The Beneficial Effect of Renin-Angiotensin-Aldosterone System Blockade in Marfan Syndrome Patients after Aortic Root Replacement.
In this study, we evaluated the long term beneficial effect of Renin-Angiotensin-Aldosterone System (RAAS) blockade therapy in treatment of Marfan aortopathy. We reviewed Marfan syndrome (MFS) patients who underwent aortic root replacement (ARR) between January 1996 and January 2011. All patients were prescribed β-blockers indefinitely. We compared major aortic events including mortality, aortic dissection, and reoperation in patients without RAAS blockade (group 1, n=27) to those with (group 2, n=63). The aortic growth rate was calculated by dividing the diameter change on CT scans taken immediately post-operatively and the latest scan available. There were no differences in clinical parameters except for age which was higher in patients with RAAS blockade. In group 1, 2 (7%) deaths, 5 (19%) aortic dissections, and 7 (26%) reoperations occurred. In group 2, 3 (5%) deaths, 2 (3%) aortic dissections, and 3 (5%) reoperations occurred. A Kaplan-Meier plot demonstrated improved survival free from major aortic events in group 2. On multivariate Cox, RAAS blockade was an independent negative predictor of major aortic events (hazard ratio 0.38, 95% confidence interval 0.30-0.43, p=0.002). Mean diameter change in descending thoracic and supra-renal abdominal aorta was significantly higher in patients without RAAS blockade (p<0.05). In MFS patients who underwent ARR, the addition of RAAS blockade to β-blocker was associated with reduction of aortic dilatation and clinical events.


Effects of acute exposures to mecoprop, mecoprop-p and their biodegradation product (2-MCP) on the larval stages of the Pacific oyster, Crassostrea gigas.
Studies have shown that pesticides are sometimes detected at rather high levels in seawater and it has been suggested that these chemical compounds could act as additional stress factor for oysters cultured in coastal environments. The effects of pesticides on marine molluscs could be particularly harmful in the early stages which correspond to critical life stages. This study aimed to assess the effects of mecoprop, mecoprop-p and their degradation compound 2-methyl-4-chlorophenol on two larval stages of Crassostrea gigas. Embryotoxic effects were assessed on veliger larvae after 36 h exposures, and both percentages of normal larvae and types of abnormalities were taken into account. The effects of the three substances were evaluated on 21-day-old pediveliger larvae by calculating metamorphosis rates after 24h exposures. The results of the embryotoxicity assay indicated that 2-methyl-4-chlorophenol was more toxic (EC50: 10.81 mg L(-1)) than its parent compounds (EC50 mecoprop: 42.55 mg L(-1); EC50 mecoprop-p: 78.85 mg L(-1)). Mecoprop in particular injured shell formation with an increase of shell abnormalities following herbicide concentrations. The active substances were not toxic to metamorphosis processes, but 2-MCP was revealed to be more toxic to the success of metamorphosis (EC50: 7.20 mg L(-1)) than to embryo-larval development. However, the toxic concentrations were several orders of magnitude higher than environmental concentrations.


Genetic diversity and epidemiology of infectious hematopoietic necrosis virus in Alaska.
Forty-two infectious hematopoietic necrosis virus (IHNV) isolates from Alaska were analyzed using the ribonuclease protection assay (RPA) and nucleotide sequencing. RPA analyses, utilizing 4 probes, N5, N3 (N gene), GF (G gene), and NV (NV gene), determined that the haplotypes of all 3 genes demonstrated a consistent spatial pattern. Virus isolates belonging to the most common haplotype groups were distributed throughout Alaska, whereas isolates in small haplotype groups were obtained from only 1 site (hatchery, lake, etc.). The temporal pattern of the GF haplotypes suggested a 'genetic acclimation' of the G gene, possibly due to positive selection on the glycoprotein. A pairwise comparison of the sequence data determined that the maximum nucleotide diversity of the isolates was 2.75% (10 mismatches) for the NV gene, and 1.99% (6 mismatches) for a 301 base pair region of the G gene, indicating that the genetic diversity of IHNV within Alaska is notably lower than in the more southern portions of the IHNV North American range. Phylogenetic analysis of representative Alaskan sequences and sequences of 12 previously characterized IHNV strains from Washington, Oregon, Idaho, California (USA) and British Columbia (Canada) distinguished the isolates into clusters that correlated with geographic origin and indicated that the Alaskan and British Columbia isolates may have a common viral ancestral lineage. Comparisons of multiple isolates from the same site provided epidemiological insights into viral transmission patterns and indicated that viral evolution, viral introduction, and genetic stasis were the mechanisms involved with IHN virus population dynamics in Alaska. The examples of genetic stasis and the overall low sequence heterogeneity of the Alaskan isolates suggested that they are evolutionarily constrained. This study establishes a baseline of genetic fingerprint patterns and sequence groups representing the genetic diversity of Alaskan IHNV isolates. This information could be used to determine the source of an IHN outbreak and to facilitate decisions in fisheries management of Alaskan salmonid stocks.


Longitudinal evidence of crystalline lens thinning in children.
Most earlier studies indicated that the eye's crystalline lens grows continually throughout life, but cross-sectional results of crystalline lens thinning during childhood have been reported. The authors investigated crystalline lens thickness in childhood using cross-sectional and longitudinal data. The Orinda Longitudinal Study of Myopia is a community-based study of normal eye growth and myopia development in school-age children. During a 1-to 3-year period, A-scan ultrasonographic lens thickness measurements of 869 children 6 through 14 years of age were analyzed. On average, between the ages of 6 and 10 years, the crystalline lens thins in its axial dimension by almost 0.2 mm. This thinning can be depicted by a cubic model. In this sample, the children with myopia had thinner crystalline lenses than the children with emmetropia of the same age. This article provides the first longitudinal evidence that the crystalline lens thins during the period of coordinated ocular growth between the ages of 6 and 10 years. Further, it shows that lens thickness is associated with refractive error. Thinner crystalline lenses in children with myopia may result from one of two underlying mechanisms: Either the crystalline lens exhausts its ability to compensate for axial elongation after undergoing accelerated lens thinning before the onset of myopia, or the crystalline lens in the myopic eye may be thinner throughout childhood, during which it thins at a rate consistent with other refractive errors. If mechanical forces link eye growth to crystalline lens compensation, more complex, visually guided feedback loops may not be needed to explain the normal eye growth that results in emmetropization.


Outcome effects of different protective hypothermia levels during cardiac arrest in rats.
Although hypothermia is widely used to protect the brain during cardiac and neurologic surgery, the optimal level of cooling has not been established. This study examined the protective effect of graded levels of surface cooling on cerebral function in rats after complete global cerebral ischemia. Groups of ketamine-anesthetized rats (13 animals in each group) were cooled to cranial temperatures of 34, 30, 27, 24, or 22 degrees C before circulatory arrest. Also a normothermic (37 degrees C) group was tested. After cooling, an 11-min circulatory arrest was produced by atraumatic chest compression. Circulatory arrest was followed by cardiopulmonary resuscitation and rewarming without postischemic intensive care. On the fifth postinsult day, neurologic outcome was scored on a 50-point neurodeficit scale (NDS 0 = normal). The percent of ischemic pyramidal neurons in the CA1 hippocampal region was also determined. There were no survivors in the normothermic group. Neurologic recovery was enhanced with 30 degrees C cranial temperature, as compared to outcome in the 34 degrees C group. Further cooling did not change outcome. The neurodeficit scales were significantly lower in all other groups compared to the 34 degrees C group on the fifth postinsult day. The percent of ischemic neurons did not change significantly as a function of cooling, but the lowest count appeared at 27 degrees C. In this model, moderate (30 degrees C) cooling improved neurologic outcome. There was no additional benefit from more extreme hypothermia.


Provider recommendations for colorectal cancer screening in elderly veterans.
Decisions regarding colorectal cancer (CRC) screening in the elderly depend on providers' assessment of likelihood of benefit partly based on patient comorbidity and past screening history. We aimed to describe providers' experiences and practice patterns regarding screening for CRC in elderly patients in the VA system. A survey was sent to VA primary care providers who had previously participated in the CanCORS-sponsored Share Thoughts on Care study and at a VA medical center. The surveys consisted of clinical vignettes that varied by patient age (75, 80, or 85 years), comorbidity, and past CRC screening history. Completed questionnaires were received from 183 of 351 providers (52%). Ninety-five percent of providers would recommend screening for a healthy 75 year old compared to 66% and 39% for a healthy 80 and 85 year old, respectively (p-values < 0.0001). Providers were more likely to recommend screening for a 75 year old with moderate CHF versus severe CHF [61% versus 15%, OR 9.0 (95% CI 5.8-14.0), p < 0.0001] and more likely to recommend screening for an 80 year old with prior colonoscopy within the preceding 10 years, versus 5 years [42% versus 23%, OR 2.6 (95% CI 1.9-3.5), p < 0.0001]. A substantial minority of respondents (range 15-21%) reported they would screen a 75 year old with an active malignancy, severe CHF, or severe COPD. Provider demographic characteristics were not significantly associated with the probability of a screening recommendation. VA providers incorporate patient age, comorbidity, and past CRC screening history into CRC screening recommendations for elderly veterans; however, substantial proportions of these recommendations are inappropriate.


The effects of inducing a follicular phase gonadotropin secretory pattern in normal women during the luteal phase.
It has been hypothesized that the slowing of the luteinizing hormone (LH) pulse frequency in the luteal phase may be necessary for the demise of the corpus luteum, the intercycle rise in baseline follicle-stimulating hormone (FSH), or ovarian follicular development in the subsequent cycle. For assessment of the physiologic role of the luteal phase LH pulse pattern, this pattern was converted to a follicular pattern in six normal women who used exogenous gonadotropin-releasing hormone administered with a portable pump (dose 50 to 100 ng/kg subcutaneously every 90 minutes beginning in the early luteal [n = 3] and midluteal [n = 3] cycle phases). There was no significant difference between the treated and the subsequent cycle for luteal progesterone production [186.3 versus 159.0 (ng/ml) day], preovulatory follicular size (23.1 versus 22.5 mm), estradiol levels, luteal phase length (15.6 versus 14.3 days), and daily gonadotropin concentrations including the intercycle FSH rise (160.5 versus 139.1 ng/ml). A follicular phase gonadotropin pulse pattern (increased frequency, decreased amplitude) in the luteal phase had no discernible effects on the corpus luteum or on follicular development in the subsequent cycle.


A qualitative exploration of Australian eyecare professional perspectives on Age-Related Macular Degeneration (AMD) care.
Despite the existence of evidence-based recommendations to decrease risk and progression of Age-Related Macular Degeneration (AMD) for some time, self-reported practices suggest that eyecare professionals' advice and people with AMD's adherence to these recommendations can be very poor. This study uses qualitative methods to explore Australian eyecare professionals' perspective on barriers to effective AMD care. Seven focus groups involving 65 optometrists were conducted by an experienced facilitator. A nominal group technique was used to identify, prioritize and semi-quantify barriers and enablers to AMD care. Participants individually ranked their perceived top five barriers and enablers with the most important granted a score of 5 and the least important a score of 1. For each barrier or enabler, the number of votes it received and its total score were recorded. Barriers and enablers selected by at least one participant in their top 5 were then qualitatively analysed, grouped using thematic analysis and total score calculated for each consolidated barrier or enabler. In-depth individual interviews were conducted with 10 ophthalmologists and 2 optometrists. Contributions were audio-recorded, transcribed verbatim and analysed with NVivo software. One hundred and sixty-nine barriers and 51 enablers to AMD care were identified in the focus groups. Of these, 102 barriers and 42 enablers were selected as one of their top 5 by at least one participant and further consolidated into 16 barriers and 10 enablers after thematic analysis. Factors impacting AMD care identified through analysis of the transcripts were coded to three categories of influence: patient-centered, practitioner-centered, and structural factors. Eyecare professionals considered poor care pathways, people with AMD's poor disease understanding / denial, and cost of care / lack of funding, as the most significant barriers to AMD care; they considered shared care model, access, and communication as the most significant enablers to good AMD care. These findings suggest that Australian eyecare professionals perceive that there is a need for improved patient support systems and appropriately funded, clearer care pathway to benefit people with AMD.


Comparison of silorane and methacrylate-based composite resins on the curing light transmission.
The aim of this study was to investigate the influence of different composite resins - Filtek P90 (silorane-based composite) and Heliomolar (methacrylate-based composite) - on light transmission and decrease in Knoop hardness between the bottom and top of cured specimens. The irradiance of a light-curing unit (LCU) was measured with a power meter (Ophir Optronics; 900 mw/cm2) and spectral distributions were obtained using a spectrometer (USB 2000). Twenty standardized cylindrical specimens (2 mm thick x 7 mm diameter) of each composite resin were obtained by curing using the LCU for 40 s. Light energy transmission through the composite was calculated (n=10). The Knoop hardness number for each surface was recorded as the mean of 3 indentations. The difference in Knoop hardness between the top and bottom (DKH) of the same specimen was calculated (n=10). The irradiance of light that passed through Filtek P90 (272 mW/cm2) was not significantly greater than that the passed through Heliomolar (271 mW/cm2). The DKH of Filtek P90 (25%) was significantly higher than that of Heliomolar (12%). There was a greater degree of subsurface polymerization of the methacrylate-based composite compared to the silorane-based composite.


Intrasexual competition and sexual selection in cooperative mammals.
In most animals, the sex that invests least in its offspring competes more intensely for access to the opposite sex and shows greater development of secondary sexual characters than the sex that invests most. However, in some mammals where females are the primary care-givers, females compete more frequently or intensely with each other than males. A possible explanation is that, in these species, the resources necessary for successful female reproduction are heavily concentrated and intrasexual competition for breeding opportunities is more intense among females than among males. Intrasexual competition between females is likely to be particularly intense in cooperative breeders where a single female monopolizes reproduction in each group. Here, we use data from a twelve-year study of wild meerkats (Suricata suricatta), where females show high levels of reproductive skew, to show that females gain greater benefits from acquiring dominant status than males and traits that increase competitive ability exert a stronger influence on their breeding success. Females that acquire dominant status also develop a suite of morphological, physiological and behavioural characteristics that help them to control other group members. Our results show that sex differences in parental investment are not the only mechanism capable of generating sex differences in reproductive competition and emphasize the extent to which competition for breeding opportunities between females can affect the evolution of sex differences and the operation of sexual selection.


Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic.
The clathrin assembly lymphoid myeloid leukemia (CALM) gene encodes a putative homologue of the clathrin assembly synaptic protein AP180. Hence the biochemical properties, the subcellular localization, and the role in endocytosis of a CALM protein were studied. In vitro binding and coimmunoprecipitation demonstrated that the clathrin heavy chain is the major binding partner of CALM. The bulk of cellular CALM was associated with the membrane fractions of the cell and localized to clathrin-coated areas of the plasma membrane. In the membrane fraction, CALM was present at near stoichiometric amounts relative to clathrin. To perform structure-function analysis of CALM, we engineered chimeric fusion proteins of CALM and its fragments with the green fluorescent protein (GFP). GFP-CALM was targeted to the plasma membrane-coated pits and also found colocalized with clathrin in the Golgi area. High levels of expression of GFP-CALM or its fragments with clathrin-binding activity inhibited the endocytosis of transferrin and epidermal growth factor receptors and altered the steady-state distribution of the mannose-6-phosphate receptor in the cell. In addition, GFP-CALM overexpression caused the loss of clathrin accumulation in the trans-Golgi network area, whereas the localization of the clathrin adaptor protein complex 1 in the trans-Golgi network remained unaffected. The ability of the GFP-tagged fragments of CALM to affect clathrin-mediated processes correlated with the targeting of the fragments to clathrin-coated areas and their clathrin-binding capacities. Clathrin-CALM interaction seems to be regulated by multiple contact interfaces. The C-terminal part of CALM binds clathrin heavy chain, although the full-length protein exhibited maximal ability for interaction. Altogether, the data suggest that CALM is an important component of coated pit internalization machinery, possibly involved in the regulation of clathrin recruitment to the membrane and/or the formation of the coated pit.


Orchestrating Directional Molecular Motions: Kinetically Controlled Supramolecular Pathways of a Helical Host on Rodlike Guests.
An aromatic oligoamide sequence was designed to fold and self-assemble into a double helical host having a cylindrical cavity complementary to linear oligocarbamate guests. Formation of helical pseudorotaxane complexes, foldaxanes, between the host and guests having binding stations of different affinities was evidenced by NMR and X-ray crystallography. Rodlike guests possessing two or three binding stations, long alkyl or oligoethylene glycol spacers or bulky barriers in-between the binding stations, and a single bulky stopper at one end were synthesized. Kinetic investigations of the threading and translation of the double helix along multistation rods were monitored by 1H NMR. Results show that multiple events may occur upon sliding of the host from the nonbulky end of the rod to reach the thermodynamically most stable state before unfolding-mediated dissociation has time to take place, including binding on intermediate stations and rapid sliding along nonbinding spacers. Conversely, installing a kinetic barrier that blocks sliding allows for the deliberate integration of a helix dissociation reassociation step in the supramolecular trajectory. Typical sliding processes can be monitored over the course of hours whereas steps involving unwinding-rewinding of the helix proceeded over the course of days. These results further demonstrate the interest in foldaxanes to design complex sequences of supramolecular events within networks of equilibria through the adjustment of the kinetics of the individual steps involved.


A case of herpetiform pemphigus with anti-desmoglein 3 IgG autoantibodies.
Herpetiform pemphigus (HP) is a rare variant of pemphigus characterized by a unique clinical phenotype of erythematous or urticarial plaques and vesicles that present in a herpetiform arrangement. Most HP cases have circulating anti-desmoglein 1 (Dsg1) IgG autoantibodies, but some HP cases have anti-desmoglein 3 (Dsg3) IgG. A 92-year-old Japanese woman presented with severely pruritic annular erythema and vesicles in a herpetiform arrangement on the trunk. No oral mucosal lesions were present. Histopathologically, these vesicles showed eosinophilic spongiosis as well as suprabasilar acantholysis. Direct immunofluorescence showed in vivo IgG deposition on keratinocyte cell surfaces, and indirect immunofluorescence showed circulating IgG autoantibodies against keratinocyte cell surfaces at a titer of 1:30. Enzyme-linked immunosorbent assay using recombinant Dsg1 and Dsg3 revealed the presence of anti-Dsg3 IgG but no anti-Dsg1 IgG autoantibodies. The lack of oral mucosal involvement and the unique clinical features favored the diagnosis of HP. It remains to be clarified why the anti-Dsg3 IgG autoantibodies in this patient induced this unique features of HP, rather than the mucosal dominant type of pemphigus vulgaris.


Use of growth factors to improve muscle healing after strain injury.
Muscle injuries represent a large number of professional and recreational sports injuries. Muscle strains habitually occur after an eccentric contraction, which often leads to an injury located in the myotendinous junction. Treatment varies widely, depending on the severity of the trauma, but has remained limited mostly to rest, ice, compression, elevation, antiinflammatory drugs, and mobilization. The authors' research group aims to develop new biologic approaches to improve muscle healing after injuries, including muscle strains. To achieve this goal, the authors investigated several parameters that will lead to the development of new strategies to enhance muscle healing. The authors first evaluated natural muscle healing after strain injuries and showed that muscle regeneration occurs in the early phase of healing but becomes impaired with time by the development of tissue fibrosis. Several growth factors capable of improving muscle regeneration were investigated; basic fibroblast growth factor, insulin-like growth factor, and nerve growth factors were identified as substances capable of enhancing muscle regeneration and improving muscle force in the strained injured muscle. The current study should aid in the development of strategies to promote efficient muscle healing and complete recovery after strain injury.


Flightlessness and phylogeny amongst endemic rails (Aves:Rallidae) of the New Zealand region.
The phylogenetic relationships of a number of flightless and volant rails have been investigated using mtDNA sequence data. The third domain of the small ribosomal subunit (12S) has been sequenced for 22 taxa, and part of the 5' end of the cytochrome-b gene has been sequenced for 12 taxa. Additional sequences were obtained from outgroup taxa, two species of jacana, sarus crane, spur-winged plover and kagu. Extinct rails were investigated using DNA extracted from subfossil bones, and in cases where fresh material could not be obtained from other extant taxa, feathers and museum skins were used as sources of DNA. Phylogenetic trees produced from these data have topologies that are, in general, consistent with data from DNA-DNA hybridization studies and recent interpretations based on morphology. Gallinula chloropus moorhen) groups basally with Fulica (coots), Amaurornis (= Megacrex) ineptus falls within the Gallirallus/Rallus group, and Gallinula (= Porphyrula) martinica is basal to Porphyrio (swamphens) and should probably be placed in that genus. Subspecies of Porphyrio porphyrio are paraphyletic with respect to Porphyrio mantelli (takahe). The Northern Hemisphere Rallus aquaticus is basal to the south-western Pacific Rallus (or Gallirallus) group. The flightless Rallus philippensis dieffenbachii is close to Rallus modestus and distinct from the volant Rallus philippensis, and is evidently a separate species. Porzana (crakes) appears to be more closely associated with Porphyrio than Rallus. Deep relationships among the rails remain poorly resolved. Rhynochetus jubatus (kagu) is closer to the cranes than the rails in this analysis. Genetic distances between flightless rails and their volant counterparts varied considerably with observed 12S sequence distances, ranging from 0.3% (Porphyrio porphyrio melanotus and P. mantelli mantelli) to 7.6% (Rallus modestus and Rallus philippensis). This may be taken as an indication of the rapidity with which flightlessness can evolve, and of the persistence of flightless taxa. Genetic data supported the notion that flightless taxa were independently derived, sometimes from similar colonizing ancestors. The morphology of flightless rails is apparently frequently dominated by evolutionary parallelism although similarity of external appearance is not an indication of the extent of genetic divergence. In some cases taxa that are genetically close are morphologically distinct from one another (e.g. Rallus (philippensis) dieffenbachii and R. modestus), whilst some morphologically similar taxa are evidently independently derived (e.g. Porphyio mantelli hochstetteri and P.m. mantelli).


The role of interagency collaboration for substance-abusing families involved with child welfare.
Meeting the needs of families involved with the child welfare system because of a substance abuse issue remains a challenge for child welfare practitioners. In order to improve services to these families, there has been an increasing focus on improving collaboration between child welfare, treatment providers, and the court systems. This paper presents the results from qualitative interviews with 104 representatives of these three systems that explore how the collaborative process works to benefit families, as well as the barriers and supports for building successful collaborations. Results indicate that collaboration has at least three major functions: building shared value systems, improving communication, and providing a "team" of support. Each of these leads to different kinds of benefits for families as well as providers and has different implications for building successful collaborative interventions. Despite these putative benefits, providers within each system, however, continue to struggle to build effective collaborations, and they face such issues as deeply ingrained mistrust and continued lack of understanding of other systems' values, goals, and perspectives. Challenges that remain for successful collaborations are discussed.


Acute Respiratory Distress Syndrome: Challenge for Diagnosis and Therapy.
Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome whose diagnosis and therapy are still in question. The aim of this review was to discuss the current challenge for the diagnosis and treatment of ARDS. Data sources were the published articles in English through December 2017 in PubMed using the following key words: "acute respiratory distress syndrome," "definition", "diagnosis," "therapy," "lung protective strategy," "right ventricular dysfunction," and "molecular mechanism." The selection of studies focused on both preclinical studies and clinical studies of therapy of ARDS. The incidence of ARDS is still high, and ARDS causes high intensive care units admissions and high mortality. The Berlin Definition proposed in 2012 is still controversial owing to lack of sensitivity and specificity. ARDS is still under recognition and it is associated with high mortality. Lung protective strategies with low tidal volume (VT) and lung recruitment should consider the physiology of ARDS because ARDS presents lung inhomogeneity; the same low VT might increase local stress and strain in some patients with low compliance, and lung recruitment could injure lungs in ARDS patients with low recruitability and hemodynamic instability. Acute cor pulmonale is common in severe ARDS. ARDS itself and some treatments could worsen acute cor pulmonale. Molecular understanding of the pathogenic contributors to ARDS has improved, but the molecular-associated treatments are still under development. ARDS is a devastating clinical syndrome whose incidence and mortality has remained high over the past 50 years. Its definition and treatments are still confronted with challenges, and early recognition and intervention are crucial for improving the outcomes of ARDS. More clinical studies are needed to improve early diagnosis and appropriate therapy.


A Behavior Change Intervention Aimed at Increasing Physical Activity Improves Clinical Control in Adults With Asthma: A Randomized Controlled Trial.
Higher levels of physical activity have been associated with better asthma clinical control. Does a behavior change intervention aimed at increasing physical activity change asthma clinical control, physical activity, sedentary time, health-related quality of life (HRQoL), and anxiety and depression symptoms? This single-blind, randomized controlled trial included participants who were allocated to an intervention group (IG) or to a control group (CG). Both groups received usual care and disease-specific education. Participants in the IG also underwent an 8-week behavior change intervention aimed at increasing physical activity. Prior to and following the intervention period, measures were made of asthma clinical control (Asthma Control Questionnaire [ACQ]), physical activity, sedentary time and sleep quality (ActiGraph), HRQoL (Asthma Quality of Life Questionnaire), and anxiety and depression symptoms (Hospital Anxiety and Depression Scale). Data on asthma exacerbations were recorded 12 months prior to and throughout the intervention period. Fifty-one participants were included (CG, n = 26; IG, n = 25). On completion of the intervention period, compared with the CG, those in the IG exhibited improvements in asthma control (mean difference [95% CI] in ACQ score, -0.8 [-1.1 to -0.4]); in daily step count, 3,605 [1,937 to 8,867] steps/d; in sleep efficiency, 9.2% [-7.1% to 21.9%]; and a reduction in sedentary time, -1.1 [-2.9 to -0.6] h/d). No between-group difference in HRQoL was observed. The percentage of participants who experienced exacerbations during the intervention period was 27% in the IG vs 60% in the CG (P = .04). The change in time spent in moderate-intensity physical activity was inversely associated with change in ACQ (r = -0.60). Compared with the CG, a higher percentage of participants in the IG reported a reduction in anxiety symptoms (43% vs 0%; P < .02). In adults with moderate to severe asthma, a comprehensive behavior change intervention that increased physical activity also produced improvements in asthma clinical control, sedentary time, sleep quality, and anxiety symptoms. ClinicalTrials.gov; No.: NCT03705702; URL: www.clinicaltrials.gov.


Evolution of invasion in a diverse set of Fusobacterium species.
The diverse Fusobacterium genus contains species implicated in multiple clinical pathologies, including periodontal disease, preterm birth, and colorectal cancer. The lack of genetic tools for manipulating these organisms leaves us with little understanding of the genes responsible for adherence to and invasion of host cells. Actively invading Fusobacterium species can enter host cells independently, whereas passively invading species need additional factors, such as compromise of mucosal integrity or coinfection with other microbes. We applied whole-genome sequencing and comparative analysis to study the evolution of active and passive invasion strategies and to infer factors associated with active forms of host cell invasion. The evolution of active invasion appears to have followed an adaptive radiation in which two of the three fusobacterial lineages acquired new genes and underwent expansions of ancestral genes that enable active forms of host cell invasion. Compared to passive invaders, active invaders have much larger genomes, encode FadA-related adhesins, and possess twice as many genes encoding membrane-related proteins, including a large expansion of surface-associated proteins containing the MORN2 domain of unknown function. We predict a role for proteins containing MORN2 domains in adhesion and active invasion. In the largest and most comprehensive comparison of sequenced Fusobacterium species to date, we have generated a testable model for the molecular pathogenesis of Fusobacterium infection and illuminate new therapeutic or diagnostic strategies. Fusobacterium species have recently been implicated in a broad spectrum of human pathologies, including Crohn's disease, ulcerative colitis, preterm birth, and colorectal cancer. Largely due to the genetic intractability of member species, the mechanisms by which Fusobacterium causes these pathologies are not well understood, although adherence to and active invasion of host cells appear important. We examined whole-genome sequence data from a diverse set of Fusobacterium species to identify genetic determinants of active forms of host cell invasion. Our analyses revealed that actively invading Fusobacterium species have larger genomes than passively invading species and possess a specific complement of genes-including a class of genes of unknown function that we predict evolved to enable host cell adherence and invasion. This study provides an important framework for future studies on the role of Fusobacterium in pathologies such as colorectal cancer.


Characterization of mutant xylanases using fourier transform ion cyclotron resonance mass spectrometry: stabilizing contributions of disulfide bridges and N-terminal extensions.
Structural properties and thermal stability of Trichoderma reesei endo-1,4-beta-xylanase II (TRX II) and its three recombinant mutants were characterized using electrospray ionization Fourier transform ion cyclotron resonance (ESI FT-ICR) mass spectrometry and hydrogen/deuterium (H/D) exchange reactions. TRX II has been previously stabilized by a disulfide bridge C110-C154 and other site-directed mutations (TRX II mutants DS2 and DS5). Very recently, a highly thermostable mutant was introduced by combining mutations of DS5 with an N-terminal disulfide bridge C2-C28 (mutant DB1). Accurate mass measurements of TRX II, DS2, DS5, and DB1 verified the expected DNA-encoded protein sequences (average mass error 1.3 ppm) and allowed unequivocal assignment of the disulfides without chemical reduction and subsequent alkylation of the expected cross-links. Moreover, H/D exchange reactions provided means for the detection of a major heat-induced conformational change comprising two interconverting conformers of very different H/D exchange rates as well as allowed the apparent melting temperatures (T(m)) to be determined (62.6, 65.1, 68.0, and 82.2 degrees C for TRX II, DS2, DS5, and DB1, respectively). Residual activity measurements verified that the enzymes inactivated at significantly lower temperatures than expected on the basis of the apparent T(m) values, strongly suggesting that the inactivation takes place through minor conformational change other than observed by H/D exchange. ESI FT-ICR analyses also revealed molecular heterogeneity in DS5 and DB1 due to the propeptide incorporation. Resulting unintentional N-terminal extensions were observed to further improve the stability of the DB1 mutant. The extension of six amino acid residues upstream from the protein N-terminus increased stability by approximately 5 degrees C.


Development of β-lactoglobulin-specific chimeric human IgEκ monoclonal antibodies for in vitro safety assessment of whey hydrolysates.
Cow's milk-derived whey hydrolysates are nutritional substitutes for allergic infants. Safety or residual allergenicity assessment of these whey hydrolysates is crucial. Currently, rat basophilic leukemia RBL-2H3 cells expressing the human IgE receptor α-chain (huFcεRIα-RBL-2H3), sensitized with serum IgE from cow's milk allergic children, are being employed to assess in vitro residual allergenicity of these whey hydrolysates. However, limited availability and inter-lot variation of these allergic sera impede standardization of whey hydrolysate safety testing in degranulation assays. An oligoclonal pool of chimeric human (chu)IgE antibodies against bovine β-lactoglobulin (a major allergen in whey) was generated to increase sensitivity, specificity, and reproducibility of existing degranulation assays. Mice were immunized with bovine β-lactoglobulin, and subsequently the variable domains of dissimilar anti-β-lactoglobulin mouse IgG antibodies were cloned and sequenced. Six chimeric antibodies were generated comprising mouse variable domains and human constant IgE/κ domains. After sensitization with this pool of anti-β-lactoglobulin chuIgEs, huFcεRIα-expressing RBL-2H3 cells demonstrated degranulation upon cross-linking with whey, native 18 kDa β-lactoglobulin, and 5-10 kDa whey hydrolysates, whereas a 3 kDa whey hydrolysate and cow's milk powder (mainly casein) showed no degranulation. In parallel, allergic serum IgEs were less sensitive. In addition, our pool anti-β-lactoglobulin chuIgEs recognized multiple allergenic immunodominant regions on β-lactoglobulin, which were also recognized by serum IgEs from cow's milk allergic children. Usage of our 'unlimited' source and well-defined pool of β-lactoglobulin-specific recombinant chuIgEs to sensitize huFcεRIα on RBL-2H3 cells showed to be a relevant and sensitive alternative for serum IgEs from cow's milk allergic patients to assess safety of whey-based non-allergic hydrolyzed formula.


Full gait cycle analysis of lower limb and trunk kinematics and muscle activations during walking in participants with and without ankle instability.
Chronic ankle instability (CAI) has previously been linked to altered lower limb kinematics and muscle activation characteristics during walking, though little research has been performed analysing the full time-series across the stance and swing phases of gait. The aim of this study was to compare trunk and lower limb kinematics and muscle activity between those with chronic ankle instability and healthy controls. Kinematics and muscle activity were measured in 18 (14 males, 4 females) healthy controls (age 22.4 ± 3.6 years, height 177.8 ± 7.6 cm, mass 70.4 ± 11.9 kg, UK shoe size 8.4 ± 1.6), and 18 (13 males, 5 females) participants with chronic ankle instability (age 22.0 ± 2.7 years, height 176.8 ± 7.9 cm, mass 74.1 ± 9.6 kg, UK shoe size 8.1 ± 1.9) during barefoot walking trials, using a combined Helen Hayes and Oxford foot model. Surface electromyography (sEMG) was recorded for the tibialis anterior and gluteus medius. Full curve statistical parametric mapping was performed using independent and paired-samples T-tests. No significant differences were observed in kinematic or sEMG variables between or within groups for the duration of the swing phase of gait. A significantly increased forefoot-tibia inversion was seen in the CAI affected limb when compared to the CAI unaffected limb at 4-16% stance (p = 0.039). No other significant differences were observed. There appears to be no differences in muscle activation and movement between CAI and healthy control groups. However, participants with CAI exhibited increased inversion patterns during the stance phase of gait in their affected limb compared to their unaffected limb. This may predispose those with CAI to episodes of giving way and further ankle sprains.


Design of Linear and Star-Shaped Macromolecular Organic Semiconductors for Photonic Applications.
One of the most desirable and advantageous attributes of organic materials chemistry is the ability to tune the molecular structure to achieve targeted physical properties. This can be performed to achieve specific values for the ionization potential or electron affinity of the material, the absorption and emission characteristics, charge transport properties, phase behavior, solubility, processability, and many other properties, which in turn can help push the limits of performance in organic semiconductor devices. A striking example is the ability to make subtle structural changes to a conjugated macromolecule to vary the absorption and emission properties of a generic chemical structure. In this Account, we demonstrate that target properties for specific photonic applications can be achieved from different types of semiconductor structures, namely, monodisperse star-shaped molecules, complex linear macromolecules, and conjugated polymers. The most appropriate material for any single application inevitably demands consideration of a trade-off of various properties; in this Account, we focus on applications such as organic lasers, electrogenerated chemiluminescence, hybrid light emitting diodes, and visible light communications. In terms of synthesis, atom and step economies are also important. The star-shaped structures consist of a core unit with 3 or 4 functional connection points, to which can be attached conjugated oligomers of varying length and composition. This strategy follows a convergent synthetic pathway and allows the isolation of target macromolecules in good yield, high purity, and absolute reproducibility. It is a versatile approach, providing a wide choice of constituent molecular units and therefore varying properties, while the products share many of the desirable attributes of polymers. Constructing linear conjugated macromolecules with multifunctionality can lead to complex synthetic routes and lower atom and step economies, inferior processability, and lower thermal or chemical stability, but these materials can be designed to provide a range of different targeted physical properties. Conventional conjugated polymers, as the third type of structure, often feature so-called "champion" properties. The synthetic challenge is mainly concerned with monomer synthesis, but the final polymerization sequence can be hard to control, leading to variable molecular weights and polydispersities and some degree of inconsistency in the properties of the same material between different synthetic batches. If a champion characteristic persists between samples, then the variation of other properties between batches can be tolerable, depending on the target application. In the case of polymers, we have chosen to study PPV-type polymers with bulky side groups that provide protection of their conjugated backbone from π-π stacking interactions. These polymers exhibit high photoluminescence quantum yields (PLQYs) in films and short radiative lifetimes and are an important benchmark to monodisperse star-shaped systems in terms of different absorption/emission regions. This Account therefore outlines the advantages and special features of monodisperse star-shaped macromolecules for photonic applications but also considers the two alternative classes of materials and highlights the pros and cons of each class of conjugated structure.


Serotonin controlling feeding and satiety.
Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' satiation and satiety. Currently, 5-HT1B, 5-HT2C and 5-HT6 receptors have been identified to mediate serotonergic satiety in different ways. The recently approved anti-obesity drug lorcaserin is a 5-HT2C receptor agonist. In brain, both hypothalamic (arcuate nucleus, paraventricular nucleus) and extrahypothalamic sites (parabrachial nucleus, nucleus of the solitary tract) have been identified to mediate the serotonergic control of satiety. Serotonin interacts within the hypothalamus with endogenous orexigenic (Neuropeptide Y/Agouti related protein) and anorectic (α-melanocyte stimulating hormone) peptides. In the nucleus of the solitary tract serotonin integrates peripheral satiety signals. Here, the 5-HT3, but possibly also the 5-HT2C receptor play a role. It has been found that 5-HT acts in concert with such peripheral signals as cholecystokinin and leptin. Despite the recent advances of our knowledge, many of the complex interactions between 5-HT and other satiety factors are not fully understood yet. Further progress in research will also advance the development of new serotonergic anti-obesity drugs.


Morphological studies of bronchial mucosal biopsies from asthmatics before and after ten years of treatment with inhaled steroids.
To examine the influence of inhaled steroids on the bronchial mucosa, biopsies from six patients with severe bronchial asthma were studied before and after ten years of daily treatment with inhaled steroids. Biopsies from six healthy subjects were also examined. In the biopsies taken from the asthmatic patients before treatment there was a significant increase in inflammatory cell numbers compared with the biopsies from the control subjects. In all patients scanning electron microscopy showed a reduced coverage by cilia. Squamous cell metaplasia was seen in two patients. After ten years of treatment the number of inflammatory cells was significantly reduced compared to that before treatment and was not different from the control biopsies. Most of the epithelial cells showed a ciliated surface. Small focal areas with non-ciliated cells could still be seen in four patients. In the two patients with squamous cell metaplasia before treatment, small areas of metaplasia could still be seen. Despite the absence of inflammation and reduced epithelial damage during treatment all patients still had bronchial hyperresponsiveness.


Severe pulmonary hypertension associated with COPD: hemodynamic improvement with specific therapy.
There is no recommendation for treating pulmonary hypertension (PH) when associated with chronic obstructive pulmonary disease (COPD). To evaluate the effect of PH-specific therapy in patients with COPD. All successive patients with severe PH [mean pulmonary arterial pressure (mPAP) ≥35 mm Hg] and COPD, who received specific PH medication and who underwent right heart catheterization at baseline and after 3-12 months of treatment, were analyzed from a prospective database. Twenty-six patients were included with a median follow-up of 14 months. Mean forced expiratory volume in 1 s was 57 ± 20% of predicted, and mean forced expiratory volume in 1 s/forced vital capacity was 47 ± 12%. Dyspnea was New York Health Association classification stage (NYHA) II in 15%, NYHA III in 81% and NYHA IV in 4%. First-line treatments were endothelin receptor antagonists in 11 patients, phosphodiesterase-5 inhibitors in 11 patients, calcium blocker in 1 patient, combination therapy in 3 patients including 2 with a prostanoid. After 6 ± 3 months, pulmonary vascular resistance decreased from 8.5 ± 3 to 6.6 ± 2 Wood units (p < 0.001), with significant improvement of cardiac index from 2.44 ± 0.43 to 2.68 ± 0.63 liters × min × m-2 (p = 0.015) and mPAP from 48 ± 9 to 42 ± 10 mm Hg (p = 0.008). There was no significant difference in dyspnea, 6-min walking distance, echocardiographic parameters or N-terminal pro-brain natriuretic peptide levels. There was no significant difference in arterial oxygen saturation after 3-12 months of treatment. Specific PH medications may improve hemodynamic parameters in COPD patients with severe PH. Appropriate prospective randomized studies are needed to evaluate the potential long-term clinical benefit of treatment.


Risk factors for gastric cancer in Latin America: a meta-analysis.
Latin America has among the highest gastric cancer incidence rates in the world, for reasons that are still unknown. In order to identify region-specific risk factors for gastric cancer, we conducted a meta-analysis summarizing published literature. Searches of PubMed and regional databases for relevant studies published up to December 2011 yielded a total of 29 independent case-control studies. We calculated summary odds ratios (OR) for risk factors reported in at least five studies, including socioeconomic status (education), lifestyle habits (smoking and alcohol use), dietary factors (consumption of fruits, total vegetables, green vegetables, chili pepper, total meat, processed meat, red meat, fish, and salt), and host genetic variants (IL1B-511T, IL1B-31C, IL1RN*2, TNFA-308A, TP53 codon 72 Arg, and GSTM1 null). Study-specific ORs were extracted and summarized using random-effects models. Chili pepper was the only region-specific factor reported in at least five studies. Consistent with multifactorial pathogenesis, smoking, alcohol use, high consumption of red meat or processed meat, excessive salt intake, and carriage of IL1RN*2 were each associated with a moderate increase in gastric cancer risk. Conversely, higher levels of education, fruit consumption, and total vegetable consumption were each associated with a moderately decreased risk. The other exposures were not significantly associated. No prospective study data were identified. Risk factor associations for gastric cancer in Latin America are based on case-control comparisons that have uncertain reliability, particularly with regard to diet; the specific factors identified and their magnitudes of association are largely similar to those globally recognized. Future studies should emphasize prospective data collection and focus on region-specific exposures that may explain high gastric cancer risk.


The Prevalence and Incidence of Attention-deficit/Hyperactivity Disorder in the Veterans Health Administration From 2009 to 2016.
The prevalence and incidence of attention-deficit/hyperactivity disorder (ADHD) have increased substantially among children and adolescents over the past decade; however, little is known regarding trends in adult populations. The objective of this study was to explore trends in the prevalence, incidence, and correlates of adult ADHD in a national sample of veterans receiving care at Veteran Affairs (VA) hospitals and clinics. A retrospective design was used to examine ADHD diagnosed in all VA primary care (PC) and mental health clinics (MHCs) from fiscal years (FYs) 2009 to 2016. Age-adjusted prevalence and incidence were calculated using direct standardization, and Poisson regressions modeled differences in trends between demographic groups. All veterans with VA PC or MHC visits during the observation period. ADHD incidence and prevalence, psychiatric comorbidity, neuropsychological evaluation. An annual average of 5.09 million (range: 4.63-5.42 million) VA patients attended a PC or MHC appointment between FY09 and FY16. During this period, age-adjusted annual prevalence increased 258% from 0.23% to 0.84% and incidence increased 240% from 0.14% to 0.48%. Black veterans and older veterans had the lowest prevalence and incidence across all years. Increases in prevalence and incidence occurred across all demographic subgroups. The proportion of patients who had a neuropsychological evaluation within 6 months before or after a new ADHD diagnosis decreased from 12.6% to 10.8% [χ(1)=16.59, P<0.001]. Overall increases and demographic differences in adult veterans diagnosed with ADHD suggest a growing need to establish the reliability of diagnostic practices to ensure appropriate and equitable care.


Critical evaluation of the surgical techniques to correct the equinus deformity.
The equinus deformity causes changes in the foot contact and may affect more proximal anatomical regions, such as the knee, hip and trunk, potentially leading to gait disorders. The equinus is usually secondary to retraction, shortening and/or spasticity of the triceps surae, and it may require surgical correction. Surgery for the correction of equinus is one of the oldest procedures in Orthopedics, and it was initially performed only at the calcaneus tendon. The technique has evolved, so that it could be customized for each patient, depending on the degree of deformity, the underlying disease, and patient´s profile. The aim is to correct the deformity, with minimal interference in muscle strength, thus reducing the incidence of disabling complications such as crouch gait and calcaneus foot. We conducted a literature search for the most common surgical techniques to correct the equinus deformity using classic books and original articles. Further, we performed a database search for articles published in the last ten years. From the anatomical perspective, the triceps surae presents five anatomical regions that can be approached surgically for the equinus correction. Due to the complexity of the equinus, orthopedic surgeons should be experienced with at least one procedure at each region. In this text, we critically approach and analyze the most important techniques for correction of the equinus, mainly to avoid complications.


Viscosity of ring polymer melts.
We have measured the linear rheology of critically purified ring polyisoprenes, polystyrenes and polyethyleneoxides of different molar masses. The ratio of the zero-shear viscosities of linear polymer melts η0,linear to their ring counterparts η0,ring at isofrictional conditions is discussed as function of the number of entanglements Z. In the unentangled regime η0,linear/η0,ring is virtually constant, consistent with the earlier data, atomistic simulations, and the theoretical expectation η0,linear/η0,ring=2. In the entanglement regime, the Z-dependence of rings viscosity is much weaker than that of linear polymers, in qualitative agreement with predictions from scaling theory and simulations. The power-law extracted from the available experimental data in the rather limited range 1<Z<20, η0,linear/η0,ring ~ Z1.2±0.3, is weaker than the scaling prediction (η0,linear/η0,ring ~ Z1.6±0.3 ) and the simulations (η0,linear/η0,ring ~ Z2.0±0.3 ). Nevertheless, the present collection of state-of-the- art experimental data unambiguously demonstrates that rings exhibit a universal trend clearly departing from that of their linear counterparts, and hence it represents a major step toward resolving a 30-year old problem.


The teaching of health care ethics to students of nursing in the UK: a pilot study.
Senior lecturers/lecturers in mental health nursing (11 in round one, nine in round two, and eight in the final round) participated in a three-round Delphi study into the teaching of health care ethics (HCE) to students of nursing. The participants were drawn from six (round one) and four (round three) UK universities. Information was gathered on the organization, methods used and content of HCE modules. Questionnaire responses were transcribed and the content analysed for patterns of interest and areas of convergence or divergence. Findings include: the majority (72.8%) of the sample believed that insufficient time was allocated to the teaching of HCE; case studies were considered a popular, although problematic, teaching method; the 'four principles' approach was less than dominant in the teaching of HCE; and virtue ethics was taught by only 36.4% of the participants. The Delphi technique proved adequate and worth while for the purposes of this study. Further empirical research could aim to replicate or contradict these findings, using a larger sample and recruiting more university departments. Reflection is required on several issues, including the depth and breadth to which ethics theory and, more controversially, meta-ethics, are taught to nursing students.


Assessment of a sequential phase extraction procedure for uranium-series isotope analysis of soils and sediments.
The study of uranium-series (U-series) isotopes in soil and sediment materials has been proposed to quantify rates and timescales of soil production and sediment transport. Previous works have studied bulk soil or sediment material, which is a complex assemblage of primary and secondary minerals and organic compounds. However, the approach relies on the fractionation between U-series isotopes in primary minerals since they were liberated from the parent rock via weathering. In addition, secondary minerals and organic compounds have their own isotopic compositions such that the composition of the bulk material may not reflect that of primary minerals. Hence, there is a need for a sample preparation procedure that allows the isolation of primary minerals in soil or fluvial sediment samples. In this study, a sequential extraction procedure to separate primary minerals from soils and sediments was assessed. The procedure was applied to standard rock sample powders (TML-3 and BCR-2) to test whether it introduced any artefactual radioactive disequilibrium. A new step was introduced to remove the clay-sized fraction (<2 µm). Significant amounts (5-14%) of U and Th were removed from the rock standards during the procedure. No significant alteration in ((234)U/(238)U) and ((230)Th/(238)U) activity ratios of the rock standards occurred during the procedure. Aliquots of soil sample were subjected to the sequential extraction process to test how each step modifies the uranium-series activity ratios and mineralogy. Although no secondary minerals were detected in the unleached soil aliquots, the sequential leaching process removed up to 17% of U and Th and modified their activity ratios by up to 3%. The modification of the activity ratios poses a demand for careful means to avoid redistribution of isotopes back to the residual phase during phase extraction.


Cumulative in-trial and post-trial effects of blood pressure and lipid lowering: systematic review and meta-analysis.
Persistent long-term benefits after discontinuation of treatment have been suggested for blood pressure-lowering and lipid-lowering treatment. We conducted a systematic review to assess the long-term effects of blood pressure (BP) lowering (BPL) and lipid lowering on all-cause and cardiovascular mortality after discontinuation of randomized treatment. We systematically searched Medline, Embase, and the Cochrane Central Register of Controlled Trials. We included large-scale randomized controlled trials of BPL or lipid lowering of at least 1 year with post-trial follow-up. We identified 13 BPL trials with 48 892 participants and 10 lipid-lowering trials with 71 370 participants. Mean in-trial and post-trial follow-up was approximately 4 and 6 years, respectively. BP and lipid levels tended to come together soon in the post-trial period. There was significant benefit of BPL on all-cause mortality during the in-trial period (relative risk 0.85, 95% confidence interval 0.81-0.89), and significant, but attenuated, benefit during overall follow-up (0.91, 0.87-0.94). Likewise, lipid lowering with statins reduced the risk of all-cause mortality during the in-trial period (0.88, 0.81-0.95), and this effect persisted during overall follow-up (0.92, 0.87-0.97). Similar findings were observed for cardiovascular death. In BPL trials, the cumulative reduction in all-cause mortality was significantly lower in trials with at least 5 years of post-trial follow-up compared with those with less than 5 years, and a similar tendency was observed for lipid-lowering trials. Benefits of BPL and lipid lowering on all-cause and cardiovascular mortality were persistent, but attenuated, after discontinuation of randomized treatment, indicating the importance of continuing therapy.


Plant-based diets and long-term health: findings from the EPIC-Oxford study.
The concept of plant-based diets has become popular due to the purported benefits for both human health and environmental impact. Although 'plant-based' is sometimes used to indicate omnivorous diets with a relatively small component of animal foods, here we take it to mean either vegetarian (plant-based plus dairy products and/or eggs) or vegan (100% plant-based). Important characteristics of plant-based diets which would be expected to be beneficial for long-term health are low intakes of saturated fat and high intakes of dietary fibre, whereas potentially deleterious characteristics are the risk of low intakes of some micronutrients such as vitamin B12, vitamin D, calcium and iodine, particularly in vegans. Vegetarians and vegans typically have lower BMI, serum LDL cholesterol and blood pressure than comparable regular meat-eaters, as well as lower bone mineral density. Vegetarians in the EPIC-Oxford study have a relatively low risk of IHD, diabetes, diverticular disease, kidney stones, cataracts and possibly some cancers, but a relatively high risk of stroke (principally haemorrhagic stroke) and bone fractures, in comparison with meat-eaters. Vegans in EPIC-Oxford have a lower risk of diabetes, diverticular disease and cataracts and a higher risk of fractures, but there are insufficient data for other conditions to draw conclusions. Overall, the health of people following plant-based diets appears to be generally good, with advantages but also some risks, and the extent to which the risks may be mitigated by optimal food choices, fortification and supplementation is not yet known.


Repeatability of [18F]FDG PET/CT total metabolic active tumour volume and total tumour burden in NSCLC patients.
Total metabolic active tumour volume (TMATV) and total tumour burden (TTB) are increasingly studied as prognostic and predictive factors in non-small cell lung cancer (NSCLC) patients. In this study, we investigated the repeatability of TMATV and TTB as function of uptake interval, positron emission tomography/computed tomography (PET/CT) image reconstruction settings, and lesion delineation method. We used six lesion delineation methods, four direct PET image-derived delineations and two based on a majority vote approach, i.e. intersection between two or more delineations (MV2) and between three or more delineations (MV3). To evaluate the accuracy of those methods, they were compared with a reference delineation obtained from the consensus of the segmentations performed by three experienced observers. Ten NSCLC patients underwent two baseline whole-body [18F]2-Fluoro-2-deoxy-2-D-glucose ([18F]FDG) PET/CT studies on separate days, within 3 days. Two scans were obtained on each day at 60 and 90 min post-injection to assess the influence of tracer uptake interval. PET/CT images were reconstructed following the European Association of Nuclear Medicine Research Ltd. (EARL) compliant settings and with point-spread-function (PSF) modelling. Repeatability between the measurements of each day was determined and the influence of uptake interval, reconstruction settings, and lesion delineation method was assessed using the generalized estimating equations model. Based on the Jaccard index with the reference delineation, the MV2 lesion delineation method was the most successful method for automated lesion segmentation. The best overall repeatability (lowest repeatability coefficient, RC) was found for TTB from 90 min of tracer uptake scans reconstructed with EARL compliant settings and delineated with 41% of lesion's maximum SUV method (RC = 11%). In most cases, TMATV and TTB repeatability were not significantly affected by changes in tracer uptake time or reconstruction settings. However, some lesion delineation methods had significantly different repeatability when applied to the same images. This study suggests that under some circumstances TMATV and TTB repeatability are significantly affected by the lesion delineation method used. Performing the delineation with a majority vote approach improves reliability and does not hamper repeatability, regardless of acquisition and reconstruction settings. It is therefore concluded that by using a majority vote based tumour segmentation approach, TMATV and TTB in NSCLC patients can be measured with high reliability and precision.


Marked sex differences in all-cause mortality on antiretroviral therapy in low- and middle-income countries: a systematic review and meta-analysis.
While women and girls are disproportionately at risk of HIV acquisition, particularly in low- and middle-income countries (LMIC), globally men and women comprise similar proportions of people living with HIV who are eligible for antiretroviral therapy. However, men represent only approximately 41% of those receiving antiretroviral therapy globally. There has been limited study of men's outcomes in treatment programmes, despite data suggesting that men living with HIV and engaged in treatment programmes have higher mortality rates. This systematic review (SR) and meta-analysis (MA) aims to assess differential all-cause mortality between men and women living with HIV and on antiretroviral therapy in LMIC. A SR was conducted through searching PubMed, Ovid Global Health and EMBASE for peer-reviewed, published observational studies reporting differential outcomes by sex of adults (≥15 years) living with HIV, in treatment programmes and on antiretroviral medications in LMIC. For studies reporting hazard ratios (HRs) of mortality by sex, quality assessment using Newcastle-Ottawa Scale (cohort studies) and an MA using a random-effects model (Stata 14.0) were conducted. A total of 11,889 records were screened, and 6726 full-text articles were assessed for eligibility. There were 31 included studies in the final MA reporting 42 HRs, with a total sample size of 86,233 men and 117,719 women, and total time on antiretroviral therapy of 1555 months. The pooled hazard ratio (pHR) showed a 46% increased hazard of death for men while on antiretroviral treatment (1.35-1.59). Increased hazard was significant across geographic regions (sub-Saharan Africa: pHR 1.41 (1.28-1.56); Asia: 1.77 (1.42-2.21)) and persisted over time on treatment (≤12 months: 1.42 (1.21-1.67); 13-35 months: 1.48 (1.23-1.78); 36-59 months: 1.50 (1.18-1.91); 61 to 108 months: 1.49 (1.29-1.71)). Men living with HIV have consistently and significantly greater hazards of all-cause mortality compared with women while on antiretroviral therapy in LMIC. This effect persists over time on treatment. The clinical and population-level prevention benefits of antiretroviral therapy will only be realized if programmes can improve male engagement, diagnosis, earlier initiation of therapy, clinical outcomes and can support long-term adherence and retention.


TNF Induction of NF-κB RelB Enhances RANKL-Induced Osteoclastogenesis by Promoting Inflammatory Macrophage Differentiation but also Limits It through Suppression of NFATc1 Expression.
TNF induces bone loss in common bone diseases by promoting osteoclast formation directly and indirectly, but it also limits osteoclast formation by inducing expression of NF-κB p100. Osteoclast precursors (OCPs) are derived from M1 (inflammatory) and M2 (resident) macrophages. However, it is not known if TNF stimulates or limits osteoclast formation through regulation of M1 or M2 differentiation or if RelB, a partner of p100, is involved. To investigate these questions, we treated bone marrow cells (BMCs) with M-CSF alone or in combination with TNF to enrich for OCPs, which we called M-OCPs and T-OCPs, respectively. We found that TNF switched CD11b+F4/80+ M-OCPs from Ly6C-Gr1- M2 to Ly6C+Gr1-CD11c+ and Ly6C-Gr1-CD11c+ M1 cells. RANKL induced osteoclast formation from both Ly6C+Gr1- and Ly6C-Gr1- T-OCPs, but only from Ly6C+Gr1- M-OCPs, which formed significantly fewer osteoclasts than T-OCPs. Importantly, Ly6C+Gr1- cells from both M- and T-OCPs have increased expression of the M1 marker genes, iNOS, TNF, IL-1β and TGFβ1, compared to Ly6C-Gr1- cells, and Ly6C-Gr1- cells from T-OCPs also have increased expression of iNOS and TGFβ1 compared to cells from M-OCPs. Both RANKL and TNF increased RelB mRNA expression. TNF significantly increased RelB protein levels, but RANKL did not because it also induced RelB proteasomal degradation. TNF inhibited RANKL-induced NFATc1 mRNA expression and osteoclast formation from M-OCPs, but not from T-OCPs, and it did not induce Ly6C+Gr1-CD11c+ or Ly6C-Gr1-CD11c+ M1 macrophages from RelB-/- BMCs. Furthermore, overexpression of RelB in M-OCPs reduced RANKL-induced osteoclast formation and NFATc1 mRNA expression, but it increased TNF-induced OC formation without affecting NFATc1 levels. Thus, TNF induction of RelB directly mediates terminal osteoclast differentiation independent of NFATc1 and limits RANKL-induced osteoclastogenesis by inhibiting NFATc1 activation. However, the dominant role of TNF is to expand the OCP pool by switching the differentiation of M-CSF-induced M2 to M1 macrophages with enhanced osteoclast forming potential. Strategies to degrade RelB could prevent TNF-induced M2/M1 switching and reduce osteoclast formation.


Comparing the effectiveness of shared versus private latrines in preventing trachoma in rural Tanzania.
Sharing latrines is common in sub-Saharan Africa with anecdotal accounts suggesting a link between water-, sanitation-, and hygiene-related disease and poorly maintained communal latrines. This study examines this link by assessing the association between shared latrines compared with private latrines and risk of trachoma. In 2007, as part of a larger case-control study, we conducted a sub-study on latrine sharing in 594 households (92 cases, 502 controls) in seven rural Tanzanian communities. Case households were defined by having a child with clinical signs of trachoma. Latrine use was associated with a decreased risk of trachoma and there was no difference in risk between households using shared compared with private latrines (adjusted odds ratio = 0.95 [95% confidence interval = 0.55-1.67]). This study emphasizes the need to promote latrine use, which can be facilitated through latrine sharing in resource scarce areas, for prevention of trachoma.


Behavioral performance follows the time course of neural facilitation and suppression during cued shifts of feature-selective attention.
A central question in the field of attention is whether visual processing is a strictly limited resource, which must be allocated by selective attention. If this were the case, attentional enhancement of one stimulus should invariably lead to suppression of unattended distracter stimuli. Here we examine voluntary cued shifts of feature-selective attention to either one of two superimposed red or blue random dot kinematograms (RDKs) to test whether such a reciprocal relationship between enhancement of an attended and suppression of an unattended stimulus can be observed. The steady-state visual evoked potential (SSVEP), an oscillatory brain response elicited by the flickering RDKs, was measured in human EEG. Supporting limited resources, we observed both an enhancement of the attended and a suppression of the unattended RDK, but this observed reciprocity did not occur concurrently: enhancement of the attended RDK started at 220 ms after cue onset and preceded suppression of the unattended RDK by about 130 ms. Furthermore, we found that behavior was significantly correlated with the SSVEP time course of a measure of selectivity (attended minus unattended) but not with a measure of total activity (attended plus unattended). The significant deviations from a temporally synchronized reciprocity between enhancement and suppression suggest that the enhancement of the attended stimulus may cause the suppression of the unattended stimulus in the present experiment.


Can the Fear-Avoidance Beliefs Questionnaire predict work status in people with work-related musculoskeletal disorders?
To investigate the predictive validity of fear avoidance beliefs as assessed by the Work Subscale (FABQ-W) of the Fear Avoidance Beliefs Questionnaire in a sample of 117 patients with a work-related musculoskeletal disorder, and identify two FABQ-W cut off points that identified participants as high or low risk of non return to work, following an interdisciplinary rehabilitation program. A retrospective analysis of patient data collected in conjunction with the Victorian Workcover Authority "Sprains and Strains" program. Sequential logistic regression analysis was used to construct a model of prediction from the baseline variables of age, disability (using the Pain Disability Index), gender and FABQ-W scores. Receiver Operator Characteristic (ROC) curves were used to identify FABQ-W cut off points that best predicted the return to work outcome. Age and initial FABQ-W scores significantly improved the predictive capabilities of the model, but gender and disability did not. The model explained between 13.1% and 18.2% of the variability in the RTW outcome. ROC curves showed maximum sensitivity was 100% for a score of ≤ 27.5, with a score of > 39.5 identified as having optimum specificity (81.9%). Individuals with low FABQ-W scores are likely to return to work, however those with high scores will not necessarily have a poor outcome. This study supports the limited utility of the FABQ-W score for screening for risk of a poor return to work outcome in patients with a work related musculoskeletal disorder.


Mitochondria-targeting and cell-penetrating peptides-co-modified HPMA copolymers for enhancing therapeutic efficacy of α-tocopheryl succinate.
Targeting drugs at mitochondria may provide an effective means of inducing cell death for cancer therapy. Here, we introduce a conjugate of a dual-ligand-modified N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer with α-tocopheryl succinate (α-TOS) (P-TOS-SS20-dNP2), which could simultaneously enhance cellular uptake via the cell-penetrating peptide dNP2 and implement delivery to mitochondria by means of the mitochondria-targeting peptide SS20. The results showed that co-modification with SS20 and dNP2 peptides successfully made up for the deficiencies of each peptide: copolymers singly modified with dNP2 were unable to increase their mitochondrial distribution in spite of increased cellular uptake, whereas copolymers singly modified with SS20 exhibited restricted mitochondrial targeting because of their poor uptake. The combination of these two functional peptides resulted in conspicuous cellular uptake and a 7.6-fold increase in accumulation in mitochondria in comparison with unmodified HPMA polymer-drug conjugates in vitro. Moreover, the dual-modified polymer-drug conjugate P-TOS-SS20-dNP2 exhibited the greatest increase in the generation of reactive oxygen species in HeLa cells, followed by great opening of mitochondrial permeability transition pores and a sharp reduction in the mitochondrial membrane potential. This further led to superior cell apoptosis in comparison with singly or non-peptide-modified HPMA copolymer-drug conjugates. The results demonstrated that combining a mitochondria-targeting peptide and a cell-penetrating peptide would substantially increase the distribution of HPMA copolymers in mitochondria, which implied an efficient strategy for promoting mitochondrial targeting efficiency.


Prevalence and characterization of extended-spectrum beta-lactamases-producing Salmonella enterica isolates in Saragossa, Spain (2001-2008).
We analyzed the prevalence of resistance to extended-spectrum cephalosporins (ESCs) among clinical strains of Salmonella enterica collected by the Laboratory of Clinical Microbiology in the University Clinical Hospital Lozano Blesa in the region of Aragón (Spain), for which very few epidemiological information exists. A total of 2,092 strains of S. enterica were identified in stool samples from patients with gastroenteritis. Five isolates showed an extended-spectrum beta-lactamase (ESBL) phenotype: four isolates of S. enterica serotype Virchow harbored the ESBL-encoding bla(CTX-M-9) gene and an isolate of serotype Enteritidis carried a bla(CTX-M-1) gene, which, to the best of our knowledge, is described here for the first time in this serotype of S. enterica. The five ESC-resistant isolates were also resistant to spectinomycin, streptomycin, kanamycin, sulfonamides, tetracycline, and trimethoprim as well as to nalidixic acid. The ESBL isolate of serotype Enteritidis, however, remained susceptible to kanamycin and nalidixic acid. A class 1 integron of 1.5 kb was detected for the four serotype Virchow isolates with the gene cassette dfrA16-aadA2. The bla(CTX-M-9) gene was carried by an ∼300-kb IncHI2 conjugative plasmid in the case of the S. enterica serotype Virchow isolates. The bla(CTX-M-1) gene was carried by an ∼100-kb IncI1-N conjugative plasmid for the serotype Enteritidis ESC-resistant isolate. All the four ESC-resistant strains of S. enterica serotype Virchow clustered together in a XbaI pulsed-field gel electrophoresis, which also revealed a strong similarity between them and some pulsotypes of S. enterica serotype Virchow from France.


Contribution of RNA polymerase concentration variation to protein expression noise.
Cell-to-cell variation in gene expression, or noise, is a general phenomenon observed within cell populations. Transcription is known to be the key stage of gene expression where noise is generated, however, how variation in RNA polymerase (RNAP) concentration contributes to gene expression noise is unclear. Here, we quantitatively investigate how variations in absolute amounts of RNAP molecules affect noise in the expression of two fluorescent protein reporters driven by identical promoters. We find that intrinsic noise is independent of variation in RNAP concentrations, whereas extrinsic noise, which is variation in gene expression due to varying cellular environments, scales linearly with variation in RNAP abundance. Specifically, the propagation of RNAP abundance variation to expressed protein noise is inversely proportional to the concentration of RNAP, which suggests that the change in noise that results from RNAP fluctuations is determined by the fraction of promoters that is not occupied by RNAP.


RNASeqBrowser: a genome browser for simultaneous visualization of raw strand specific RNAseq reads and UCSC genome browser custom tracks.
Strand specific RNAseq data is now more common in RNAseq projects. Visualizing RNAseq data has become an important matter in Analysis of sequencing data. The most widely used visualization tool is the UCSC genome browser that introduced the custom track concept that enabled researchers to simultaneously visualize gene expression at a particular locus from multiple experiments. Our objective of the software tool is to provide friendly interface for visualization of RNAseq datasets. This paper introduces a visualization tool (RNASeqBrowser) that incorporates and extends the functionality of the UCSC genome browser. For example, RNASeqBrowser simultaneously displays read coverage, SNPs, InDels and raw read tracks with other BED and wiggle tracks -- all being dynamically built from the BAM file. Paired reads are also connected in the browser to enable easier identification of novel exon/intron borders and chimaeric transcripts. Strand specific RNAseq data is also supported by RNASeqBrowser that displays reads above (positive strand transcript) or below (negative strand transcripts) a central line. Finally, RNASeqBrowser was designed for ease of use for users with few bioinformatic skills, and incorporates the features of many genome browsers into one platform. The features of RNASeqBrowser: (1) RNASeqBrowser integrates UCSC genome browser and NGS visualization tools such as IGV. It extends the functionality of the UCSC genome browser by adding several new types of tracks to show NGS data such as individual raw reads, SNPs and InDels. (2) RNASeqBrowser can dynamically generate RNA secondary structure. It is useful for identifying non-coding RNA such as miRNA. (3) Overlaying NGS wiggle data is helpful in displaying differential expression and is simple to implement in RNASeqBrowser. (4) NGS data accumulates a lot of raw reads. Thus, RNASeqBrowser collapses exact duplicate reads to reduce visualization space. Normal PC's can show many windows of NGS individual raw reads without much delay. (5) Multiple popup windows of individual raw reads provide users with more viewing space. This avoids existing approaches (such as IGV) which squeeze all raw reads into one window. This will be helpful for visualizing multiple datasets simultaneously. RNASeqBrowser and its manual are freely available at http://www.australianprostatecentre.org/research/software/rnaseqbrowser or http://sourceforge.net/projects/rnaseqbrowser/.


Chemo-radiotherapy for localized pancreatic cancer: increased dose intensity and reduced acute toxicity with concomitant radiotherapy and protracted venous infusion 5-fluorouracil.
Although concomitant radiation therapy (RT) and bolus 5-Fluorouracil (5-FU) have been shown to improve survival in locally confined pancreatic cancer, most patients will eventually succumb to their disease. Since 1994, we have attempted to improve efficacy by administering 5-FU as a protracted venous infusion (PVI). This study compares treatment intensity and acute toxicity of consecutive protocols of concurrent RT and 5-FU by bolus injection or PVI. Since 1986, 74 patients with resected or locally advanced pancreatic cancer were treated with continuous course RT and concurrent 5-FU by bolus injection (n = 44) or PVI throughout the course of RT (n = 30). Dose intensity was assessed for both 5-FU and radiotherapy. Toxicity endpoints which could be reliably and objectively quantified (e.g., neutropenia, weight loss, treatment interruption) were evaluated. Cumulative 5-FU dose (mean = 7.2 vs. 2.5 gm/m2, p < 0.001) and weekly 5-FU dose (mean = 1.3 vs. 0.5 gm/m2/wk, p < 0.001) were significantly higher for patients receiving PVI 5-FU. Following pancreaticoduodenectomy, 95% of PVI patients maintained a RT dose intensity of > or = 900 cGy/wk, compared with 63% of those receiving bolus 5-FU (p = 0.02). No difference was seen for patients with locally advanced disease (72% vs. 76%, p = n.s.). Grade II-III neutropenia was less common for patients treated with PVI (13% vs. 34%, p = 0.05). Grade II-III thrombocytopenia was uncommon (< or = 3%) in both treatment groups. Mean percent weight loss (3.8% vs. 4.1%, p = n.s.) and weight loss > or = 5% of pre-treatment weight (21% vs. 31%, p = n.s.) were similar for PVI and bolus treatment groups, respectively. Treatment interruptions for hematologic, gastrointestinal or other acute toxicities were less common for patients receiving PVI 5-FU (10% vs. 25%, p = 0.11). Concurrent RT and 5-FU by PVI was well tolerated and permitted greater chemotherapy and radiotherapy dose intensity with reduced hematologic toxicity and fewer treatment interruptions compared with RT and bolus 5-FU. Longer follow-up will be needed to assess late effects and the impact on overall survival.


Associations of educational attainment, occupation, social class and major depressive disorder among Han Chinese women.
The prevalence of major depressive disorder (MDD) is higher in those with low levels of educational attainment, the unemployed and those with low social status. However the extent to which these factors cause MDD is unclear. Most of the available data comes from studies in developed countries, and these findings may not extrapolate to developing countries. Examining the relationship between MDD and socio economic status in China is likely to add to the debate because of the radical economic and social changes occurring in China over the last 30 years. We report results from 3,639 Chinese women with recurrent MDD and 3,800 controls. Highly significant odds ratios (ORs) were observed between MDD and full time employment (OR = 0.36, 95% CI = 0.25-0.46, logP = 78), social status (OR = 0.83, 95% CI = 0.77-0.87, logP = 13.3) and education attainment (OR = 0.90, 95% CI = 0.86-0.90, logP = 6.8). We found a monotonic relationship between increasing age and increasing levels of educational attainment. Those with only primary school education have significantly more episodes of MDD (mean 6.5, P-value = 0.009) and have a clinically more severe disorder, while those with higher educational attainment are likely to manifest more comorbid anxiety disorders. In China lower socioeconomic position is associated with increased rates of MDD, as it is elsewhere in the world. Significantly more episodes of MDD occur among those with lower educational attainment (rather than longer episodes of disease), consistent with the hypothesis that the lower socioeconomic position increases the likelihood of developing MDD. The phenomenology of MDD varies according to the degree of educational attainment: higher educational attainment not only appears to protect against MDD but alters its presentation, to a more anxious phenotype.


Antimicrobial Agents-induced Hypokalemia: A Possible Causality Association.
Drugs including some of the antimicrobial agents (AMAs) can cause mild to severe intensity of hypokalemia, which leads to cardiac, muscular, renal, gastrointestinal, and metabolic manifestations. To explore the possible association of AMAs use and the development of hypokalemia as an adverse drug reaction (ADR). Retrospective analysis of spontaneously individual case safety reports (ICSRs) received during January 2015 to September 2017 for any reduction in serum potassium levels following the use of AMAs. Such ICSRs were further analyzed for age, gender, seriousness and severity of hypokalemia, outcome, concomitant drugs, management of hypokalemia, and causality assessment using WHO-UMC causality assessment scale. Out of total 2,880 spontaneous ICSR, 53 had report title of hypokalemia. In almost half of these (27) ICSRs, AMAs were suspected to induced hypokalemia. Ceftriaxone (24.5%) and azithromycin (10.5%) were most suspected AMAs. Females (74.19%) aged between 21 years and 40 years experienced more AMA induced hypokalemia. The mild, moderate, and severe hypokalemia was present in 53.8%, 40.7%, and 7.4% of ICSRs, respectively. Drug-drug interaction of AMA with either furosemide, hydrocortisone and/or deriphyllin was present in six ICSRs. Causal association of all the ICSRs with AMA induced hypokalemia was possible. Antimicrobial agents (especially ceftriaxone and azithromycin)-induced hypokalemia alert needs to be investigated. Further, healthcare professionals are advocated to take caution by monitoring serum potassium levels routinely for such patients. Rehan HS, Hotha P, Antimicrobial Agentsinduced Hypokalemia: A Possible Causality Association. Indian J Crit Care Med 2019;23(4):175-177.


Depression among carers of AIDS-orphaned and other-orphaned children in Umlazi Township, South Africa.
South Africa faces the challenge of supporting the well-being of adults caring for growing numbers of AIDS-orphaned children. These adults play a critical role in responses to the epidemic, but little information exists in regard to their mental health needs. This paper reports on findings from n=1599 adults, recruited through representative household sampling, who serve as primary carers for children in Umlazi Township, an HIV-endemic community. Overall, 22% of participants were carers of AIDS-orphaned children, 11% were carers of other-orphaned children and 67% were carers of non-orphaned children. Prevalence of depression was 30.3%. Orphan carers, regardless of whether they cared for AIDS-orphaned or other-orphaned children, were significantly more likely than carers of non-orphaned children to meet the clinical threshold for depression (35.2% vs. 27.9%, p < 0.01). In multivariate logistic regressions, food insecurity and being a female carer were identified as additional risk factors for greater depression. In contrast, households with access to running water and households dependent on salaries as the main source of income were identified as protective factors for disparities in depression. Mental health interventions are urgently needed to address an increased risk for depression among all orphan carers, not just those caring for AIDS-orphaned children.


Linking cultural competency and community service: a partnership between students, faculty, and the community.
The purpose of the migrant health initiative is to give medical students the opportunity to provide clinical services, at appropriate levels of training, to a population that reflects a different ethnic and economic background than medical students typically see in the clinical setting. This initiative integrates concepts of cultural competency with experiential learning. The migrant health initiative provides an infrastructure for a cultural competency educational program in the first two years of medical school within an essentials of clinical medicine course (ECM). The ECM course emphasizes the impacts of family, society, and community on the delivery of patient health care. Experience in the provision of clinical care to migrant workers provides an exceptional opportunity to expose students to a medically underserved, diverse group of people and to provide care to persons with a different language. The program was developed from grass-roots initiatives of students and the region's Area Health Education Center (AHEC). Historically, migrant workers provide the majority of the labor for harvesting onions in southeast Georgia. In April 2000, the regional AHEC organized a one-day clinic for migrant workers, staffed by one local physician and allied health students. Care was provided to over 400 laborers. As a result of the response by the migrant workforce, the AHEC developed a partnership with the local community to expand the health care services to this underserved group. Five medical students, working with the school's associate dean for curriculum and local AHEC, had observed a migrant health clinic organized by the AHEC and were seeking ongoing community service opportunities. Based on the interest and enthusiasm of the students, a faculty-supervised migrant health elective was developed for first- and second-year students. The number of students who wanted to take the elective exceeded the available opportunities. The ECM course will be enhanced with an integrated and longitudinal curriculum that focuses on migrant health care; the revised ECM course will provide students with the knowledge, skills, attitudes, and behaviors to care for individuals from different cultures. First-year students will be able to volunteer to work in the program. Second-year students will participate in at least one migrant health clinic, traveling only three hours but providing a different world with medical care. In addition, the opportunities for medical students to participate in a community health initiative and to work with nursing and allied health students will enhance their public health knowledge and their team and leadership skills. The partnership between students, faculty, and the community provides the mechanism to thoughtfully develop and integrate cultural issues and experiences into the curriculum. Students have recently received a Caring for Community five-year grant from the Association of American Medical Colleges. Program expansions will continue into the third-year medicine clerkship and include a senior elective. The program expansions will result in a migrant health initiative that will be coordinated; comprehensive; and expand student knowledge, skills, and experiences in cultural health care.


Spatial and seasonal variation in diversity and structure of microbial biofilms on marine plastics in Northern European waters.
Plastic pollution is now recognised as a major threat to marine environments and marine biota. Recent research highlights that diverse microbial species are found to colonise plastic surfaces (the plastisphere) within marine waters. Here, we investigate how the structure and diversity of marine plastisphere microbial community vary with respect to season, location and plastic substrate type. We performed a 6-week exposure experiment with polyethylene terephthalate (PET) bottles in the North Sea (UK) as well as sea surface sampling of plastic polymers in Northern European waters. Scanning electron microscopy revealed diverse plastisphere communities comprising prokaryotic and eukaryotic microorganisms. Denaturing gradient gel electrophoresis (DGGE) and sequencing analysis revealed that plastisphere microbial communities on PET fragments varied both with season and location and comprised of bacteria belonging to Bacteroidetes, Proteobacteria, Cyanobacteria and members of the eukaryotes Bacillariophyceae and Phaeophyceae. Polymers sampled from the sea surface mainly comprised polyethylene, polystyrene and polypropylene particles. Variation within plastisphere communities on different polymer types was observed, but communities were primarily dominated by Cyanobacteria. This research reveals that the composition of plastisphere microbial communities in marine waters varies with season, geographical location and plastic substrate type.


Tumour suppressor CYLD is a negative regulator of the mitotic kinase Aurora-B.
The familial cylindromatosis tumour suppressor CYLD contains three cytoskeleton-associated protein glycine-rich (CAP-Gly) domains and a deubiquitinase domain. The tumour-suppressing function of CYLD has been attributed to its deubiquitinase domain, which removes lysine-63-linked polyubiquitin chains from target proteins, leading to the inhibition of cell survival and proliferation. In this study, we have detected an interaction of CYLD with the mitotic kinase Aurora-B. The interaction is mediated by the third CAP-Gly domain of CYLD and results in suppression of Aurora-B activity. Mechanistic studies reveal that the inhibition of Aurora-B activity by CYLD is independent of its deubiquitinase activity. Instead, CYLD interacts with protein phosphatase 2A (PP2A) and promotes the ability of PP2A to bind and dephosphorylate Aurora-B at threonine-232. Cylindromatosis-associated truncating mutations of CYLD abolish its interaction with PP2A, its enhancing effect on the PP2A/Aurora-B interaction, and its inhibitory effect on Aurora-B activity. These findings uncover Aurora-B and PP2A as novel binding partners of CYLD and suggest that CYLD negatively regulates Aurora-B activity through acting on the PP2A axis.


Prosthetic Joint Infection due to Actinomyces species: A case series and review of literature.
Background: Actinomyces prosthetic joint infections (APJIs) are rare and optimal medical and surgical treatment strategies are unknown. The purpose of our study was to characterize the demographics, risk factors, management and outcomes of patients with PJIs due to Actinomyces spp. Methods: Using a retrospective cohort study design, the medical records of all patients with Actinomyces spp. total hip or knee arthroplasty infection (APJI) seen at a single institution between January 1, 1969 and December 31, 2016 were reviewed. We abstracted information including patient demographics, co-morbidities, joint age, surgical history, microbiology, management and outcomes. A simultaneous literature search via PubMed was performed to identify cases of APJI published in literature and a descriptive analysis was performed. Results: Eleven cases were identified over a 47 year study period at our institution. Seven patients (64%) were female. The median age at the time of diagnosis of infection was 71 years (range, 57-89). The knee was involved in six cases (55%) followed by the hip in 5 (45 %) cases. Three cases had dentures, broken teeth, or poor dentition. Actinomyces odonotlyticus was the most commonly found subspecies at our institution. Median ESR and CRP values were 61mm/hr and 64 mg/L respectively. Eight (72%) patients were managed with 2 stage exchange. Most patients received a course of beta-lactam therapy for 6 weeks. Ten cases (91%) were free of failure after a median duration of follow-up of 2 years (range, 0.67 - 5 years). The median duration from joint arthroplasty to the onset of symptoms was 162 days, range (20-3318). Six (54%) had a history of prior PJI with a different microorganism at the same joint site and 4 patients had history of prior 2 stage exchange (36%). In the literature group, we identified 12 cases and the most common subspecies was Actinomyces israelii; most patients underwent two stage exchange and were treated with 6 weeks of beta lactam antibiotics. Conclusions: Based on our observational study, Actinomyces PJI presents as a late complication of TJR, may be associated with prior PJI at the index joint and antecedent dental manipulation may portend as an additional risk factor. Treatment includes two stage exchange and beta- lactam therapy for 6weeks. These results will help clinicians in improved understanding and management of APJIs which although are rare but warrant special attention as population with implanted joint arthroplasties continues to rise.