and mindfulness-based therapies can reduce sleep initiation problems and related daytime dysfunction, along with concomitant anxiety symptoms, among at-risk adolescents. (PsycINFO Database Record


Association between lumbopelvic pain, disability and sick leave during pregnancy – a comparison of three Scandinavian cohorts.
To explore the association between disability and sick leave due to lumbopelvic pain in pregnant women in 3 cohorts in Sweden and Norway and to explore possible factors of importance to sick leave. A further aim was to compare the prevalence of sick leave due to lumbopelvic pain. Pregnant women (n = 898) from two cohorts in Sweden and one in Norway answered to questionnaires in gestational weeks 10–24; two of the cohorts additionally in weeks 28–38. Logistic regression models were performed with sick leave due to lumbopelvic pain as dependent factor. Disability, pain, age, parity, cohort, civilian status, and occupational classification were independents factors. In gestational weeks 10–24 the regression model included 895 cases; 38 on sick leave due to lumbopelvic pain. Disability, pain and cohort affiliation were associated with sick leave. In weeks 28–38, disability, pain and occupation classification were the significant factors. The prevalence of lumbopelvic pain was higher in Norway than in Sweden (65%, vs 58% and 44%; p < 0.001). Disability, pain intensity and occupation were associated to sick leave due to lumbopelvic pain. Yet, there were significant variations between associated factors among the cohorts, suggesting that other factors than workability and the social security system are also of importance.


Experiences of lay counsellors who provide VCT for PMTCT of HIV and AIDS in the Capricorn District, Limpopo Province.
Human immune deficiency virus (HIV) and acquired immune-deficiency syndrome (AIDS) still carry a stigma in the community. Many people do not know their status and they are still reluctant to be tested including pregnant women despite the fact that Voluntary Counselling and Testing (VCT) is offered for free in South Africa. In South Africa VCT for HIV and AIDS is offered by lay counsellors in public hospitals and clinics. The study conducted by Mate, Bennet, Mphatswe, Barker and Rollins (2009:5483) outlined that in South Africa the prevention of mother-to-child transmission (PMTCT) of HIV guidelines have raised hope that the national goal of reducing perinatal HIV transmission rates to less than 5% can be attained. A qualitative, exploratory, descriptive and contextual study was conducted in 15 public clinics of the Polokwane Municipality in the Capricorn District, Limpopo Province. The purpose of the study was to determine the experiences of the lay counsellors who provide VCT for the PMTCT of HIV and AIDS in the Capricorn District, Limpopo Province. Data were collected through one-to-one interviews using a semi-structured guide (De Vos et al, 2006:296). The findings of the study reflected the following: the content of training and counselling skills received by lay counsellors were satisfactory, there was lack of counsellor support and in-service education. A program for in-service education and support for all lay counsellors who have had VCT training should be conceptualised and implemented.


Clinical Practice Guideline: Irritable bowel syndrome with constipation and functional constipation in the adult.
In this Clinical Practice Guideline we discuss the diagnostic and therapeutic approach of adult patients with constipation and abdominal complaints at the confluence of the irritable bowel syndrome spectrum and functional constipation. Both conditions are included among the functional bowel disorders, and have a significant personal, healthcare, and social impact, affecting the quality of life of the patients who suffer from them. The first one is the irritable bowel syndrome subtype, where constipation represents the predominant complaint, in association with recurrent abdominal pain, bloating, and abdominal distension. Constipation is characterized by difficulties with or low frequency of bowel movements, often accompanied by straining during defecation or a feeling of incomplete evacuation. Most cases have no underlying medical cause, and are therefore considered as a functional bowel disorder. There are many clinical and pathophysiological similarities between both disorders, and both respond similarly to commonly used drugs, their primary difference being the presence or absence of pain, albeit not in an "all or nothing" manner. Severity depends not only upon bowel symptom intensity but also upon other biopsychosocial factors (association of gastrointestinal and extraintestinal symptoms, grade of involvement, and perception and behavior variants). Functional bowel disorders are diagnosed using the Rome criteria. This Clinical Practice Guideline has been made consistent with the Rome IV criteria, which were published late in May 2016, and discuss alarm criteria, diagnostic tests, and referral criteria between Primary Care and gastroenterology settings. Furthermore, all the available treatment options (exercise, fluid ingestion, diet with soluble fiber-rich foods, fiber supplementation, other dietary components, osmotic or stimulating laxatives, probiotics, antibiotics, spasmolytics, peppermint essence, prucalopride, linaclotide, lubiprostone, biofeedback, antidepressants, psychological therapy, acupuncture, enemas, sacral root neurostimulation, surgery) are discussed, and practical recommendations are made regarding each of them.


Childhood maternal care is associated with DNA methylation of the genes for brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) in peripheral blood cells in adult men and women.
In adults, reporting low and high maternal care in childhood, we compared DNA methylation in two stress-associated genes (two target sequences in the oxytocin receptor gene, OXTR; one in the brain-derived neurotrophic factor gene, BDNF) in peripheral whole blood, in a cross-sectional study (University of Basel, Switzerland) during 2007-2008. We recruited 89 participants scoring < 27 (n = 47, 36 women) or > 33 (n = 42, 35 women) on the maternal care subscale of the Parental Bonding Instrument (PBI) at a previous assessment of a larger group (N = 709, range PBI maternal care = 0-36, age range = 19-66 years; median 24 years). 85 participants gave blood for DNA methylation analyses (Sequenom(R) EpiTYPER, San Diego, CA) and cell count (Sysmex PocH-100i™, Kobe, Japan). Mixed model statistical analysis showed greater DNA methylation in the low versus high maternal care group, in the BDNF target sequence [Likelihood-Ratio (1) = 4.47; p = 0.035] and in one OXTR target sequence Likelihood-Ratio (1) = 4.33; p = 0.037], but not the second OXTR target sequence [Likelihood-Ratio (1) < 0.001; p = 0.995). Mediation analyses indicated that differential blood cell count did not explain associations between low maternal care and BDNF (estimate = -0.005, 95% CI = -0.025 to 0.015; p = 0.626) or OXTR DNA methylation (estimate = -0.015, 95% CI = -0.038 to 0.008; p = 0.192). Hence, low maternal care in childhood was associated with greater DNA methylation in an OXTR and a BDNF target sequence in blood cells in adulthood. Although the study has limitations (cross-sectional, a wide age range, only three target sequences in two genes studied, small effects, uncertain relevance of changes in blood cells to gene methylation in brain), the findings may indicate components of the epiphenotype from early life stress.


Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy.
The study investigates if alpha-lipoic acid is neuroprotective against chemotherapy induced neurotoxicity, if mitochondrial damage plays a critical role in toxic neurodegenerative cascade, and if neuroprotective effects of alpha-lipoic acid depend on mitochondria protection. We used an in vitro model of chemotherapy induced peripheral neuropathy that closely mimic the in vivo condition by exposing primary cultures of dorsal root ganglion (DRG) sensory neurons to paclitaxel and cisplatin, two widely used and highly effective chemotherapeutic drugs. This approach allowed investigating the efficacy of alpha-lipoic acid in preventing axonal damage and apoptosis and the function and ultrastructural morphology of mitochondria after exposure to toxic agents and alpha-lipoic acid. Our results demonstrate that both cisplatin and paclitaxel cause early mitochondrial impairment with loss of membrane potential and induction of autophagic vacuoles in neurons. Alpha-lipoic acid exerts neuroprotective effects against chemotherapy induced neurotoxicity in sensory neurons: it rescues the mitochondrial toxicity and induces the expression of frataxin, an essential mitochondrial protein with anti-oxidant and chaperone properties. In conclusion mitochondrial toxicity is an early common event both in paclitaxel and cisplatin induced neurotoxicity. Alpha-lipoic acid protects sensory neurons through its anti-oxidant and mitochondrial regulatory functions, possibly inducing the expression of frataxin. These findings suggest that alpha-lipoic acid might reduce the risk of developing peripheral nerve toxicity in patients undergoing chemotherapy and encourage further confirmatory clinical trials.


Androgen receptor signaling regulates DNA repair in prostate cancers.
We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy synergizes with ionizing radiation. Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output, which correlates with expression of a set of DNA repair genes. Using RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with ionizing radiation plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical nonhomologous end-joining. We demonstrate that the AR regulates a network of DNA repair genes, providing a potential mechanism by which androgen deprivation synergizes with radiotherapy for prostate cancer.


Advancing Healthcare Reform: The American Heart Association's 2020 Statement of Principles for Adequate, Accessible, and Affordable Health Care: A Presidential Advisory From the American Heart Association.
The mission of the American Heart Association is to be a relentless force for a world of longer, healthier lives. The American Heart Association has consistently prioritized the needs and perspective of the patient in taking positions on healthcare reform while recognizing the importance of biomedical research, providers, and healthcare delivery systems in advancing the care of patients and the prevention of disease. The American Heart Association's vision for healthcare reform describes the foundational changes needed for the health system to serve the best interests of patients and to achieve health care and coverage that are adequate, accessible, and affordable for everyone living in the United States. The American Heart Association is committed to advancing the dialogue around healthcare reform and has prepared this updated statement of our principles, placed in the context of the advances in coverage and care that have occurred after the passage of the Affordable Care Act, the rapidly changing landscape of healthcare delivery systems, and our evolving recognition that efforts to prevent cardiovascular disease can have synergistic benefit in preventing other diseases and improving overall well-being. These updated principles focus on expanding access to affordable health care and coverage; enhancing the availability of evidence-based preventive services; eliminating disparities that limit the availability and equitable delivery of health care; strengthening the public health infrastructure to respond to social determinants of health; prioritizing and accelerating investments in biomedical research; and growing a diverse, culturally competent health and healthcare workforce prepared to meet the challenges of delivering high-value health care.


Antioxidant vitamins reduce acute meal-induced memory deficits in adults with type 2 diabetes.
Memory impairment is observed in adults with type 2 diabetes mellitus (T2DM), with further acute deficits after meal ingestion. This study explored whether postprandial oxidative stress was a contributor to these meal-induced memory deficits. Sixteen adults with T2DM (mean age, 63.5 +/- 2.1 years) who were not regularly taking high-dose antioxidant supplements were fed a high-fat meal, the same test meal with vitamins C (1000 mg) and E (800 IU) tablets, or water on 3 separate occasions. After meal ingestion, a battery of cognitive tests were administered, which included measures of delayed verbal memory, assessed at 60 and 105 minutes after meal ingestion. Relative to water consumption, the high-fat meal resulted in poorer performance at 105 minutes postingestion on measures of delayed verbal recall (word list and paragraph recall) and working memory (Digit-Span Forward). Coconsumption of antioxidant vitamins and high-fat meal prevented this meal-induced deficit such that performance on these tasks was indistinguishable from that after water intake. At the same time point, a small but significant improvement on the word-naming and color-naming components of Stroop was observed after meal ingestion, relative to water, irrespective of whether antioxidants were consumed, demonstrating the specificity of meal-induced impairments to memory function. Executive function, assessed by Trails Parts A and B, was not influenced by meal or antioxidant ingestion. In adults with T2DM, coconsumption of antioxidant vitamins minimizes meal-induced memory impairment, implicating oxidative stress as a potential contributor to these decrements.


Emotion-Cognition Interaction in Nonhuman Primates: Cognitive Avoidance of Negative Stimuli in Baboons (Papio papio)
It is well established that emotion and cognition interact in humans, but such an interaction has not been extensively studied in nonhuman primates. We investigated whether emotional value can affect nonhuman primates' processing of stimuli that are only mentally represented, not visually available. In a short-term memory task, baboons memorized the location of two target squares of the same color, which were presented with a distractor of a different color. Through prior long-term conditioning, one of the two colors had acquired a negative valence. Subjects were slower and less accurate on the memory task when the targets were negative than when they were neutral. In contrast, subjects were faster and more accurate when the distractors were negative than when they were neutral. Some of these effects were modulated by individual differences in emotional disposition. Overall, the results reveal a pattern of cognitive avoidance of negative stimuli, and show that emotional value alters cognitive processing in baboons even when the stimuli are not physically present. This suggests that emotional influences on cognition are deeply rooted in evolutionary continuity.


The Long-Term Effects of Developmental Hypoxia on Cardiac Mitochondrial Function in Snapping Turtles.
It is well established that adult vertebrates acclimatizing to hypoxic environments undergo mitochondrial remodeling to enhance oxygen delivery, maintain ATP, and limit oxidative stress. However, many vertebrates also encounter oxygen deprivation during embryonic development. The effects of developmental hypoxia on mitochondrial function are likely to be more profound, because environmental stress during early life can permanently alter cellular physiology and morphology. To this end, we investigated the long-term effects of developmental hypoxia on mitochondrial function in a species that regularly encounters hypoxia during development-the common snapping turtle (Chelydra serpentina). Turtle eggs were incubated in 21% or 10% oxygen from 20% of embryonic development until hatching, and both cohorts were subsequently reared in 21% oxygen for 8 months. Ventricular mitochondria were isolated, and mitochondrial respiration and reactive oxygen species (ROS) production were measured with a microrespirometer. Compared to normoxic controls, juvenile turtles from hypoxic incubations had lower Leak respiration, higher P:O ratios, and reduced rates of ROS production. Interestingly, these same attributes occur in adult vertebrates that acclimatize to hypoxia. We speculate that these adjustments might improve mitochondrial hypoxia tolerance, which would be beneficial for turtles during breath-hold diving and overwintering in anoxic environments.


Hydrologic and biogeochemical controls of river subsurface solutes under agriculturally enhanced ground water flow.
The relative influences of hydrologic processes and biogeochemistry on the transport and retention of minor solutes were compared in the riverbed of the lower Merced River (California, USA). The subsurface of this reach receives ground water discharge and surface water infiltration due to an altered hydraulic setting resulting from agricultural irrigation. Filtered ground water samples were collected from 30 drive point locations in March, June, and October 2004. Hydrologic processes, described previously, were verified by observations of bromine concentrations; manganese was used to indicate redox conditions. The separate responses of the minor solutes strontium, barium, uranium, and phosphorus to these influences were examined. Correlation and principal component analyses indicate that hydrologic processes dominate the distribution of trace elements in the ground water. Redox conditions appear to be independent of hydrologic processes and account for most of the remaining data variability. With some variability, major processes are consistent in two sampling transects separated by 100 m.


Are interventions focused on gender-norms effective in preventing domestic violence against women in low and lower-middle income countries? A systematic review and meta-analysis.
One in three women experience intimate partner violence worldwide, according to many primary studies. However, systematic review and meta-analysis of intimate partner violence is very limited. Therefore, we set to summarize the findings of existing primary studies to generate evidence for informed decisions to tackle domestic violence against women in low and lower-middle income countries. Studies were searched from main databases (Medline via PubMed, EMBASE, CINAHL, PopLine and Web of Science), Google scholar and other relevant sources using electronic and manual techniques. Published and unpublished studies written in English and conducted among women aged (15-49 years) from 1994 to 2017 were eligible. Data were extracted independently by two authors, and recorded in Microsoft Excel sheet. Heterogeneity between included studies was assessed using I2, and publication bias was explored using visual inspection of funnel plot. Statistical analysis was carried out to determine the pooled prevalence using Comprehensive Meta-Analysis software. In addition, sub-group analysis was carried out by study-setting and types of intimate partner violence. Fifty two studies were included in the systematic review. Of these, 33 studies were included in the meta-analysis. The pooled prevalence of lifetime intimate partner violence was 55% (95% CI: 52, 59%). Of these, main categories were lifetime physical violence [39% (95% CI: 33, 45%); psychological violence [45% (95% CI: 40, 52%)] and sexual violence [20% (95% CI: 17, 23%)]. Furthermore, the pooled prevalence of current intimate partner violence was 38% (95% CI: 34, 43%). Of these, physical violence [25% (95% CI: 21, 28%)]; psychological violence [30% (95% CI: 24, 36%)] and sexual violence [7.0% (95% CI: 6.6, 7.5%)] were the pooled prevalence for the major types of intimate partner violence. In addition, concurrent intimate partner violence was 13% (95% CI: 12, 15%). Individual, relationship, community and societal level factors were associated with intimate partner violence. Traditional community gender-norm transformation, stakeholders' engagement, women's empowerment, intervention integration and policy/legal framework were highly recommended interventions to prevent intimate partner violence. Lifetime and current intimate partner violence is common and unacceptably high. Therefore, concerned bodies will need to design and implement strategies to transform traditional gender norms, engage stakeholders, empower women and integrate service to prevent violence against women. PROSPERO: 2017: CRD42017079977 .


[AMD Annals: a model of continuous monitoring and improvement of the quality of diabetes care].
in recent years, several initiatives have been launched by the Associazione medici diabetologi (AMD) in the context of a national quality improvement program.These activities include: identification of specific indicators of quality of diabetes care, development of a software to calculate such indicators by using routine clinical data, creation of a network of diabetes clinics and analysis and publication of the results in ad hoc reports (AMD Annals). Through the best performer approach, each centre could compare its own performance not only with the theoretical targets suggested by existing guidelines, but also with the results achieved by the best centres operating within the same healthcare system.We evaluated whether the involvement of diabetes clinics into the AMD Annals initiative improved the quality of care over 4 years. a controlled before and after study was performed to compare data collected from 2004 to 2007 by two groups of centres: group A included centres that had been involved in the project since the first edition of AMD Annals; group B included centres only involved in the last edition. overall, 124 diabetes clinics provided data on over 100,000 type 2 diabetes patients/year seen from 2004 to 2007. process indicators included the proportion of patients with at least one measurement of HbA1c, blood pressure and lipid profile during the previous 12 months. Intermediate outcomes included percentages of patients with levels of HbA1c ≤ 7%, blood pressure ≤ 130/85 mmHg and LDL-cholesterol <100 mg/dl (favourable indicators), and the percentages of patients with levels of HbA1c ≥ 9%, blood pressure ≥ 140/90 mmHg and LDL-cholesterol ≥ 130 mg/dl (unfavourable indicators). Percentages of patients treated with insulin, two or more antihypertensive agents, and statins were also evaluated. A multilevel analysis adjusted for age, gender, diabetes duration, and clustering effect was applied to investigate the changes in the indicators between the two groups of centres during 4 years. lipid profile monitoring increased more in group A (+6.2% from 2004 to 2007) than in group B (+2.4%), while HbA1c and blood pressure monitoring did not change over time in both groups. As for the outcomes considered, the percentage of patients with HbA1c ≤ 7% increased by 6% in group A and by 1.3%in group B, while the proportion of patients achieving the blood pressure target increased in group A (+6.4%), but not in group B (-1.4%). A reduction in the percentage of patients with blood pressure ≥ 140/90 mmHg was found in group A (-7.3%) but not in group B (-0.9%). Marked improvements in the proportion of patients with LDL-cholesterol at target were documented in both groups (group A: +10.5%; group B: +12.2%.) The proportion of patients treated with insulin increased in group A only (+5.8%), while the use of statins grew by 20%in both groups.The proportion of individuals treated with two or more antihypertensive drugs increased by 3.6% in group A and by 1.6% in group B. the AMD Annals approach can be considered as a case model for quality improvement activities in chronic diseases and a tool to evaluate the level of adoption/acceptance of guidelines in clinical practice. The considerable success documented was obtained without allocation of extra resources or financial incentives but simply through a physician-led effort made possible by the commitment of the specialists involved.


Fabrication of a 60-nm-diameter perfectly round metal-dot array over a large area on a plastic substrate using nanoimprint lithography and self-perfection by liquefaction.
Typically, nanopatterning on plastic substrates has poor fidelity, poor adhesion, and low yield. Here the proposal of and the first experiment using a new fabrication method that overcomes the above obstacles and has achieved arrays of 60-nm-diameter, perfectly round metal dots over a large area on a polyethylene terephthalate (PET) substrate with high fidelity and high yield is reported. This new method is based on the use of a thin hydrogen silsesquioxane (HSQ) layer on top of PET, nanoimprint lithography, and self-perfection by liquefaction (SPEL). The HSQ layer offers excellent thermal protection to the PET substrate during SPEL, as well as good surface adhesion and etching resistance. Nanoimprinting plus a lift off created a large-area array of Cr squares (100 nm x 130 nm) on HSQ and SPEL changed each Cr square into a perfectly round Cr dot with a diameter of 60 nm, reducing the Cr footprint area by 78%. Compared to bare PET, the use of HSQ also reduced the variation in the diameter of the Cr dots from 11.3 nm (standard deviation) to 1.7 nm, an improvement of over 660%. This new technology can be scaled to much larger areas (including roll-to-roll web processing) and thus potentially has applications in various fields.


Psychiatric interventions with returning soldiers at Walter Reed.
War is a malefic force and results in many psychiatric and medical casualties. Psychiatry's involvement with soldiers experiencing psychological stress resulting from combat experience has been reported for many years (Zajtchuk, 1995). It has been demonstrated that a myriad of diagnosis to include depression, anxiety, somatoform, adjustment disorders and psychotic behaviors also emerge (Wain et al., 1996, 2005a). Nearly all survivors exposed to traumatic events briefly exhibit one or more stress related symptoms (Morgan et al., 2003). In many instances these symptoms dissipate within a reasonable amount of time. However, symptoms persisting for a prolonged period following a traumatic event increase the probability of developing stress-related psychiatric disorders.


Measurements of fundamental properties of homogeneous tissue phantoms.
We present the optical measurement techniques used in human skin phantom studies. Their accuracy and the sources of errors in microscopic parameters' estimation of the produced phantoms are described. We have produced optical phantoms for the purpose of simulating human skin tissue at the wavelength of 930 nm. Optical coherence tomography was used to measure the thickness and surface roughness and to detect the internal inhomogeneities. A more detailed study of phantom surface roughness was carried out with the optical profilometer. Reflectance, transmittance, and collimated transmittance of phantoms were measured using an integrating-sphere spectrometer setup. The scattering and absorption coefficients were calculated with the inverse adding-doubling method. The reduced scattering coefficient at 930 nm was found to be 1.57±0.14 mm(−1) and the absorption was 0.22±0.03 mm(−1) . The retrieved optical properties of phantoms are in agreement with the data found in the literature for real human tissues.


Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease.
Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear. We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice. In nested case-control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis. The presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.).


Population structure of multi- and extensively drug-resistant Mycobacterium tuberculosis strains in South Africa.
Genotyping of multidrug-resistant (MDR) Mycobacterium tuberculosis strains isolated from tuberculosis (TB) patients in four South African provinces (Western Cape, Eastern Cape, KwaZulu-Natal, and Gauteng) revealed a distinct population structure of the MDR strains in all four regions, despite the evidence of substantial human migration between these settings. In all analyzed provinces, a negative correlation between strain diversity and an increasing level of drug resistance (from MDR-TB to extensively drug-resistant TB [XDR-TB]) was observed. Strains predominating in XDR-TB in the Western and Eastern Cape and KwaZulu-Natal Provinces were strongly associated with harboring an inhA promoter mutation, potentially suggesting a role of these mutations in XDR-TB development in South Africa. Approximately 50% of XDR-TB cases detected in the Western Cape were due to strains probably originating from the Eastern Cape. This situation may illustrate how failure of efficient health care delivery in one setting can burden health clinics in other areas.


Critical and independent role for SOCS3 in either myeloid or T cells in resistance to Mycobacterium tuberculosis.
Suppressor of cytokine signalling 3 (SOCS3) negatively regulates STAT3 activation in response to several cytokines such as those in the gp130-containing IL-6 receptor family. Thus, SOCS3 may play a major role in immune responses to pathogens. In the present study, the role of SOCS3 in M. tuberculosis infection was examined. All Socs3(fl/fl) LysM cre, Socs3(fl/fl) lck cre (with SOCS3-deficient myeloid and lymphoid cells, respectively) and gp130(F/F) mice, with a mutation in gp130 that impedes binding to SOCS3, showed increased susceptibility to infection with M. tuberculosis. SOCS3 binding to gp130 in myeloid cells conveyed resistance to M. tuberculosis infection via the regulation of IL-6/STAT3 signalling. SOCS3 was redundant for mycobacterial control by macrophages in vitro. Instead, SOCS3 expression in infected macrophages and DCs prevented the IL-6-mediated inhibition of TNF and IL-12 secretion and contributed to a timely CD4+ cell-dependent IFN-γ expression in vivo. In T cells, SOCS3 expression was essential for a gp130-independent control of infection with M. tuberculosis, but was neither required for the control of infection with attenuated M. bovis BCG nor for M. tuberculosis in BCG-vaccinated mice. Socs3(fl/fl) lck cre mice showed an increased frequency of γδ+ T cells in different organs and an enhanced secretion of IL-17 by γδ+ T cells in response to infection. Socs3(fl/fl) lck cre γδ+ T cells impaired the control of infection with M. tuberculosis. Thus, SOCS3 expression in either lymphoid or myeloid cells is essential for resistance against M. tuberculosis via discrete mechanisms.


Effects of age and muscle action type on acute strength and power recovery following fatigue of the leg flexors.
Short-term strength and power recovery patterns following fatigue have received little research attention, particularly as they pertain to age-specific responses, and the leg flexors (i.e., hamstrings) muscle group. Thus, research is warranted addressing these issues because both age-related alterations in the neuromuscular system and mode of muscle action (e.g., eccentric, concentric, isometric) may differentially influence recovery responses from fatigue. The aim of this study was to investigate the strength and power recovery responses for eccentric, concentric, and isometric muscle actions of the leg flexors in young and older men following an isometric, intermittent fatigue-inducing protocol. Nineteen young (age = 25 ± 3 years) and nineteen older (71 ± 4) men performed maximal voluntary contractions (MVCs) for eccentric, concentric, and isometric muscle actions followed by a fatigue protocol of intermittent (0.6 duty cycle) isometric contractions of the leg flexors at 60% of isometric MVC. MVCs of each muscle action were performed at 0, 7, 15, and 30 min following fatigue. Peak torque (PT) and mean power values were calculated from the MVCs and the eccentric/concentric ratio (ECR) was derived. For PT and mean power, young men showed incomplete recovery at all time phases, whereas the older men had recovered by 7 min. Eccentric and isometric muscle actions showed incomplete recovery at all time phases, but concentric recovered by 7 min, independent of age. The ECR was depressed for up to 30 min following fatigue. More rapid and pronounced recovery in older men and concentric contractions may be related to physiological differences specific to aging and muscle action motor unit patterns. Individuals and clinicians may use these time course responses as a guide for recovery following activity-induced fatigue.


Entrainment of the human circadian clock to the natural light-dark cycle.
The electric light is one of the most important human inventions. Sleep and other daily rhythms in physiology and behavior, however, evolved in the natural light-dark cycle [1], and electrical lighting is thought to have disrupted these rhythms. Yet how much the age of electrical lighting has altered the human circadian clock is unknown. Here we show that electrical lighting and the constructed environment is associated with reduced exposure to sunlight during the day, increased light exposure after sunset, and a delayed timing of the circadian clock as compared to a summer natural 14 hr 40 min:9 hr 20 min light-dark cycle camping. Furthermore, we find that after exposure to only natural light, the internal circadian clock synchronizes to solar time such that the beginning of the internal biological night occurs at sunset and the end of the internal biological night occurs before wake time just after sunrise. In addition, we find that later chronotypes show larger circadian advances when exposed to only natural light, making the timing of their internal clocks in relation to the light-dark cycle more similar to earlier chronotypes. These findings have important implications for understanding how modern light exposure patterns contribute to late sleep schedules and may disrupt sleep and circadian clocks.


A Virus Hosted in Malaria-Infected Blood Protects against T Cell-Mediated Inflammatory Diseases by Impairing DC Function in a Type I IFN-Dependent Manner.
Coinfections shape immunity and influence the development of inflammatory diseases, resulting in detrimental or beneficial outcome. Coinfections with concurrent Plasmodium species can alter malaria clinical evolution, and malaria infection itself can modulate autoimmune reactions. Yet, the underlying mechanisms remain ill defined. Here, we demonstrate that the protective effects of some rodent malaria strains on T cell-mediated inflammatory pathologies are due to an RNA virus cohosted in malaria-parasitized blood. We show that live and extracts of blood parasitized by Plasmodium berghei K173 or Plasmodium yoelii 17X YM, protect against P. berghei ANKA-induced experimental cerebral malaria (ECM) and myelin oligodendrocyte glycoprotein (MOG)/complete Freund's adjuvant (CFA)-induced experimental autoimmune encephalomyelitis (EAE), and that protection is associated with a strong type I interferon (IFN-I) signature. We detected the presence of the RNA virus lactate dehydrogenase-elevating virus (LDV) in the protective Plasmodium stabilates and we established that LDV infection alone was necessary and sufficient to recapitulate the protective effects on ECM and EAE. In ECM, protection resulted from an IFN-I-mediated reduction in the abundance of splenic conventional dendritic cell and impairment of their ability to produce interleukin (IL)-12p70, leading to a decrease in pathogenic CD4+ Th1 responses. In EAE, LDV infection induced IFN-I-mediated abrogation of IL-23, thereby preventing the differentiation of granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing encephalitogenic CD4+ T cells. Our work identifies a virus cohosted in several Plasmodium stabilates across the community and deciphers its major consequences on the host immune system. More generally, our data emphasize the importance of considering contemporaneous infections for the understanding of malaria-associated and autoimmune diseases.IMPORTANCE Any infection modifies the host immune status, potentially ameliorating or aggravating the pathophysiology of a simultaneous inflammatory condition. In the course of investigating how malaria infection modulates the severity of contemporaneous inflammatory diseases, we identified a nonpathogenic mouse virus in stabilates of two widely used rodent parasite lines: Plasmodium berghei K173 and Plasmodium yoelii 17X YM. We established that the protective effects of these Plasmodium lines on cerebral malaria and multiple sclerosis are exclusively due to this virus. The virus induces a massive type I interferon (IFN-I) response and causes quantitative and qualitative defects in the ability of dendritic cells to promote pathogenic T cell responses. Beyond revealing a possible confounding factor in rodent malaria models, our work uncovers some bases by which a seemingly innocuous viral (co)infection profoundly changes the immunopathophysiology of inflammatory diseases.


TIP49b, a regulator of activating transcription factor 2 response to stress and DNA damage.
Activating transcription factor 2 (ATF2/CRE-BP1) is implicated in transcriptional control of stress-responsive genes. A yeast two-hybrid screen identified TBP-interacting protein 49b (TIP49b), a component of the INO80 chromatin-remodeling complex, as a novel ATF2-interacting protein. TIP49b's association with ATF2 is phosphorylation dependent and requires amino acids 150 to 248 of ATF2 (ATF2(150-248)), which are implicated in intramolecular inhibition of ATF2 transcriptional activities. Forced expression of TIP49b efficiently attenuated ATF2 transcriptional activities under normal growth conditions as well as after UV treatment, ionizing irradiation, or activation of p38 kinase, all of which induced ATF2 phosphorylation and increased TIP49b-ATF2 association. Constitutive expression of ATF2(150-248) peptide outcompeted TIP49b interaction with ATF2 and alleviated the suppression of ATF2 transcriptional activities. Expression of ATF2(150-248) in fibroblasts or melanoma but not in ATF2-null cells caused a profound G(2)M arrest and increased degree of apoptosis following irradiation. The interaction between ATF2 and TIP49b constitutes a novel mechanism that serves to limit ATF2 transcriptional activities and highlights the central role of ATF2 in the control of the cell cycle and apoptosis in response to stress and DNA damage.


Inadvertent discontinuation of percutaneous nephrostomy catheters in adult native kidneys: incidence and percutaneous management.
To evaluate the incidence and consequences of complete inadvertent percutaneous nephrostomy catheter discontinuation in native kidneys of adults. In addition, this study evaluated the success rate of nephrostomy tract recannulation. Retrospective analysis was performed in adult patients who underwent percutaneous nephrostomy between January 2000 and December 2005. Patients' conditions were evaluated for complete inadvertent discontinuation of use of the nephrostomy catheters and success of subsequent recannulation procedures. Habitual discontinuation was defined by three catheter discontinuation episodes in one patient. Conditions of patients with inadvertent discontinuation were assessed for major complications before and after the recannulation, including the need for de novo nephrostomy to reestablish clinically needed access. The incidences of inadvertent discontinuation and primary assisted recannulation tract maintenance were calculated according to the Kaplan-Meier method. Successful versus unsuccessful recannulation procedures were compared for tract age, length of time the drain was out of the tract, and catheter diameter with use of the Mann-Whitney U test. A total of 283 patients underwent 325 percutaneous nephrostomies. The inadvertent catheter discontinuation rates at 6, 12, 24, and 36 months were 26%, 36%, 53%, and 62%, respectively. For the same time intervals, the primary recannulation assisted tract maintenance rates were 94%, 86%, 77%, and 72%, respectively. Habitual discontinuation was seen in 3.2% of the total population and 19.1% of discontinuation cases. The technical success rates of all and first-time recannulations were 85% and 74%, respectively. Tract maturity was the only variable that was statistically significant between successful and unsuccessful recannulations (P < .0001). A total of 3.5% of patients required new nephrostomies. Despite the high incidence of inadvertent discontinuation of nephrostomy catheters, the major complication rate was only 3.5%, indicating the efficacy of tract recannulation, especially in mature tracts.


Localization of dystrophin isoform Dp71 to the inner limiting membrane of the retina suggests a unique functional contribution of Dp71 in the retina.
The electroretinograms (ERGs) of patients with Duchenne muscular dystrophy and an allelic variant of the mdx mouse (mdxCv3) have been shown to be abnormal. Analysis of five allelic variants of the mdx mouse with mutations in the dystrophin gene has shown that there is a correlation between the position of the mutation and the severity of the ERG abnormality. Three isoforms are expressed in the retina: Dp427, Dp260 and Dp71. Using indirect immunofluorescence and isoform-specific antibodies on retinal sections from three allelic mdx mouse strains, we have examined the localization of each of the isoforms. We show that Dp71 expression does not overlap with Dp427 and Dp260 expression at the outer plexiform layer (OPL). Instead, Dp71 is localized to the inner limiting membrane (ILM) and to retinal blood vessels. Moreover, we show that Dp260 and Dp71 differ structurally at their respective C-termini. In addition, we find that the proper localization of the beta-dystroglycan is dependent upon both Dp260 at the OPL and Dp71 expression at the ILM. Thus, Dp260 and Dp71 are non-redundant isoforms that are located at different sites within the retina yet have a common interaction with beta-dystroglycan. Our data suggest that both Dp71 and Dp260 contribute distinct but essential roles to retinal electrophysiology.


Functional importance of covalent homodimer of reelin protein linked via its central region.
Reelin is a 3461-residue secreted glycoprotein that plays a critical role in brain development through its action on target neurons. Although it is known that functional reelin protein exists as multimer formed by interchain disulfide bond(s) as well as through non-covalent interactions, the chemical nature of the multimer assembly has been elusive. In the present study, we identified, among 122 cysteines present in full-length reelin, the single critical cysteine residue (Cys(2101)) responsible for the covalent multimerization. C2101A mutant reelin failed to assemble into disulfide-bonded multimers, whereas it still exhibited non-covalently associated high molecular weight oligomeric states in solution. Detailed analysis of tryptic fragments produced from the purified reelin proteins revealed that the minimum unit of the multimer is a homodimeric reelin linked via Cys(2101) present in the central region and that this cysteine does not connect to the N-terminal region of reelin, which had been postulated as the primary oligomerization domain. A surface plasmon resonance binding assay confirmed that C2101A mutant reelin retained binding capability toward two neuronal receptors apolipoprotein E receptor 2 and very low density lipoprotein receptor. However, it failed to show signaling activity in the assay using the cultured neurons. These results indicate that an intact higher order architecture of reelin multimer maintained by both Cys(2101)-mediated homodimerization and other non-covalent association present elsewhere in the reelin primary structure are essential for exerting its full biological activity.


Effects of curcumin and ursolic acid on the mitochondrial coupling efficiency and hydrogen peroxide emission of intact skeletal myoblasts.
Curcumin may improve blood glucose management, but the mechanism is not fully established. We demonstrated that curcumin (40 μM) reduced the mitochondrial coupling efficiency (percentage of oxygen consumption coupled to ATP synthesis) of intact skeletal muscle cells. A 30-minute pretreatment with curcumin reduced mitochondrial coupling efficiency by 17.0 ± 0.4% relative to vehicle (p < 0.008). Curcumin pretreatment also decreased the rate of hydrogen peroxide emission by 43 ± 13% compared to vehicle (p < 0.05). Analysis of cell respiration in the presence of curcumin revealed a 40 ± 4% increase in the rate of oxygen consumption upon curcumin administration (p < 0.05 compared to vehicle). No difference in mitochondrial coupling efficiency was observed between vehicle- and curcumin-pretreated cells after permeabilization of cell membranes (p > 0.7). The interaction between curcumin and ursolic acid, another natural compound that may improve blood glucose management, was also examined. Pretreatment with ursolic acid (0.12 μM) increased the mitochondrial coupling efficiency of intact cells by 4.1 ± 1.1% relative to vehicle (p < 0.008) and attenuated the effect of curcumin when the two compounds were used in combination. The observed changes to mitochondrial coupling efficiency and hydrogen peroxide emission were consistent with the established effects of curcumin on blood glucose control. Our findings also show that changes to mitochondrial coupling efficiency after curcumin pretreatment may go undetected unless cells are assessed in the intact condition.


Distribution of the pco Gene Cluster and Associated Genetic Determinants among Swine Escherichia coli from a Controlled Feeding Trial.
Copper is used as an alternative to antibiotics for growth promotion and disease prevention. However, bacteria developed tolerance mechanisms for elevated copper concentrations, including those encoded by the pco operon in Gram-negative bacteria. Using cohorts of weaned piglets, this study showed that the supplementation of feed with copper concentrations as used in the field did not result in a significant short-term increase in the proportion of pco-positive fecal Escherichia coli. The pco and sil (silver resistance) operons were found concurrently in all screened isolates, and whole-genome sequencing showed that they were distributed among a diversity of unrelated E. coli strains. The presence of pco/sil in E. coli was not associated with elevated copper minimal inhibitory concentrations (MICs) under a variety of conditions. As found in previous studies, the pco/sil operons were part of a Tn7-like structure found both on the chromosome or on plasmids in the E. coli strains investigated. Transfer of a pco/sil IncHI2 plasmid from E. coli to Salmonella enterica resulted in elevated copper MICs in the latter. Escherichia coli may represent a reservoir of pco/sil genes transferable to other organisms such as S. enterica, for which it may represent an advantage in the presence of copper. This, in turn, has the potential for co-selection of resistance to antibiotics.


Contact Lenses for Keratoconus- Current Practice.
Keratoconus is a chronic, bilateral, usuallly asymmetrical, non-inflammatory, ectatic disorder, being characterized by progressive steepening, thinning and apical scarring of the cornea. Initially, the patient is asymptomatic, but the visual acuity gradually decreases, resulting in significant vision loss due to the development of irregular astigmatism, myopia, corneal thinning and scarring. The classic treatment of visual rehabilitation in keratoconus is based on spectacles and contact lenses (CLs). To summarize the types of CLs used in the treatment of keratoconus. This is literature review of several important published articles focusing on the visual rehabilitation in keratoconus with CLs. Gas permeable (GP) CLs have been found to achieve better best corrected visual acuity than spectacles, eliminating 3rd-order coma root-mean-square (RMS) error, 3rd-order RMS, and higher-order RMS. However, they have implicated in reduction of corneal basal epithelial cell and anterior stromal keratocyte densities. Soft CLs seem to provide greater comfort and lower cost, but the low oxygen permeability (if the lens is not a silicone hydrogel), and the inability to mask moderate to severe irregular astigmatism are the main disadvantages of them. On the other hand, scleral CLs ensure stable platforms, which eliminate high-order aberrations and provide good centration and visual acuity. Their main disadvantages include the difficulties in application and removal of these lenses along with corneal flattening and swelling. The modern hybrid CLs are indicated in cases of poor centration, poor stability or intolerance with GP lenses. Finally, piggyback CL systems effectively ameliorate visual acuity, but they have been related to corneal neovascularization and giant papillary conjunctivitis. CLs seem to rehabilitate visual performance, diminishing the power of the cylinder and the high-order aberrations. The final choice of CLs is based on their special features, the subsequent corneal changes and the patient's needs.


Comparison of long-pulsed alexandrite laser and topical tretinoin-ammonium lactate in axillary acanthosis nigricans: A case series of patients in a before-after trial.
Acanthosis nigricans (AN) is a brown to black, velvety hyperpigmentation of the skin that usually involves cutaneous folds. Treatment of AN is important regarding cosmetic reasons and various therapeutic modalities have been used for these purposes. The goal of this study was to compare the effectiveness of long-pulsed alexandrite laser and topical tretinoin-ammonium lactate for treatment of axillary-AN. Fifteen patients with bilateral axillary-AN were studied in Razi Hospital, Tehran, Iran. Diagnosis was confirmed by two independent dermatologists. Each side skin lesion was randomly allocated to either topical mixed cream of tretinoin 0.05%- ammonium lactate 12% or long-pulsed alexandrite laser. Duration of treatment was 14 weeks. At endpoint, the mean percent reduction from baseline in pigmentation area was compared between the two groups. The study population consisted of 15 patients three males and 12, females. The mean age of patients was 28.5±4.9 years. The mean percent reduction was 18.3±10.6%, in tretinoin/ammonium lactate group and 25.7±11.8% in laser group (P=0.004). These findings indicate that the application of alexandrite laser is a relative effective method for treatment of axillary-AN. However, this issue requires further studies with prolonged follow-up period.


Genomic epidemiology of age-associated meningococcal lineages in national surveillance: an observational cohort study.
Invasive meningococcal disease (IMD) is a worldwide health issue that is potentially preventable with vaccination. In view of its sporadic nature and the high diversity of Neisseria meningitidis, epidemiological surveillance incorporating detailed isolate characterisation is crucial for effective control and understanding the evolving epidemiology of IMD. The Meningitis Research Foundation Meningococcus Genome Library (MRF-MGL) exploits whole-genome sequencing (WGS) for this purpose and presents data on a comprehensive and coherent IMD isolate collection from England and Wales via the internet. We assessed the contribution of these data to investigating IMD epidemiology. WGS data were obtained for all 899 IMD isolates available for England and Wales in epidemiological years 2010-11 and 2011-12. The data had been annotated at 1720 loci, analysed, and disseminated online. Information was also available on meningococcal population structure and vaccine (Bexsero, GlaxoSmithKline, Brentford, Middlesex, UK) antigen variants, which enabled the investigation of IMD-associated genotypes over time and by patients' age groups. Population genomic analyses were done with a hierarchical gene-by-gene approach. The methods used by MRF-MGL efficiently characterised IMD isolates and information was provided in plain language. At least 20 meningococcal lineages were identified, three of which (hyperinvasive clonal complexes 41/44 [lineage 3], 269 [lineage 2], and 23 [lineage 23]) were responsible for 528 (59%) of IMD isolates. Lineages were highly diverse and showed evidence of extensive recombination. Specific lineages were associated with IMD in particular age groups, with notable diversity in the youngest and oldest individuals. The increased incidence of IMD from 1984 to 2010 in England and Wales was due to successive and concurrent epidemics of different lineages. Genetically, 74% of isolates were characterised as encoding group B capsules: 16% group Y, 6% group W, and 3% group C. Exact peptide matches for individual Bexsero vaccine antigens were present in up to 26% of isolates. The MRF-MGL represents an effective, broadly applicable model for the storage, analysis, and dissemination of WGS data that can facilitate real-time genomic pathogen surveillance. The data revealed information crucial to effective deployment and assessment of vaccines against N meningitidis. Meningitis Research Foundation, Wellcome Trust, Public Health England, European Union.


A whey protein-based multi-ingredient nutritional supplement stimulates gains in lean body mass and strength in healthy older men: A randomized controlled trial.
Protein and other compounds can exert anabolic effects on skeletal muscle, particularly in conjunction with exercise. The objective of this study was to evaluate the efficacy of twice daily consumption of a protein-based, multi-ingredient nutritional supplement to increase strength and lean mass independent of, and in combination with, exercise in healthy older men. Forty-nine healthy older men (age: 73 ± 1 years [mean ± SEM]; BMI: 28.5 ± 1.5 kg/m2) were randomly allocated to 20 weeks of twice daily consumption of either a nutritional supplement (SUPP; n = 25; 30 g whey protein, 2.5 g creatine, 500 IU vitamin D, 400 mg calcium, and 1500 mg n-3 PUFA with 700 mg as eicosapentanoic acid and 445 mg as docosahexanoic acid); or a control (n = 24; CON; 22 g of maltodextrin). The study had two phases. Phase 1 was 6 weeks of SUPP or CON alone. Phase 2 was a 12 week continuation of the SUPP/CON but in combination with exercise: SUPP + EX or CON + EX. Isotonic strength (one repetition maximum [1RM]) and lean body mass (LBM) were the primary outcomes. In Phase 1 only the SUPP group gained strength (Σ1RM, SUPP: +14 ± 4 kg, CON: +3 ± 2 kg, P < 0.001) and lean mass (LBM, +1.2 ± 0.3 kg, CON: -0.1 ± 0.2 kg, P < 0.001). Although both groups gained strength during Phase 2, upon completion of the study upper body strength was greater in the SUPP group compared to the CON group (Σ upper body 1RM: 119 ± 4 vs. 109 ± 5 kg, P = 0.039). We conclude that twice daily consumption of a multi-ingredient nutritional supplement increased muscle strength and lean mass in older men. Increases in strength were enhanced further with exercise training. ClinicalTrials.gov NCT02281331.


Phenex: ontological annotation of phenotypic diversity.
Phenotypic differences among species have long been systematically itemized and described by biologists in the process of investigating phylogenetic relationships and trait evolution. Traditionally, these descriptions have been expressed in natural language within the context of individual journal publications or monographs. As such, this rich store of phenotype data has been largely unavailable for statistical and computational comparisons across studies or integration with other biological knowledge. Here we describe Phenex, a platform-independent desktop application designed to facilitate efficient and consistent annotation of phenotypic similarities and differences using Entity-Quality syntax, drawing on terms from community ontologies for anatomical entities, phenotypic qualities, and taxonomic names. Phenex can be configured to load only those ontologies pertinent to a taxonomic group of interest. The graphical user interface was optimized for evolutionary biologists accustomed to working with lists of taxa, characters, character states, and character-by-taxon matrices. Annotation of phenotypic data using ontologies and globally unique taxonomic identifiers will allow biologists to integrate phenotypic data from different organisms and studies, leveraging decades of work in systematics and comparative morphology.


Development of sucking patterns in pre-term infants with bronchopulmonary dysplasia.
Pre-term infants with bronchopulmonary dysplasia (BPD) are at risk of acquiring brain abnormalities. Combined with ongoing breathing difficulties, this may influence the development of their sucking patterns. To determine the longitudinal development of sucking patterns from birth until 10 weeks' post-term age in pre-term infants with and without BPD. The sucking patterns of 16 pre-term infants with BPD and 15 pre-term infants without BPD were prospectively assessed with the Neonatal Oral-Motor Assessment Scale. The infants were matched for gestational age (<30 weeks). We recorded approximately 12 feeding episodes per infant, from 34 until 50 weeks' post-menstrual age. We diagnosed the infants' sucking patterns as normal, dysfunctional, or disorganized. Then, we examined the development of the sucking patterns in relation to relevant clinical characteristics. Thirty (21%) of 142 feeding episodes of the pre-term infants with BPD and 36 (23%) of 156 of those without BPD were diagnosed as normal (non-significant). Of the abnormal patterns, 3 were diagnosed as dysfunctional and 229 as disorganized. Before term-equivalent age, definitely abnormal sucking patterns were more prevalent in the pre-term infants with BPD than in those without BPD: 69 (49%) and 47 (30%) episodes, respectively (χ(2) = 10.7, p < 0.01). In particular, the abnormal patterns including the item 'incoordination', defined as the inability to coordinate sucking and swallowing with breathing, were more prevalent: 36 and 15%, respectively (χ(2) = 6.37, p < 0.05). There was no difference between the two groups regarding the age at which they acquired normal sucking patterns. Relevant clinical characteristics did not influence the development of the sucking patterns. The developmental characteristic of sucking patterns in infants with BPD was that these infants were unable to coordinate swallowing with breathing. This was the case especially prior to term-equivalent age; after term-equivalent age, the development of sucking closely resembled that of pre-term infants without BPD.


2'-O-ribose methylation of cap2 in human: function and evolution in a horizontally mobile family.
The 5' cap of human messenger RNA consists of an inverted 7-methylguanosine linked to the first transcribed nucleotide by a unique 5'-5' triphosphate bond followed by 2'-O-ribose methylation of the first and often the second transcribed nucleotides, likely serving to modify efficiency of transcript processing, translation and stability. We report the validation of a human enzyme that methylates the ribose of the second transcribed nucleotide encoded by FTSJD1, henceforth renamed HMTR2 to reflect function. Purified recombinant hMTr2 protein transfers a methyl group from S-adenosylmethionine to the 2'-O-ribose of the second nucleotide of messenger RNA and small nuclear RNA. Neither N(7) methylation of the guanosine cap nor 2'-O-ribose methylation of the first transcribed nucleotide are required for hMTr2, but the presence of cap1 methylation increases hMTr2 activity. The hMTr2 protein is distributed throughout the nucleus and cytosol, in contrast to the nuclear hMTr1. The details of how and why specific transcripts undergo modification with these ribose methylations remains to be elucidated. The 2'-O-ribose RNA cap methyltransferases are present in varying combinations in most eukaryotic and many viral genomes. With the capping enzymes in hand their biological purpose can be ascertained.


Multidisciplinary Rehabilitation is Efficacious and Induces Neural Plasticity in Multiple Sclerosis even when Complicated by Progressive Multifocal Leukoencephalopathy.
A 48-year-old woman with multiple sclerosis (MS), treated with natalizumab for more than one year without clinical and magnetic resonance imaging (MRI) signs of disease activity, was diagnosed with definite progressive multifocal leukoencephalopathy (PML). She presented with subacute motor deficit of the right upper limb (UL), followed by involvement of the homolateral leg and urinary urgency. The patient was treated with steroids and plasma exchange. On follow-up MRI scans, the PML lesion remained stable and no MS rebounds were observed, but the patient complained of a progressive worsening of the right UL motor impairment, becoming dependent in most activities of daily living. A cycle of multidisciplinary rehabilitation (MDR) was then started, including daily sessions of UL robot therapy and occupational therapy. Functional MRI (fMRI) was acquired before and at the end of the MDR cycle using a motor task which consisted of 2 runs: in one run the patient was asked to observe while the second one consisted of hand grasping movements. At the end of the rehabilitation period, both the velocity and the smoothness of arm trajectories during robot-based reaching movements were significantly improved. After MDR, compared with baseline, fMRI showed significantly increased functional activation within the sensory-motor network in the active, motor task, while no significant differences were found in the observational task. MDR in MS, including robot-assisted UL training, seems to be clinically efficacious and to have a significant impact on brain functional reorganization on a short-term, even in the presence of superimposed tissue damage provoked by PML.


A direct comparison of real time PCR on plasma and blood to detect Plasmodium falciparum infection in children.
Estimation of Plasmodium falciparum parasitaemia can vary with the method used and time of sampling. Quantitative real time PCR (qPCR) on whole blood or plasma samples has previously been shown to be more sensitive than thick film microscopy. However the efficiencies of each method have not been compared using samples obtained from infants less than one year old. A multiple of statistical approaches were used to compare the performance of qPCR on whole blood or plasma to detect the 18 S ribosomal gene of P. falciparum in 548 samples from children aged 2.5 or 24 months. Parasite prevalence in matched samples was compared using Mcnemar's test and agreement of positive results quantified as Kappa scores. Parasite prevalences between different age groups were compared by Fisher's test. Results from analyses by thick film microscopy were also available from children at 24 months and their correlation to each qPCR method examined by the Spearman's test. Finally the association of P. falciparum infection with the incidence of multiple malaria episodes from contact to 24 months of age was evaluated using negative binomial regression. These analyses showed that qPCR from whole blood detected approximately 3-fold more cases of infection than plasma qPCR. Both qPCR methods agreed well with each other although qPCR from plasma had a greater agreement with microscopy (96.85%) than did qPCR from blood (69.7%). At 24 months the prevalence of infection detected by all methods was associated with anaemia (p<0.05). The data presented here demonstrates that low levels of parasitaemia are better detected by qPCR using parasite DNA from whole blood than from plasma. However plasma samples provide a viable substitute when parasite smears are unavailable.


Antimicrobial activity of mul-1867, a novel antimicrobial compound, against multidrug-resistant Pseudomonas aeruginosa.
There is an urgent need for new antimicrobial compounds to treat various lung infections caused by multidrug-resistant Pseudomonas aeruginosa (MDR-PA). We studied the potency of Mul-1867 against MDR-PA isolates from patients with cystic fibrosis, chronic obstructive pulmonary disease, and ventilator-associated pneumonia. The minimal inhibitory concentrations (MICs) and minimum biofilm eliminating concentrations (MBECs), defined as the concentrations of drug that kill 50 % (MBEC50), 90 % (MBEC90), and 100 % (MBEC100) of the bacteria in preformed biofilms, were determined by using the broth macrodilution method. Mul-1867 exhibited significant activity against MDR-PA and susceptible control strains, with MICs ranging from 1.0 to 8.0 µg/mL. Mul-1867 also possesses anti-biofilm activity against mucoid and non-mucoid 24-h-old MDR-PA biofilms. The MBEC50 value was equal to onefold the MIC. The MBEC90 value ranged from two to fourfold the MIC. Moreover, Mul-1867 completely eradicated mature biofilms at the concentrations tested, with MBEC100 values ranging between 16- and 32-fold the MIC. Mul-1867 was non-toxic to Madin-Darby canine kidney (MDCK) cells at concentrations up to 256 µg/mL. Overall, these data indicate that Mul-1867 is a promising locally acting antimicrobial for the treatment and prevention of P. aeruginosa infections.


Induction of biologically active interleukin-8 from lung epithelial cells by Burkholderia (Pseudomonas) cepacia products.
The frequency of isolation of Burkholderia cepacia from the sputum of cystic fibrosis (CF) patients is increasing. Using the human A549 lung epithelial cell line, we have investigated the ability of B. cepacia exoproducts to stimulate interleukin-8 (IL-8) release. Cell-free supernatants from a panel of CF clinical, non-CF clinical, and nonclinical B. cepacia isolates were found to stimulate IL-8 release, with levels ranging from 11.8 +/- 2.8 to 80.0 +/- 3.5 ng/ml. A similar pattern was seen at the level of the IL-8 mRNA. The bioactivity of the IL-8 was confirmed by examining its effect on the intracellular free calcium in neutrophils and inhibition by a neutralizing anti-IL-8 antibody. B. cepacia lipopolysaccharide, which was able to stimulate IL-8 release from monocytes, did not release IL-8 from the A549 cells. Furthermore, the stimulating ability of the bacterial cell-free supernatant was not diminished by polymyxin B, was markedly reduced by boiling, and appeared unrelated to N-acylhomoserine lactones. The ability of B. cepacia to elicit IL-8 release from epithelial cells may be important in the pathology of CF.


Genetic bases of pheochromocytoma and paraganglioma.
The genetics of pheochromocytoma and paraganglioma (PPGL) has become increasingly complex over the last two decades. The list of genes involved in the development of these tumors has grown steadily, and there are currently more than 20 driver genes implicated in either the hereditary or the sporadic nature of the disease. Although genetic diagnosis is achieved in about 75-80% of patients, genetic etiology remains unexplained in a significant percentage of cases. Patients lacking a genetic diagnosis include not only those with apparently sporadic PPGL but also patients with a family history of the disease or with multiple tumors, that meet the criteria to be considered as candidates for carrying germline mutations in yet undiscovered genes. Mutations in known PPGL genes deregulate three main signaling pathways (hypoxia, kinase signaling, and Wnt-signaling pathways), which could be the starting point for the development of personalized treatment for PPGL patients. Furthermore, the integration of results from several genomic high-throughput platforms enables the discovery of regulatory mechanisms that cannot be identified by analyzing each piece of information separately. These strategies are powerful tools for elucidating optimal therapeutic options based on molecular biomarkers in PPGL and represent an important step toward the achievement of precision medicine for patients with metastatic PPGL.


The pharmacokinetics of meloxicam in vultures.
Vulture populations across the Asian subcontinent have declined dramatically in the last 15 years and are now on the verge of extinction. Although the cause of the population decline was initially unknown, the decrease has recently been conclusively linked to the use of the nonsteroidal anti-inflammatory drug diclofenac in cattle that inadvertently ended up in the vulture food chain. With the vulture numbers continuing to decline by up to 48% a year, the Indian, Nepali and Pakistan governments have recently banned the manufacture and importation of veterinary diclofenac. They have also suggested meloxicam as an alternate anti-inflammatory for use in cattle. This recommendation was based on extensive acute safety studies in the African White-backed vulture (Gyps africanus), which evaluated worst case scenarios of maximum intake based on a once in three day feeding pattern. However, the possible cumulative pharmacokinetic and pharmacodynamic effects in vultures receiving multiple daily doses of meloxicam over time were not assessed. At present very little pharmacokinetic or pharmacodynamic information is available to add further support for the safety of meloxicam in this animal species. This article discusses the oral and intramuscular pharmacokinetics of meloxicam in Cape Griffon vultures (Gyps coprotheres). Therapeutic drug monitoring was also undertaken in White-backed, Egyptian (Neophron pernopterus) and one Lappet Faced vulture (Torgos tracheliotos). In all these species, meloxicam was characterized by a short half-life of elimination. The rapid metabolism of meloxicam in combination with a short duration of effect in the studied species Gyps vultures shown in this study makes it unlikely that the drug could accumulate. This confirms the safety of repeated exposure to meloxicam in vultures of this genus.


Negative linear compressibility.
While all materials reduce their intrinsic volume under hydrostatic (uniform) compression, a select few actually expand along one or more directions during this process of densification. As rare as it is counterintuitive, such "negative compressibility" behaviour has application in the design of pressure sensors, artificial muscles and actuators. The recent discovery of surprisingly strong and persistent negative compressibility effects in a variety of new families of materials has ignited the field. Here we review the phenomenology of negative compressibility in this context of materials diversity, placing particular emphasis on the common structural motifs that recur amongst known examples. Our goal is to present a mechanistic understanding of negative compressibility that will help inform a clear strategy for future materials design.


Arabin cervical pessary in women at high risk of preterm birth: a magnetic resonance imaging observational follow-up study.
To help elucidate the mechanism of action of the Arabin cervical pessary in pregnancies at high risk for preterm delivery. Cervical length and uterocervical angle were evaluated in relation to gestational age in 198 pregnancies not at high risk for preterm birth that underwent clinical fetal magnetic resonance imaging (MRI). Additionally, in 73 singleton pregnancies at high risk for preterm birth, an Arabin cervical pessary was placed at 14-33 weeks' gestation. We performed MRI of the cervix immediately before and after placement and at monthly follow-up until removal of the pessary. In a subgroup of 54 pregnancies with a short cervix and pessary placement at 17-31 weeks' gestation, the uterocervical angle and cervical length at follow-up were compared with the preplacement values. In pregnancies not at high risk for preterm birth, the uterocervical angle did not vary, but cervical length showed a significant decrease with gestational age (r = -0.15, P < 0.05). Among the high-risk patients, the cervical pessary was successfully placed at first attempt in 60 (82.2%) and by the second attempt in 66 (90.4%), remaining well positioned until removal. In five patients we failed to place the pessary after two attempts, in one patient the pessary dislodged during follow-up and in one case the pessary was partly placed in the external cervical canal and triggered labor the next day. Among the subgroup of 54 patients, the median uterocervical angle immediately after pessary placement was significantly more acute than that prior to placement in the 46 (85.2%) who delivered after 34 weeks (132° vs 146°, P < 0.01), but was unchanged in the eight patients who delivered before 34 weeks (143° vs 152°, P > 0.05). In patients at high risk for preterm delivery, correct placement of the Arabin cervical pessary should be checked immediately; this can be performed quickly and easily using MRI. This study provides some evidence that, in singleton pregnancies with a short cervix, a cervical pessary delays birth through a mechanical effect on the uterocervical angle.


Lanreotide autogel and insulin sensitivity markers: report of 5 acromegalic patients and literature review.
To evaluate the short-term effects of Lanreotide Autogel on insulin sensitivity markers among acromegalic patients with pituitary tumors. Prospective clinical trial with six months of follow-up. A tertiary endocrinology clinic. Naïve patients (patient No. 1 and patient No. 3) and patients who experienced prior somatostatin analogue treatment (patient No. 2, patient No. 4, and patient No. 5) were included. Before and after 6 months of Lanreotide Autogel therapy, insulin sensitivity in each subject was determined using homeostasis model assessment of insulin resistance and beta-cell function formula. Euglycemic hyperinsulinemic clamp test was also performed to evaluate whole insulin sensitivity and was indicated as an 'M' index. All patients experienced reduction in their HOMA-beta. We noted major HOMA-beta decreases accompanied by pronounced increases in M indices for patients Nos. 1, 2 and 3 (1.03 vs. 8.22, 2.98 vs. 4.70, and 5.09 vs. 13.09, respectively). The increases in M indices of these patients were with marked decreases in GH levels (34.20 vs. 15.30 microg/l, 4.25 vs. 0.74 and 5.0 vs. 0.66 ng/mL, respectively). Minor decline in HOMA-beta and worsened M index and almost stable GH were observed in patients Nos. 4 and 5. Except for patient No. 3, all participants showed declining HOMA-IR. Short-term Lanreotide Autogel treatment has been observed to improve M indices of acromegalic patients whose GH levels exhibited marked reduction. This amelioration seemed to be related to decreases in GH levels rather than to a direct drug effect.


Multiple Otx binding sites required for expression of the Strongylocentrotus purpuratus Spec2a gene.
The control region of the aboral ectoderm-specific Spec2a gene of Strongylocentrotus purpuratus contains a 188-bp enhancer element, the RSR enhancer, required for temporal activation and aboral ectoderm/mesenchyme cell expression. Within the enhancer is a positive cis-regulatory element with the core consensus sequence TAATCC, which is capable of binding the sea urchin orthodenticle-related homeobox protein SpOtx. In this report, we extend our analysis of the RSR enhancer by dissecting it into smaller pieces and testing these pieces in an enhancer activation assay. The 188-bp enhancer region could not be divided without partial loss of activity, and two of the three pieces tested exhibited some activity. Using site-directed mutagenesis, we showed that three Otx consensus binding sites were responsible for the activity of the enhancer, acting in a non-cooperative manner to yield full activity. Mutagenizing the three Otx sites and a fourth one just upstream abolished all activity in the context of the complete Spec2a control region. Bandshift analysis revealed that the Otx sites were able to bind SpOtx, suggesting that this transcription factor mediates positive control at these sites. Non-SpOtx binding sites overlapping two of the Otx sites may also play a role in Spec2a expression. Using a lacZ reporter gene, we showed that a 76-bp DNA fragment containing two of the Otx sites was sufficient for aboral ectoderm/mesenchyme cell expression. These results suggest that the RSR enhancer plus an upstream DNA element required for mesenchyme cell repression are necessary and sufficient for the proper temporal activation and aboral ectoderm expression of the Spec2a gene and that the Otx elements play a positive role in this process.


Characterization of optical diffraction gratings by use of a neural method.
Optical scatterometry by use of a neural network is now recognized as an efficient method for retrieving dimensions of gratings in semiconductors or glasses. For an on-line control, a small number of measurements and a rapid data treatment are needed. We demonstrate that these requirements can be met by combining data preprocessing and a proper neural learning method. A good accuracy is attainable with the measurement of only a few orders, even in the presence of experimental errors, with a reduction in learning and computing time.


Standard deviation of anthropometric Z-scores as a data quality assessment tool using the 2006 WHO growth standards: a cross country analysis.
Height- and weight-based anthropometric indicators are used worldwide to characterize the nutritional status of populations. Based on the 1978 WHO/National Center for Health Statistics (NCHS) growth reference, the World Health Organization has previously indicated that the standard deviation (SD) of Z-scores of these indicators is relatively constant across populations, irrespective of nutritional status. As such, the SD of Z-scores can be used as quality indicators for anthropometric data. In 2006, WHO published new growth standards. Here, we aim to assess whether the SD of height- and weight-based Z-score indicators from the 2006 WHO growth standards can still be used to assess data quality. We examined data on children aged 0-59 months from 51 Demographic and Health Surveys (DHS) in 34 developing countries. We used 2006 growth standards to assign height-for-age Z-scores (HAZ), weight-for-age Z-scores (WAZ), weight-for-height Z-scores (WHZ) and body-mass-index-for-age Z-scores (BMIZ). We also did a stratified analysis by age group. The SD for all four indicators were independent of their respective mean Z-scores across countries. Overall, the 5th and 95th percentiles of the SD were 1.35 and 1.95 for HAZ, 1.17 and 1.46 for WAZ, 1.08 and 1.50 for WHZ and 1.08 and 1.55 for BMIZ. Our results concur with the WHO assertion that SD is in a relatively small range for each indicator irrespective of where the Z-score mean lies, and support the use of SD as a quality indicator for anthropometric data. However, the ranges of SDs for all four indicators analysed were consistently wider than those published previously by WHO.


Racial disparities in hypertension control, but not treatment intensification.
Racial disparities in hypertension control are well documented, yet the contribution of providers to these disparities remains unclear. The objective of this study was to examine whether provider management of uncontrolled hypertension differed by patient race. In a retrospective cohort of 16,881 hypertensive adults in six academic primary care practices from 1/2004 to 12/2006, we evaluated hypertension control in black vs. white patients according to expert guidelines and, among those with uncontrolled hypertension, whether antihypertensive drugs were intensified by providers. Generalized estimating equations accounted for clustering and adjusted sequentially and additively for patient, provider, and practice characteristics, as well as health-care utilization and antihypertensive medication potency. Black patients' visits (55.5% of 132,730 visits) had a higher unadjusted odds (1.63, 95% confidence interval (CI) 1.57-1.69) of uncontrolled hypertension than white patients' visits; the fully adjusted odds ratio remained significant (1.40, CI 1.33-1.48, P < 0.001). Among 66,327 visits with uncontrolled hypertension, no intensification of antihypertensive drugs was less likely for blacks' visits before adjustment (0.80, CI 0.76-0.83, P < 0.001) but moderated in the fully adjusted model (adjusted odds ratio 0.93, CI 0.87-0.99, P < 0.05) compared with whites' visits. Accounting for provider race, intensification was more likely at black patients' visits compared with white patients' visits. In our study, black patients had poorer hypertension control, and providers were more likely to intensify antihypertensive drugs at visits of black compared with white patients as appropriate. These data suggest that more research is needed to understand racial disparities in hypertension control.


Management of COMPlicAted intra-abdominal collectionS after colorectal Surgery (COMPASS): protocol for a multicentre, observational, prospective international study of drain placement practices in colorectal surgery.
Postoperative drains have historically been used for the prevention and early detection of intra-abdominal collections. However, current evidence suggests that prophylactic drain placement following colorectal surgery has no significant clinical benefit. This is reflected in the enhanced recovery after surgery (ERAS) guidelines, which recommend against their routine use. The Ileus Management International study found more than one-third of participating centres across the world routinely used drains in the majority of colorectal resections. The aim of the present study is to audit international compliance with ERAS guidelines regarding the use of postoperative drains in colorectal surgery. This prospective, multicentre audit will be conducted via the student- and trainee-led EuroSurg Collaborative network across Europe, South Africa and Australasia. Data will be collected on consecutive patients undergoing elective and emergency colorectal surgery with 30-day follow-up. This will include any colorectal resection, formation of colostomy/ileostomy and reversal of stoma. The primary end-point will be adherence to ERAS guidelines for intra-abdominal drain placement. Secondary outcomes will include the following: time to diagnosis of intra-abdominal postoperative collections; output and time to removal of drains; and 30-day postoperative complications defined by the Clavien-Dindo classification. This protocol describes the methodology for the first international audit of intra-abdominal drain placement after colorectal surgery. The study will be conducted across a large collaborative network with quality assurance and data validation strategies. This will provide a clear understanding of current practice and novel evidence regarding the efficacy and safety of intra-abdominal drain placement in colorectal surgical patients.


Epidemiological patterns of scurvy among Ethiopian refugees.
In the Horn of Africa, scurvy is a serious public health problem for refugees who are dependent on standard relief food (cereals, legumes, and oil). To assess the risk factors and to quantify the potential magnitude of scurvy among these displaced communities, we reviewed data collected from 1985 to 1987 by relief programmes in five refugee camps in Somalia and one in the Sudan. Outbreaks of clinical scurvy occurred among refugees in all the camps from 3 to 4 months after their arrival. The incidence of scurvy in two camps was, respectively, 14% over a period of 4 months and 19.8% over a period of 18 months. Prevalences of scurvy estimated from random population samples in the six study camps ranged from 13.6% to 44%. The risk of developing scurvy increased significantly with the length of time that refugees had been in the camps and was also significantly higher among those who were older and among females, particularly those of childbearing age. The prevalence of scurvy among refugees was similar, irrespective of whether or not they had attended supplementary feeding programmes. The control measures that were implemented had a moderate and slow impact on the disease. In both Somalia and the Sudan the relief food distributed to the refugees was almost completely deficient in vitamin C, while the environment where the camps were located precluded an adequate supply of fresh food. To avoid scurvy among refugee communities in this area of Africa it is therefore recommended that vitamin C supplements be added to the relief food at an early stage of a crisis.


Enhancing 'Whole-of-Government' Response to Biological Events in Korea: Able Response 2014.
Since 2011, the Republic of Korea (ROK) and United States (U.S.) have been collaborating to conduct inter- and intra-governmental exercises to jointly respond to biological events in Korea. These exercises highlight U.S. interest in increasing its global biosurveillance capability and the ROK's interest in improving cooperation among ministries to respond to crises. With Able Response (AR) exercises, the ROK and U.S. have improved coordination among US and ROK government and defense agencies responding to potential bio-threats and identified additional areas on which to apply refinements in policies and practices. In 2014, the AR exercise employed a Biosurveillance Portal (BSP) to facilitate more effective communication among participating agencies and countries including Australia. In the present paper, we seek to provide a comprehensive assessment of the AR 2014 (AR14) exercise and make recommendations for future improvements. Incorporating a more realistic response in future scenarios by integrating a tactical response episode in the exercise is recommended.


Effect of butterfly-shaped sulfur-bridged ligand and counter anions on the catalytic activity and diastereoselectivity of organobismuth complexes.
In the direct Mannich reaction and synthesis of α,β-unsaturated ketones, the use of organobismuth complexes as catalysts leads to high diastereoselectivity and products of single trans conformation. In this paper, we illustrate the relationship between structure and catalytic activity as well as diastereoselectivity of organobismuth complexes having a 5,6,7,12-tetrahydrodibenz [c,f][1,5]thiobismocine framework as well as bearing a butterfly-shaped sulfur-bridged ligand and tunable anions. With the exposed bismuth center acting as a Lewis acid site and the uncoordinated lone pair electrons of sulfur as a Lewis base site, the cationic organobismuth complexes work as bifunctional Lewis acid/base catalysts. Due to the steric influence of the butterfly-shaped structure and synergistic effect of Lewis acid and Lewis base centers, the complexes can direct substrate attack in organic synthesis. By adjusting the electron-withdrawing ability of the counter anions, the S-Bi bond strength can be regulated, leading to a significant change in Lewis acidity and Lewis basicity as well as catalytic activity. Through synergistic modulation of the above effects, one can control the diastereoselectivity of the organobismuth complexes for the generation of a single diastereoisomer.


Energy Harvesting from Brines by Reverse Electrodialysis Using Nafion Membranes.
Ion exchange membranes (IEMs) have consolidated applications in energy conversion and storage systems, like fuel cells and battery separators. Moreover, in the perspective to address the global need for non-carbon-based and renewable energies, salinity-gradient power (SGP) harvesting by reverse electrodialysis (RED) is attracting significant interest in recent years. In particular, brine solutions produced in desalination plants can be used as concentrated streams in a SGP-RED stack, providing a smart solution to the problem of brine disposal. Although Nafion is probably the most prominent commercial cation exchange membrane for electrochemical applications, no study has investigated yet its potential in RED. In this work, Nafion 117 and Nafion 115 membranes were tested for NaCl and NaCl + MgCl2 solutions, in order to measure the gross power density extracted under high salinity gradient and to evaluate the effect of Mg2+ (the most abundant divalent cation in natural feeds) on the efficiency in energy conversion. Moreover, performance of commercial CMX (Neosepta) and Fuji-CEM 80050 (Fujifilm) cation exchange membranes, already widely applied for RED applications, were used as a benchmark for Nafion membranes. In addition, complementary characterization (i.e., electrochemical impedance and membrane potential test) was carried out on the membranes with the aim to evaluate the predominance of electrochemical properties in different aqueous solutions. In all tests, Nafion 117 exhibited superior performance when 0.5/4.0 M NaCl fed through 500 µm-thick compartments at a linear velocity 1.5 cm·s-1. However, the gross power density of 1.38 W·m-2 detected in the case of pure NaCl solutions decreased to 1.08 W·m-2 in the presence of magnesium chloride. In particular, the presence of magnesium resulted in a drastic effect on the electrochemical properties of Fuji-CEM-80050, while the impact on other membranes investigated was less severe.


External validation of comorbid patterns of anxiety disorders in children and adolescents.
To evaluate the external validity of comorbid patterns of anxiety disorders among youth who presented to an anxiety disorders clinic, comorbid cases were compared to "pure" anxiety disorder cases. Children and adolescents (N=329; mean age=10.04 years) and parents were administered structured interviews and four groups were formed, Pure Anxiety, Anxiety+Anxiety, Anxiety+Externalizing, and Anxiety+Depressive, and compared along with four external validation criteria: sociodemographics, clinical phenomenology, psychosocial, and family factors. All comorbid groups were more severe than the pure anxiety group on clinical phenomenology and psychosocial factors. The Anxiety+Depressive Disorders group was most severe on all criteria except sociodemographics. Results provide evidence for the external validity of comorbid diagnostic presentations among anxiety disorders, as there was differential meaningfulness in the diagnostic presentation of a pure anxiety disorder versus anxiety disorder comorbid with other disorders. Assessment and future research implications are discussed.


Desipramine plasma concentration and antidepressant response.
The relationship of desipramine hydrochloride plasma concentration and antidepressant response was determined in 30 depressed inpatients treated for three weeks with desipramine. All patients had a nondelusional unipolar depression, met DSM-III criteria for major depressive episode with melancholia, and had a Hamilton score of 18 or greater after one week of hospitalization without medication. Eighty-nine percent of the patients with plasma concentrations above 115 ng/mL responded, in contrast to 14% of those with concentrations below this level, a significant difference (Fisher's exact test, P less than .001). Ten initial nonresponders were converted to responders when dosage increase raised desipramine plasma concentration to 125 ng/mL or above. In clinical practice a plasma concentration of 125 ng/mL would be a useful guideline as a threshold above which desipramine is likely to be effective.


Alterations in the molecular determinants of bladder compliance at hydrostatic pressures less than 40 cm. H2O.
Bladder outlet obstruction with intravesical pressures exceeding 40 cm. H2O often results in irreversible renal damage. Bladder outlet obstruction also results in alterations in bladder physiology, including wall thickening, reduced compliance and decreased capacity. If unchecked these changes may lead to the subsequent need for bladder augmentation. From a biomechanical standpoint, compliance is primarily related to extracellular matrix deposition, which in turn is dependent on the balanced activity of proteolytic enzymes (that is matrix metalloproteinases [MMPs]) and their endogenous inhibitors (that is tissue inhibitors of metalloproteinases [TIMPs]). To date, the threshold pressure above which alterations in these key determinants of bladder compliance occur has not been determined. Therefore, using a novel device of our own design, we applied hydrostatic pressures in the physiological range to human bladder smooth muscle cells to determine the effect on MMPs, TIMP-1 and transcription of the major structural collagens (types I and III). Human bladder smooth muscle cells (staining positive for alpha-smooth muscle actin) were plated at a density of 100,000 cells per 10 cm.2 and cultured for 2 days in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal bovine serum. Cells were subsequently exposed to pressures of 0.3, 20 and 40 cm. H2O for 1, 3, 7 and 24 hours in serum-free DMEM. A computer interface maintained pressure levels for the duration of the experiments and collected pressure data. MMP-1 and 3, and TIMP-1 immunoassay and zymography for MMP-2 and 9 were performed. Polymerase chain reaction for human collagen types I and III was performed following reverse transcription of total purified mRNA. All experiments were repeated 3 times and statistical analysis was performed using a 2-tailed Student t test. Exposure of bladder smooth muscle cells to a sustained hydrostatic pressure of 20 cm. H2O for 7 hours in serum-free DMEM resulted in a time dependent decrease in MMP-1, 2 and 9 activity (15%, 37% and 25%) compared to controls maintained at atmospheric pressure (p <0.01). TIMP-1 levels increased an average of 10% after exposure to 20 cm. H2O. These changes became statistically significant when the cells were exposed to 40 cm. H2O pressure for 3, 7 and 24 hours (+14%, +21% and +50%, respectively). No statistically significant differences in MMP-3 and collagen type I or III mRNA levels were observed. Our results reveal that MMP-1, 2 and 9 are significantly down-regulated in a time and pressure dependent fashion following exposure of bladder smooth muscle cells to 20 cm. H2O for as little as 7 hours. TIMP-1 levels increased under similar conditions. These alterations in MMPs and TIMP-1 favor accumulation of extracellular matrix, structural components associated with bladder wall thickness and decreased compliance. These results are consistent with previous data from animal models of complete outlet obstruction. Our results support the concept that pressures 40 cm. H2O or less contribute to molecular changes consistent with decreased compliance associated with bladder dysfunction.