Does the Critical Shoulder Angle Correlate With Rotator Cuff Tear Progression?
The critical shoulder angle (CSA) has been reported to be associated with rotator cuff disease and has been suggested as an etiology for cuff tears. However, it is unclear whether acromial morphologic characteristics such as CSA are a cause or effect because all studies to date have been retrospective. (1) How often can the CSA be reliably measured? (2) Is the CSA associated with rotator cuff disease? (3) Is the CSA correlated with baseline tear size or tear enlargement? (4) Does the CSA change with time? In this retrospective comparison of longitudinally collected data, patients with asymptomatic rotator cuff tears underwent ultrasonography and standardized AP radiographs at enrollment and yearly thereafter during a median of 4 years. Three hundred ninety-five patients were included, of whom 14 were excluded as they were not yet eligible for 2-year followup and 68 (18%) were lost to followup, leaving 313 study patients who were evaluated with 1433 radiographs. Patients with adhesive capsulitis with normal rotator cuffs and radiographically normal scapulae were included as control subjects (119 subjects). Two observers (PNC, DS) measured the CSA in a blinded fashion. Radiographs that met Suter-Henninger criteria for CSA measurement reliability were included. For the study group, 179 of the 313 (57%) patients with radiographs that met Suter-Henninger criteria were further analyzed; the remainder were excluded from this study. For the control group, 50 of 119 (42%) subjects met criteria and were further analyzed. Tear enlargement was found in 94 patients, and the CSA was compared in patients with tears and control subjects, and in tears with or without enlargement, and was correlated with tear size. In a subgroup of the study group in which 59 of 179 patients had a minimum of 3 years between initial and followup radiographs, two CSA measurements were performed to measure change. In total, of the 1552 radiographs evaluated, only 326 (21%) were of sufficient quality to measure the CSA. The CSA was higher among patients with cuff tears than control subjects (34° ± 4° versus 32° ± 4°; mean difference, 2.0°; 95% CI, 0.7°-3.2°; p = 0.003). The CSA did not correlate with baseline tear length (ρ = 0.22, p = 0.090) or width (ρ = 0.16, p = 0.229). The CSA was not different between tears that enlarged and those that were stable (34° ± 3° versus 34° ± 4°; mean difference, 0.2°; 95% CI, -0.9° to -1.4°; p = 0.683). The CSA did not change over time (CSA Time 1: mean 33° ± 4° SD; CSA Time 2: mean 33° ± 4° SD; mean difference, -0.2°; 95% CI, -0.6° to 0.1°; p = 0.253). Even with a longitudinal protocol, most radiographs are of insufficient quality for CSA measurement. Although patients with a history of degenerative cuff disease have higher CSA values than control subjects, the difference is small enough that it could be influenced by measurement error in practice; in any case, a difference of the magnitude we observed is likely to be clinically unimportant. The CSA is not correlated with tear size or tear progression, and does not seem to change with time. These results suggest that the CSA is unlikely to be related to rotator cuff disease. Level II, prognostic study.


Factors influencing the use of supervised delivery services in Garu-Tempane District, Ghana.
There is evidence that supervised delivery has the potential to improve birth outcomes for both women and newborns. However, not all women especially in low-income settings like Ghana use supervised delivery services during childbirth. The purpose of this study was to estimate the prevalence of supervised delivery and determine factors that influence use of supervised delivery services in a local district of Ghana. A retrospective cross-sectional survey of 322 randomly sampled postpartum women who delivered between January and December 2016 in the Garu-Tempane District was conducted. Structured questionnaires were used to collect data. Descriptive, binary and multivariate logistic regression analysis techniques were used to analyse data. Although antenatal care attendance among respondents was very high 291(90.4%), prevalence of supervised birth was only 219(68%). More than a quarter 103(32%) of the postpartum women delivered their babies at home without skilled birth attendants. After controlling for possible confounders in multivariable logistic regression analyses, factors that strongly independently predicted supervised delivery were religion (p < 0.01), distance to health facility (p < 0.05), making at least 4 antenatal care visits (p < 0.01), national health insurance scheme registration (p < 0.01), satisfaction with services received during antenatal care (p < 0.01), need partner's approval before delivering in health facility (p < 0.01), woman's thoughts that her religious beliefs prohibited health facility delivery(p < 0.01), and woman's belief that there are norms in her community that did not support health facility delivery (p < 0.01). There is need for targeted interventions, including community mobilization and health education, and male partner involvement to help generate local demand for, and uptake of, supervised delivery services. Improvement in the quality of services in health facilities, including ensuring respect and dignity for service users, would also be essential.


Pediatric Gartland Type-IV Supracondylar Humeral Fractures Have Substantial Overlap with Flexion-Type Fractures.
Knowledge is limited about the diagnosis and treatment of modified Gartland type-IV supracondylar humeral fractures. We determined the prevalence of type-IV fractures, identified preoperative characteristics associated with these injuries, and assessed operative treatment characteristics. We retrospectively identified patients <16 years of age who underwent operative treatment of a supracondylar humeral fracture at 2 centers between 2008 and 2016. We compared patient, injury, and treatment characteristics between type-IV and type-III fracture groups (1:4, cases:controls). Preoperative radiographs were assessed by 4 pediatric orthopaedists blinded to fracture type. The odds of a fracture being type IV were assessed using univariate logistic regression for individual radiographic parameters. Significance was set at alpha = 0.05. Type-IV fractures accounted for 39 (1.3%) of the supracondylar humeral fractures treated operatively during the study period. A type-IV fracture was associated with the following radiographic parameters: flexion angulation (odds ratio [OR] = 17; 95% confidence interval [CI] = 4.9 to 59), valgus angulation (OR = 5.6; 95% CI = 1.6 to 20), and lateral translation (OR = 4.1; 95% CI = 1.6 to 11) of the distal fragment; osseous apposition between the proximal and distal fragments (OR = 4.0; 95% CI = 1.8 to 9.0); and propagation of the fracture line toward the diaphysis of the proximal segment (OR = 9.2; 95% CI = 1.6 to 53). We found no significant differences in patient or injury characteristics between the groups. Compared with type-III fractures, type-IV fractures were treated more frequently with open reduction and percutaneous pinning (13% compared with 3.8%; p = 0.04) and were associated with longer mean operative time (82 ± 42 compared with 63 ± 28 minutes; p = 0.001). We identified 5 preoperative radiographic parameters associated with greater odds of a supracondylar humeral fracture being type IV rather than type III. No patient or injury characteristic differed significantly between the groups. Substantial overlap likely exists between type-IV and flexion-type fractures. Type-IV fractures were associated with longer operative time and were treated with open reduction more frequently than were type-III fractures. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Complete genome sequence of Nitrobacter hamburgensis X14 and comparative genomic analysis of species within the genus Nitrobacter.
The alphaproteobacterium Nitrobacter hamburgensis X14 is a gram-negative facultative chemolithoautotroph that conserves energy from the oxidation of nitrite to nitrate. Sequencing and analysis of the Nitrobacter hamburgensis X14 genome revealed four replicons comprised of one chromosome (4.4 Mbp) and three plasmids (294, 188, and 121 kbp). Over 20% of the genome is composed of pseudogenes and paralogs. Whole-genome comparisons were conducted between N. hamburgensis and the finished and draft genome sequences of Nitrobacter winogradskyi and Nitrobacter sp. strain Nb-311A, respectively. Most of the plasmid-borne genes were unique to N. hamburgensis and encode a variety of functions (central metabolism, energy conservation, conjugation, and heavy metal resistance), yet approximately 21 kb of a approximately 28-kb "autotrophic" island on the largest plasmid was conserved in the chromosomes of Nitrobacter winogradskyi Nb-255 and Nitrobacter sp. strain Nb-311A. The N. hamburgensis chromosome also harbors many unique genes, including those for heme-copper oxidases, cytochrome b(561), and putative pathways for the catabolism of aromatic, organic, and one-carbon compounds, which help verify and extend its mixotrophic potential. A Nitrobacter "subcore" genome was also constructed by removing homologs found in strains of the closest evolutionary relatives, Bradyrhizobium japonicum and Rhodopseudomonas palustris. Among the Nitrobacter subcore inventory (116 genes), copies of genes or gene clusters for nitrite oxidoreductase (NXR), cytochromes associated with a dissimilatory nitrite reductase (NirK), PII-like regulators, and polysaccharide formation were identified. Many of the subcore genes have diverged significantly from, or have origins outside, the alphaproteobacterial lineage and may indicate some of the unique genetic requirements for nitrite oxidation in Nitrobacter.


Dimethylphosphinate bridged binuclear Rh(i) catalysts for the alkoxycarbonylation of aromatic C-H bonds.
A variety of binuclear rhodium(i) complexes featuring two bridging dimethylphosphinate ligands ((CH3)2PO2-) have been prepared and tested in the alkoxycarbonylation of aromatic C-H bonds. The complex [Rh(μ-κO,O'-(CH3)2PO2)(cod)]2 has been prepared by a reaction of [Rh(μ-MeO)(cod)]2 with 2 equivalents of dimethylphosphinic acid. Binuclear complexes [Rh(μ-κO,O'-(CH3)2PO2)(CO)L]2 (L = PPh3, P(OMe)Ph2 and P(OPh)3) were obtained by carbonylation of the related mononuclear complexes [Rh(κO-(CH3)2PO2)(cod)(L)], which were prepared in situ by the reaction of [Rh(μ-κO,O'-(CH3)2PO2)(cod)]2 with 2 equivalents of L. Conversely, if L = IPr, the reaction of [Rh(μ-κO,O'-(CH3)2PO2)(CO)L]2 with carbon monoxide affords the mononuclear complex [Rh(κO-(CH3)2PO2)(CO)2IPr]. The subsequent reaction with trimethylamine N-oxide gives the corresponding binuclear complex [Rh(μ-κO,O'-(CH3)2PO2)(CO)(IPr)]2 by abstraction of one of the carbonyl ligands. Complexes [Rh(μ-κO,O'-(CH3)2PO2)(cod)]2 and [Rh(κO-(CH3)2PO2)(cod)(L)] (L = IPr, PPh3, P(OMe)Ph2, P(OPh)3) are active precatalysts in the alkoxycarbonylation of C-H bonds, with the ligand system playing a key role in the catalytic activity. The complexes that feature more labile Rh-L bonds give rise to better catalysts, probably due to the more straightforward substitution of L by a second carbonyl ligand, since a more electrophilic carbonyl carbon atom is more susceptible toward aryl migration. In fact, complexes [Rh(μ-κO,O'-(CH3)2PO2)(CO)2]2 and [Rh(μ-Cl)(CO)2]2, generated in situ from [Rh(μ-κO,O'-(CH3)2PO2)(cod)]2 and [Rh(μ-Cl)(cod)2]2, respectively, are the most active catalysts tested in this work.


Caspase recruitment domain 15 mutations and rheumatic diseases.
The purpose of this article is to review the foundational work and current developments on a group of rheumatic disorders associated with mutations in the caspase recruitment domain 15/nucleotide oligomerization domain 2 gene. To date, there are at least 10 arthritic conditions for which specific genetic mutations have been demonstrated. They include familial Mediterranean fever; tumor necrosis factor receptor associated periodic syndrome; hyper immunoglobulin D syndrome; neonatal onset multisystemic inflammatory disease; pyogenic arthritis pyoderma gangrenosum and acne; Muckle-Wells syndrome; familial cold autoinflammatory syndrome; immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; Crohn's disease; and familial and sporadic sarcoid granulomatous arthritis. This review focuses on recent progress in the last two diseases and the caspase recruitment domain 15 genetic defects with which they are associated. Up to 50% of patients with familial granulomatous arthritis (Blau's syndrome), 90% of those with sporadic granulomatous arthritis (early-onset sarcoidosis), and 40% of individuals with Crohn's disease have documented mutations in the caspase recruitment domain 15 gene. Although histologically, Crohn's disease and familial and sporadic sarcoid granulomatous arthritis are distinct from rheumatoid arthritis because of the defining presence (albeit in not all cases) of non-caseating granulomata in the synovial and intestinal tissues, respectively, they still represent a promising model of both chronic synovitis and uveitis. In addition, once the actual mechanism is discovered by which defects of the caspase recruitment domain 15 gene product lead to chronic arthritis, it may uncover unsuspected biologic targets for therapeutics.


A statistical framework for testing modularity in multidimensional data.
Modular variation of multivariate traits results from modular distribution of effects of genetic and epigenetic interactions among those traits. However, statistical methods rarely detect truly modular patterns, possibly because the processes that generate intramodular associations may overlap spatially. Methodologically, this overlap may cause multiple patterns of modularity to be equally consistent with observed covariances. To deal with this indeterminacy, the present study outlines a framework for testing a priori hypotheses of modularity in which putative modules are mathematically represented as multidimensional subspaces embedded in the data. Model expectations are computed by subdividing the data into arrays of variables, and intermodular interactions are represented by overlapping arrays. Covariance structures are thus modeled as the outcome of complex and nonorthogonal intermodular interactions. This approach is demonstrated by analyzing mandibular modularity in nine rodent species. A total of 620 models are fit to each species, and the most strongly supported are heuristically modified to improve their fit. Five modules common to all species are identified, which approximately map to the developmental modules of the mandible. Within species, these modules are embedded within larger "super-modules," suggesting that these conserved modules act as building blocks from which covariation patterns are built.


The International Bathymetric Chart of the Arctic Ocean Version 4.0.
Bathymetry (seafloor depth), is a critical parameter providing the geospatial context for a multitude of marine scientific studies. Since 1997, the International Bathymetric Chart of the Arctic Ocean (IBCAO) has been the authoritative source of bathymetry for the Arctic Ocean. IBCAO has merged its efforts with the Nippon Foundation-GEBCO-Seabed 2030 Project, with the goal of mapping all of the oceans by 2030. Here we present the latest version (IBCAO Ver. 4.0), with more than twice the resolution (200 × 200 m versus 500 × 500 m) and with individual depth soundings constraining three times more area of the Arctic Ocean (∼19.8% versus 6.7%), than the previous IBCAO Ver. 3.0 released in 2012. Modern multibeam bathymetry comprises ∼14.3% in Ver. 4.0 compared to ∼5.4% in Ver. 3.0. Thus, the new IBCAO Ver. 4.0 has substantially more seafloor morphological information that offers new insights into a range of submarine features and processes; for example, the improved portrayal of Greenland fjords better serves predictive modelling of the fate of the Greenland Ice Sheet.


Molecular modeling and in vitro activity of an HIV-1-encoded glutathione peroxidase.
Based on theoretical evidence, it has been proposed that HIV-1 may encode several selenoprotein modules, one of which (overlapping the env gp41-coding region) has highly significant sequence similarity to the mammalian selenoprotein glutathione peroxidase (GPx; EC ). The similarity score of the putative HIV-1 viral GPx homolog relative to an aligned set of known GPx is 6.3 SD higher than expected for random sequences of similar composition. Based on that alignment, a molecular model of the HIV-1 GPx was constructed by homology modeling from the bovine GPx crystal structure. Despite extensive truncation relative to the cellular GPx gene, the structural core and the geometry of the catalytic triad of selenocysteine, glutamine, and tryptophan are well conserved in the viral GPx. All of the insertions and deletions predicted by the alignment proved to be structurally feasible. The model is energetically favorable, with a computed molecular mechanics strain energy close to that of the bovine GPx structure, when normalized on a per-residue basis. However, considering the remote homology, this model is intended only to provide a working hypothesis allowing for a similar active site and structural core. To validate the theoretical predictions, we cloned the hypothetical HIV-1 gene and found it to encode functional GPx activity when expressed as a selenoprotein in mammalian cells. In transfected canine kidney cells, the increase in GPx activity ranged from 21% to 43% relative to controls (average 30%, n = 9, P < 0.0001), whereas, in transfected MCF7 cells, which have low endogenous GPx activity, a near 100% increase was observed (average 99%, n = 3, P < 0.05).


Sex chromosomes and sexual selection in poeciliid fishes.
We propose that the evolution of female preferences can be strongly influenced by linkage of attractive male traits to the Y chromosome and female preferences to the X chromosome in male heterogametic species. Such linkage patterns are predicted by models of the evolution of sexually antagonistic genes. Subsequent recombination of attractive male characters from the Y to the X would create physical linkage between attractive male trait and preference. A literature survey shows that Y linkage of potentially sexually antagonistic traits is common in poeciliid fishes and other species with sex chromosomes that are not well differentiated, but may also occur in taxa with degenerate Y chromosomes. In the guppy, attractive male traits are primarily Y and X linked; a literature review of the inheritance of sex-limited attractive male characters suggests that 16 are Y linked, 24 recombine between the X and Y, two are X linked, and two are autosomal. Crosses and backcrosses between high female preference (Endler's live-bearers) and low female preference (Rio San Miguel) guppy populations show that this character has a strong additive genetic component and that it will be possible to investigate the physical linkage of male and female sexually selected characters in this species through mapping studies.


Stent thrombosis in early-generation drug-eluting stents versus newer-generation everolimus-eluting stent assorted by LVEF.
Everolimus drug-eluting stents (EES) are superior to early-generation drug-eluting stents (DES), releasing sirolimus (SES) or paclitaxel (PES) in preventing stent thrombosis (ST). Since an impaired LVEF seems to increase the risk of ST, we aimed to investigate the difference in outcome of patients with varying LVEF using EES versus early-generation DES. In a prospective cohort study, we compared the risk of ST in patients in three LVEF subgroups: normal (LVEF >50%), mildly impaired (LVEF >40% and ≤50%) and moderate-severely impaired (LVEF ≤40%). Within these various LVEF groups, we compared EES with SES and PES after adjustment for baseline differences. We assessed a cohort of 5363 patients, with follow-up of up to 4 years and available LVEF. Overall definite ST occurred in 123 (2.3%) patients. ST rates were higher in the LVEF moderate-severely impaired group compared with the normal LVEF group (2.8% vs 2.1%; HR 1.82; CI 1.10 to 3.00). Especially early ST (EST) was more frequent in the moderate-severely impaired LVEF group (HR 2.20; CI 1.06 to 4.53). Overall rates of definite ST were lower in patients using EES compared with patients using SES or PES in all LVEF groups. Interaction terms were not statistically significant. ST rates were higher in the moderate-severely impaired LVEF group compared with the normal LVEF group when using SES or PES, but not significantly different when using EES. EES was associated with a lower risk of definite ST compared with early-generation DES. This lower risk was independent of LVEF, even though ST rates were higher in patients with a moderate-severely impaired LVEF. MEC-2013-262.


The natural history of violence.
In the past, human violence was associated with food shortage, but recently it has increased even in relatively well-fed societies. The reason appears from studies of monkeys under relaxed, spacious conditions and under crowding stress. Uncrowded monkeys have unaggressive leaders, rarely quarrel, and protect females and young. Crowded monkeys (even well-fed) have brutal bosses, often quarrel, and wound and kill each other, including females and young. Crowding has similar behaviour effects on other mammals, with physiological disturbances including greater susceptibility to infections. All this appears to be a regular response to overpopulation, reducing the population before it has depleted its natural resources. Human beings, like monkeys and other mammals, need ample space, and become more violent when crowded. Human history is marked by population cycles: population outgrows resources, the resulting violence, stress and disease mortality cuts down the population, leading to a relief period of social and cultural progress, till renewed population growth produces the next crisis. The modern population crisis is world-wide, and explains the increase of violence even in well-fed societies. The solution to the problem of violence is to substitute voluntary birth control for involuntary death control, and bring about relaxed conditions for a reduced world population.


Disordered protein-graphene oxide co-assembly and supramolecular biofabrication of functional fluidic devices.
Supramolecular chemistry offers an exciting opportunity to assemble materials with molecular precision. However, there remains an unmet need to turn molecular self-assembly into functional materials and devices. Harnessing the inherent properties of both disordered proteins and graphene oxide (GO), we report a disordered protein-GO co-assembling system that through a diffusion-reaction process and disorder-to-order transitions generates hierarchically organized materials that exhibit high stability and access to non-equilibrium on demand. We use experimental approaches and molecular dynamics simulations to describe the underlying molecular mechanism of formation and establish key rules for its design and regulation. Through rapid prototyping techniques, we demonstrate the system's capacity to be controlled with spatio-temporal precision into well-defined capillary-like fluidic microstructures with a high level of biocompatibility and, importantly, the capacity to withstand flow. Our study presents an innovative approach to transform rational supramolecular design into functional engineering with potential widespread use in microfluidic systems and organ-on-a-chip platforms.


Scaling-laws of human broadcast communication enable distinction between human, corporate and robot Twitter users.
Human behaviour is highly individual by nature, yet statistical structures are emerging which seem to govern the actions of human beings collectively. Here we search for universal statistical laws dictating the timing of human actions in communication decisions. We focus on the distribution of the time interval between messages in human broadcast communication, as documented in Twitter, and study a collection of over 160,000 tweets for three user categories: personal (controlled by one person), managed (typically PR agency controlled) and bot-controlled (automated system). To test our hypothesis, we investigate whether it is possible to differentiate between user types based on tweet timing behaviour, independently of the content in messages. For this purpose, we developed a system to process a large amount of tweets for reality mining and implemented two simple probabilistic inference algorithms: 1. a naive Bayes classifier, which distinguishes between two and three account categories with classification performance of 84.6% and 75.8%, respectively and 2. a prediction algorithm to estimate the time of a user's next tweet with an R(2) ≈ 0.7. Our results show that we can reliably distinguish between the three user categories as well as predict the distribution of a user's inter-message time with reasonable accuracy. More importantly, we identify a characteristic power-law decrease in the tail of inter-message time distribution by human users which is different from that obtained for managed and automated accounts. This result is evidence of a universal law that permeates the timing of human decisions in broadcast communication and extends the findings of several previous studies of peer-to-peer communication.


T. cruzi: sensitization to macrophage killing by eosinophil peroxidase.
In this study, we report that trypomastigotes of T. cruzi coated with eosinophil peroxidase (EPO) become sensitized to killing by normal macrophages that are unable to kill uncoated organisms. EPO bound to the surface of the organisms without affecting their extracellular viability. The intracellular killing of EPO-coated trypomastigotes could be inhibited by catalase and azide, suggesting that toxicity was mediated through the small amounts of hydrogen peroxide generated by the phagocytic event in normal macrophages and the peroxidatic activity of EPO. EPO-coated organisms could be killed in a cellfree system by the addition of H2O2 and either iodide, bromide, or chloride. Omission of H2O2 decreased but did not prevent the killing of trypanosomes by the cellfree system and this residual toxicity was abolished by catalase. This suggests that H2O2 generated by trypanosomes contributes to the death of EPO-coated organisms. EPO-coated organisms could also be killed extracellularly when exposed to normal macrophages at high parasite to cell ratios or when a high phagocytic load of another particle was given simultaneously. This effect could be inhibited by both azide and catalase, but not by superoxide dismutase. This suggests that enough H202 is released by phagocytosis of a high number of organisms to generate toxic concentrations of H2O2 outside the confines of the vacuolar system.


Pancreatic neuroendocrine tumors.
Pancreatic neuroendocrine neoplasms (pNENs) are a heterogeneous group of tumors including well differentiated pancreatic neuroendocrine tumors (pNETs) and neuroendocrine carcinomas (pNECs). The incidence of pNENs has increased over the past few decades. Although, the understanding and interest for this tumor have also increased significantly, the debate about classification and diagnosis continues. Although the primary treatment for pNENs is surgical resection, there is still a lack of effective therapeutic options for patients with advanced unresectable pNENs. Although many therapeutic methods have proven effective, the choice of treatment and specific programs are still unclear. Our article presents an overview of pNENs, with a focus on their diagnostic work-up, clinical presentation and treatment options.


Antiangiogenic therapies in non-small-cell lung cancer.
Angiogenesis is frequent in non-small-cell lung cancer (nsclc) and is associated with more aggressive disease. Many clinical trials have evaluated the addition of antiangiogenic therapy to standard therapies for patients with nsclc. Bevacizumab, a monoclonal antibody directed against serum vascular endothelial growth factor, in combination with carboplatin-paclitaxel chemotherapy, has been shown to improve survival for patients with nsclc. However, bevacizumab-based therapy is not suitable for many nsclc patients, including those with squamous histology, poor performance status, brain metastases, and the presence of bleeding or thrombotic disorders. Similar efficacy has also been seen with carboplatin-pemetrexed followed by maintenance pemetrexed chemotherapy. In the second-line setting, the addition of ramucirumab to docetaxel-or the addition of bevacizumab to paclitaxel-has resulted in a modest improvement in efficacy, although the clinical importance of those findings is questionable. Many trials in nsclc have also evaluated oral antiangiogenic compounds, both in the first line in combination with chemotherapy and upon disease progression either as combination or single-agent therapy. No clear improvements in overall survival have been observed, although a subgroup analysis of a trial evaluating the addition of nintedanib to docetaxel showed improved survival that was limited to patients with adenocarcinoma. Those findings require validation, however. All of the oral antiangiogenic agents result in added toxicities. Some agents have resulted in an increased risk of death, limiting their development. Available evidence supports a limited number of antiangiogenic therapies for patients with nsclc, but no biomarkers to help in patient selection are currently available, and additional translational research is needed to identify predictive biomarkers for antiangiogenic therapy.


The central role of the chemokine receptor, CXCR4, in haemopoietic stem cell transplantation: will CXCR4 antagonists contribute to the treatment of blood disorders?
Recent clinical trials have used CXCR4 antagonists for the rapid mobilization of CD34(+) haemopoietic stem/progenitor cells (HSC/HPC) from the bone marrow to the blood in patients refractory to granulocyte-colony-stimulating factor (G-CSF). These antagonists not only mobilize non-cycling cells with a higher proportion of repopulating cells, but also enhance CD34(+) cell mobilization when used in combination with G-CSF. Here, we review the importance of CXCR4 and its ligand CXCL12 in haemopoiesis, and the potential roles of CXCR4 antagonists in the clinical HSC transplant setting.


Assessment of a numerical model to reproduce event-scale erosion and deposition distributions in a braided river.
Numerical morphological modeling of braided rivers, using a physics-based approach, is increasingly used as a technique to explore controls on river pattern and, from an applied perspective, to simulate the impact of channel modifications. This paper assesses a depth-averaged nonuniform sediment model (Delft3D) to predict the morphodynamics of a 2.5 km long reach of the braided Rees River, New Zealand, during a single high-flow event. Evaluation of model performance primarily focused upon using high-resolution Digital Elevation Models (DEMs) of Difference, derived from a fusion of terrestrial laser scanning and optical empirical bathymetric mapping, to compare observed and predicted patterns of erosion and deposition and reach-scale sediment budgets. For the calibrated model, this was supplemented with planform metrics (e.g., braiding intensity). Extensive sensitivity analysis of model functions and parameters was executed, including consideration of numerical scheme for bed load component calculations, hydraulics, bed composition, bed load transport and bed slope effects, bank erosion, and frequency of calculations. Total predicted volumes of erosion and deposition corresponded well to those observed. The difference between predicted and observed volumes of erosion was less than the factor of two that characterizes the accuracy of the Gaeuman et al. bed load transport formula. Grain size distributions were best represented using two φ intervals. For unsteady flows, results were sensitive to the morphological time scale factor. The approach of comparing observed and predicted morphological sediment budgets shows the value of using natural experiment data sets for model testing. Sensitivity results are transferable to guide Delft3D applications to other rivers.


Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance.
The antimicrotubular agent docetaxel is a widely used chemotherapeutic drug for the treatment of multiple solid tumors and is predominantly dependent on hepatic disposition. In this study, we evaluated drug uptake transporters capable of transporting radiolabeled docetaxel. By screening an array of drug uptake transporters in HeLa cells using a recombinant vaccinia-based method, five organic anion-transporting polypeptides (OATP) capable of docetaxel uptake were identified: OATP1A2, OATP1B1, OATP1B3, OATP1C1, and Oatp1b2. Kinetic analysis of docetaxel transport revealed similar kinetic parameters among hepatic OATP1B/1b transporters. An assessment of polymorphisms (SNPs) in SLCO1B1 and SLCO1B3 revealed that a number of OATP1B1 and OATP1B3 variants were associated with impaired docetaxel transport. A Transwell-based vectorial transport assay using MDCKII stable cells showed that docetaxel was transported significantly into the apical compartment of double-transfected (MDCKII-OATP1B1/MDR1 and MDCKII-OATP1B3/MDR1) cells compared with single-transfected (MDCKII-OATP1B1 and MDCKII-OATP1B3) cells (P < 0.05) or control (MDCKII-Co) cells (P < 0.001). In vivo docetaxel transport studies in Slco1b2(-/-) mice showed approximately >5.5-fold higher plasma concentrations (P < 0.01) and approximately 3-fold decreased liver-to-plasma ratio (P < 0.05) of docetaxel compared with wild-type (WT) mice. The plasma clearance of docetaxel in Slco1b2(-/-) mice was 83% lower than WT mice (P < 0.05). In conclusion, this study demonstrates the important roles of OATP1B transporters to the hepatic disposition and clearance of docetaxel, and supporting roles of these transporters for docetaxel pharmacokinetics.


Spatial distribution of DARPP-32 in dendritic spines.
The phosphoprotein DARPP-32 (dopamine and cyclic adenosine 3´, 5´-monophosphate-regulated phosphoprotein, 32 kDa) is an important component in the molecular regulation of postsynaptic signaling in neostriatum. Despite the importance of this phosphoprotein, there is as yet little known about the nanoscale distribution of DARPP-32. In this study we applied superresolution stimulated emission depletion microscopy (STED) to assess the expression and distribution of DARPP-32 in striatal neurons. Primary culture of striatal neurons were immunofluorescently labeled for DARPP-32 with Alexa-594 and for the dopamine D1 receptor (D1R) with atto-647N. Dual-color STED microscopy revealed discrete localizations of DARPP-32 and D1R in the spine structure, with clustered distributions in both head and neck. Dissected spine structures reveal that the DARPP-32 signal rarely overlapped with the D1R signal. The D1R receptor is positioned in an "aggregated" manner primarily in the spine head and to some extent in the neck, while DARPP-32 forms several neighboring small nanoclusters spanning the whole spine structure. The DARPP-32 clusters have a mean size of 52 +/- 6 nm, which is close to the resolution limit of the microscope and corresponds to the physical size of a few individual phosphoprotein immunocomplexes. Dissection of synaptic proteins using superresolution microscopy gives possibilities to reveal in better detail biologically relevant information, as compared to diffraction-limited microscopy. In this work, the dissected postsynaptic topology of the DARPP-32 phosphoprotein provides strong evidence for a compartmentalized and confined distribution in dendritic spines. The protein topology and the relatively low copy number of phosphoprotein provides a conception of DARPP-32's possibilities to fine-tune the regulation of synaptic signaling, which should have an impact on the performance of the neuronal circuits in which it is expressed.


Indirect nanoplasmonic sensing: ultrasensitive experimental platform for nanomaterials science and optical nanocalorimetry.
Indirect nanoplasmonic sensing is a novel experimental platform for measurements of thermodynamics and kinetics in/on nanomaterials and thin films. It features simple experimental setup, high sensitivity, small sample amounts, high temporal resolution (<10(-3) s), operating conditions from UHV to high pressure, wide temperature range, and applicability to any nano- or thin film material. The method utilizes two-dimensional arrangements of nanoplasmonic Au sensor-nanoparticles coated with a thin dielectric spacer layer onto which the sample material is deposited. The measured signal is spectral shifts of the Au-sensor localized plasmons, induced by processes in/on the sample material. Here, the method is applied to three systems exhibiting nanosize effects, (i) the glass transition of confined polymers, (ii) catalytic light-off on Pd nanocatalysts, and (iii) thermodynamics and kinetics of hydrogen uptake/release in Pd nanoparticles <5 nm. In (i) and (iii), dielectric changes in the sample are detected, while (ii) demonstrates a novel optical nanocalorimetry method.


Infanticide and reproductive restraint in a polygynous social mammal.
Alpha male chacma baboons experience uncontested access to individual estrus females. Consequently, alpha male paternity certainty is high and underpins significant levels of infanticide by immigrant males that, in turn, has selected for male defense of infants. There is also, however, a high probability that alpha males will be absent during the period when their own offspring are vulnerable, suggesting selection for additional countermeasures. We use data from a long-term study to test the prediction that alpha male chacma baboons cede reproductive opportunities to subordinate males and that this leads to the presence of other fathers that can serve as a buffer against infanticidal attack. We found that subordinate males obtained significantly more conceptive opportunities than predicted by priority of access alone, and that this occurred because alpha males did not consort all receptive periods. There was no evidence that this was due to energetic constraint, large male cohorts, alpha male inexperience, or the competitive strength of queuing subordinates. The number of males who benefited from concession and the length of time that they were resident relative to those who did not benefit in this way greatly reduced the probability that infants of alpha males would face immigrant males without a surrogate father whose own offspring were vulnerable. The absence of such males was associated with observed infanticide as well as, unexpectedly, an increased likelihood of takeover when alpha males with vulnerable infants were present.


Population vulnerabilities and capacities related to health: a test of a model.
Variability in the health of human populations is greater in economically vulnerable areas. We tested whether this variability reflects and can be explained by: (1) underlying vulnerabilities and capacities of populations and/or (2) differences in the distribution of individual socioeconomic status between populations. Health outcomes were rates of mortality from 12 causes (cardiovascular disease, malignant neoplasms, accidents, chronic lower respiratory disease, cerebrovascular disease, pneumonia and influenza, diseases of the nervous system, suicide, chronic liver disease and cirrhosis, diabetes, homicide, HIV/AIDS) for 59 New York City neighborhoods in 2000. Negative binomial regression models were fit with a measure of socioeconomic vulnerability, median income, predicting each mortality rate. Overdispersion of each model was used to assess whether variability in mortality rates increased with increasing neighborhood socioeconomic vulnerability. To assess the two hypotheses, we examined changes in the variability of mortality rates (as indicated by changes in overdispersion of the models) for outcomes with significant non-constant variability after accounting for (1) vulnerabilities and capacities (social control, quality of local schools, unemployment, low education), and (2) the distribution of individual socioeconomic status (low income, poverty, socioeconomic distribution, high income). Some variability in all mortality rates was explained by accounting for a range of potential vulnerabilities and capacities, supporting the first explanation. However, variability in some causes of mortality was also explained in part by accounting for the distribution of individual resources, supporting the second explanation. The results are consistent with a theory of underlying socioeconomic vulnerabilities of human populations. In areas with lower levels of income, other characteristics of those neighborhoods exacerbate or temper the economic vulnerability, leading to more or less healthy conditions. Understanding the vulnerabilities and capacities that characterize populations may help us better understand the production of population health, and may inform efforts aimed at improving population health.


Evaluation of technician supervised treadmill exercise testing in a cardiac chest pain clinic.
To determine the efficacy and safety of trained cardiac technicians independently performing treadmill exercise stress tests as part of the assessment of patients with suspected angina pectoris. Retrospective comparison of 250 exercise tests performed by cardiac technicians and 225 tests performed by experienced cardiology clinical assistants (general practitioners who perform regular NHS cardiology duties), and consultant cardiologists over the same time period. Regional cardiac centre with a dedicated cardiac chest pain clinic. All patients were referred by their general practitioners with a history of recent onset of chest pain, which was suspected to be angina pectoris. Peak workload achieved, symptoms, indications for termination, complications. The diagnostic yield of technician supervised tests (percentage positive or negative) was similar to that of medically supervised tests (76% v 69%, NS). The average peak workload achieved by patients was less by 1.2 mets (p < 0.005). This was probably due to more tests being terminated earlier due to chest pain and ST segment depression in the technician group compared with doctors (10% and 16% v 5% and 11% respectively, p = 0.06 and 0.07). One patient in the technician supervised group developed a supraventricular tachycardia during the recovery phase of the exercise test. Technician supervised stress testing is associated with a high diagnostic rate and low complication rate in patients with suspected ischaemic heart disease. Its efficacy is comparable to tests supervised by experienced doctors and its use should be encouraged.


Computer-based surgical planning and custom-made titanium implants for cranial fibrous dysplasia.
The procedure of reconstruction after the removal of cranial fibrous dysplasia (FD) must be precise to achieve good functional and aesthetic results. Intraoperative modeling of implants is difficult and may cause cosmetic disturbances. To present our experience with the treatment of cranial FD using preoperative computer-based surgical planning of tumor removal with reconstruction of the cranium with custom-made titanium implants. Four patients underwent surgical treatment for cranial FD over a 2-year period. All patients were male with a mean age of 25.25 years and had monostotic-type FD. Computed tomography (CT) with 0.5-mm slices was obtained preoperatively. Computer-based planning of the tumor removal was performed, and a template was created by the computer to determine the margins of tumor removal. After this procedure, the preoperative computer-based construction of the titanium implant was performed. The patients underwent surgical treatment, and the tumor was removed with the use of this template. Then, the titanium implant was inserted onto the bone defect and fixed with mini-screws. Patients were followed up by periodic CT scans. The histological diagnosis of all patients was FD. No intraoperative or postoperative complications have occurred. Postoperative CT scans showed complete tumor removal and confirmed appropriate cosmetic reconstruction. The mean follow-up period was 15.25 months. Computer-based surgical planning associated with the production of custom-made titanium implants is a highly promising method for the treatment of cranial FD. Better radiological and cosmetic outcomes could be obtained by this technique with interdisciplinary work with medical designers.


Fluorescence kinetics of aqueous solutions of tetracycline and its complexes with Mg2+ and Ca2+.
The fluorescence spectra of acidified aqueous solutions of tetracycline (tcH3+) exhibit three components with slightly different degrees of anisotropy: the 'blue' component (lambdad approximately equal to 475 nm) decays on the timescale of a few picoseconds; the second, most intense component (lambdad approximately equal to 530 nm) shows decay times of about 25 (H3O+) and 70 ps (D3O+); the third component (lambdad approximately equal to 650 nm) is longer lived (tau approximately equal to 200 ps). All three fluorescence components appear quasi-instantaneously, thus providing evidence that the relaxation processes which give rise to the unusually large Stokes shifts occur on a (sub-)picosecond timescale. The effect of H/D exchange suggests that these relaxation processes involve excited-state intramolecular proton transfer (ESIPT) of OH10 and/or OH12, but does not exclude a change in the hydrogen-bonding pattern to the solvent molecules. The low overall fluorescence yield of the fully protonated form must be correlated to the presence of a very fast decaying species. In alkaline aqueous solution, the fluorescence of the dianion (tc2-) essentially comprises two components; the decay time of the stronger, shorter-lived component is about 30 ps, that of the weaker, longer-lived one about 160 ps. The relative amplitude of the latter is larger at pH 11 than at pH 8.5, in accordance with the increase in the steady-state fluorescence intensity upon increasing the pH from 8.5 to 11. Complexation of the dianion with divalent metal ions like Mg2+ or Ca2+ leads to a strong enhancement of the steady-state fluorescence. In the time-resolved spectra, the decay time of the major fluorescence component exhibits approximately a five-fold increase in comparison to the major component of the dianion. It is about 150 ps in both types of complexes. The decay times of the minor component are increased to about 500 (Mg2+) and 320 ps (Ca2+). The absence of the ultra-fast component in the fluorescence of the dianion and its metal complexes provides evidence that a reaction of OH 12 must be responsible for the ultra-fast fluorescence component in tcH3+. The existence of a component with a lifetime of several tens of picoseconds in all samples suggests the involvement of hydrogen bonding at OH10 during the formation of the emitting species. DFT calculations for the isolated molecule provide evidence that ESIPT is indeed an energetically allowed relaxation process for those isomers that have only one intramolecular hydrogen bond to O11. The ESIPT process yields primary photoproducts that should emit at much longer wavelengths, thereby explaining the unusually large fluorescence Stokes shift.


Multicenter comparative study of a new ELISA, PLATELIA RABIES II, for the detection and titration of anti-rabies glycoprotein antibodies and comparison with the rapid fluorescent focus inhibition test (RFFIT) on human samples from vaccinated and non-vaccinated people.
The envelope glycoprotein G of rabies virus induces the production of neutralising antibodies, which are important in protection against rabies. Therefore, titration of anti-envelope glycoprotein antibodies is a good indicator of the degree of immunity in people during anti-rabies treatment or after vaccination. According to the World Health Organization (WHO) guidelines, a booster vaccine dose should be given if the rabies antibody titre falls below 0.5 IU/ml. Titration of anti-rabies antibodies is also useful for plasma centers in the preparation and standardization of human anti-rabies gamma-globulins for therapeutic use and to a lesser extent for the diagnosis of rabies in human sera and cerebrospinal fluid (CSF). This paper presents a new enzyme-linked immunosorbent assay (ELISA), PLATELIA RABIES II, developed for rabies envelope glycoprotein antibody detection or titration and its comparison to the current reference method (RFFIT). The data collected during validation of the test in a multicenter study are analysed to give a sound overall knowledge of the capabilities of the PLATELIA RABIES II, for instance specificity, linearity, accuracy, precision, detection limit and quantitation limit. To this aim, human serum samples from a total of 1348 vaccinated or non-vaccinated people were tested in parallel using the new ELISA and the RFFIT for the presence of anti-rabies antibodies. Data generated indicate a linear relationship across the range of titration between the two methods. The sensitivity reaches 98.6% and the specificity 99.4%. This study indicates that this new ELISA test is as sensitive and specific as the current standardized reference method. The method is simple, safe, rapid and can be considered as a useful alternative to the neutralisation test.


Dietary variety predicts low body mass index and inadequate macronutrient and micronutrient intakes in community-dwelling older adults.
Low body mass index (BMI) and micronutrient deficiencies are associated with increased morbidity and mortality rates in old age. Whether adverse patterns of dietary variety predict both low BMI and low micronutrient intakes in older adults was investigated. A cross-sectional analysis of national survey data was conducted in 1174 healthy adult men and women (ages 21 to 90 years) who provided physiologically plausible dietary data in the 1994-1996 Continuing Survey of Food Intakes by Individuals. Measurements included reported energy intake, protein intake (percentage meeting Recommended Dietary Allowance), micronutrient intakes (percentage meeting Estimated Average Requirements for 14 micronutrients), and BMI. Adults who were 61 years or older consumed a greater total variety of foods, chose foods from a wider range of food groups, had a greater variety of micronutrient-dense foods and energy-weak foods, and had a lower variety of micronutrient-weak foods compared with adults ages 21 to 60 years (p < .05 to.001). However, older adults with low BMIs (< 22 kg/m2) consumed a lower variety of energy-dense foods compared with older adults with higher BMIs (p < .05). The variety of energy-dense foods predicted both energy intake and BMI at all ages in multiple regression models controlling for confounding variables (R2 = .124 for energy, R2 = .574 for BMI, p < .001). A higher percentage of older persons had inadequate micronutrient intakes compared with younger persons (p < .05), especially vitamin E, calcium, and magnesium, but consumption of a particularly wide variety of micronutrient-rich foods helped counterbalance these trends (p < .05). Older adults who had a low BMI and consumed a low variety of micronutrient-dense foods were particularly at nutritional risk, with only 65.4% consuming the Recommended Dietary Allowance for protein and none meeting the Estimated Average Requirements for all 14 micronutrients. In contrast to previous suggestions that older persons consume a monotonous diet, this study showed that adults who were 61 years or older consumed a greater total food variety, and a greater variety of micronutrient-dense and energy-weak foods, compared with adults who were 60 years or younger. Although consumption of a low variety of energy-dense foods may contribute to reduced energy intake and body weight at any age, the variety of micronutrient-dense foods consumed needs to increase in old age to prevent micronutrient deficiencies. These findings suggest that all adults need advice on the changing needs for dietary variety with aging to maintain health, and that older persons with low BMI are particularly vulnerable to dietary shortfalls.


Child sexual abuse and links to HIV and orphanhood in urban Zimbabwe.
Evidence of a link between sexual violence and HIV is growing; however, studies among children are scarce. The authors sought to characterise child sexual abuse in Harare, Zimbabwe, and explore its links with HIV and orphanhood. Records for new clients attending a child sexual abuse clinic from July 2004 to June 2005 were computerised and reviewed. Information on characteristics, medical examinations, laboratory tests and perpetrators were summarised. Orphan prevalence was compared with Demographic and Health Survey (DHS) 2005/2006 data for Harare, and a household-based survey in a neighbouring community. Over 1 year, 1194 new clients (90% female) aged 7 weeks to 16 years were assessed, with 93% of boys and 59% of girls classified clinically as prepubertal. 94% of clients reported penetrative sexual abuse, occurring most often in the child's home. Most perpetrators were identified as relatives or neighbours by children under 12 years, and 'boyfriends' by adolescent girls. At presentation, 31/520 (6%) clients tested were HIV-positive. Where recorded, 39 (6%) clients presented within 3 days of abuse, and 36 were given postexposure prophylaxis for HIV (PEP). Among female clients, orphan prevalence was higher than in the DHS (OR=1.7; 1.4 to 2.2) and neighbouring community (OR=1.7; 0.7 to 4.3). High numbers of children in Harare experience penetrative sexual abuse, and most present too late for PEP. More immediate presentation of sexual abuse can help to prevent HIV and recurrent abuse, and assist in examination and prosecution. Orphanhood emerged as a possible risk factor for sexual abuse and an important area for further research.


Contextual barriers to implementation in primary care: an ethnographic study of a programme to improve chronic kidney disease care.
Context is important in implementation-we know that what works in one setting may not work in the same way elsewhere. Primary care has been described as a unique context both in relation to the care delivered and efforts to carry out research and implementation of new evidence. To explore some of the distinctive features of the primary care environment that may influence implementation. We conducted an ethnographic study involving observations, interviews and documentary analysis of the ENABLE-CKD project, which involved general practices implementing a chronic kidney disease care bundle and offering self-management support tools to patients. Analysis was based on the constant comparative method. Four elements of the primary care environment emerged as important influences on the extent to which implementation was successful. First, the nature of delivering care in this setting meant that prioritizing one condition over others was problematic. Second, the lack of alignment with financial and other incentives affected engagement. Third, the project team lacked mechanisms through which engagement could be mandated. Fourth, working relationships within practices impacted on engagement. Those seeking to implement interventions in primary care need to consider the particular context if they are to secure successful implementation. We suggest that there are particular kinds of interventions, which may be best suited to the primary care context.


Radiofrequency ablation of paroxysmal atrial fibrillation: factors determining long-term clinical efficacy.
Most of the studies on this subject have reported predictors of recurrence of atrial fibrillation after catheter ablation with relatively short follow-up periods. To retrospectively evaluate predictors of long-term recurrence of paroxysmal atrial fibrillation (AF) in patients undergoing pulmonary vein isolation following one single procedure. The authors studied a total of 139 patients (102 men; mean age of 55 +/- 12 years) undergoing radiofrequency ablation using the ostial or extra-ostial techniques for left atrial approach, combined or not with cavotricuspid isthmus ablation (CTI). Pre, intra and post-ablation variables were evaluated using univariate and multivariate analyses to determine the predictors of recurrence of AF after one procedure. After a 33 +/- 12-month follow-up, we observed that a longer time of history of AF, use of more antiarrhythmic drugs, and recurrence of AF within 60 days post-procedure increased the risk of long-term recurrence of AF. On the other hand, the association of atrial flutter and concomitant CTI ablation reduced the risk of recurrence of AF. Clinical variables such as time of history of AF and a larger number of antiarrhythmic drugs already used influenced the outcomes of catheter ablation. In patients with associated atrial flutter, simultaneous CTI block significantly reduced the long-term recurrence of atrial fibrillation.


Mapping the polymorphic transformation gateway vibration in crystalline 1,2,4,5-tetrabromobenzene.
The thermosalient behavior of 1,2,4,5-tetrabromobenzene (TBB) is related to a temperature-induced polymorphic structural change. The mechanism behind the phase transition has been investigated in this work using low-frequency (10-250 cm-1) Raman spectroscopy and solid-state density functional theory simulations. Careful adjustments of the probing laser power permitted thermal control of the polymorph populations and enabled high-quality Raman vibrational spectra to be obtained for both the β (low temperature) and γ (high temperature) forms of TBB. Numerous well-defined vibrational features appear in the Raman spectra of both polymorphs which could be assigned to specific motions of the solid-state TBB molecules. It was discovered that the lowest-frequency vibration at 15.5 cm-1 in β-TBB at 291 K is a rotational mode that functions as a gateway for inducing the polymorphic phase transition to γ-TBB, and serves as the initiating step in the storage of mechanical strain for subsequent macroscopic release. Computationally mapping the potential energy surface along this vibrational coordinate reveals that the two TBB polymorphs are separated by a 2.40 kJ mol-1 barrier and that γ-TBB exhibits an enhanced cohesion energy that stabilizes its structure.


Multispecies Trapped-Ion Node for Quantum Networking.
Trapped atomic ions are a leading platform for quantum information networks, with long-lived identical qubit memories that can be locally entangled through their Coulomb interaction and remotely entangled through photonic channels. However, performing both local and remote operations in a single node of a quantum network requires extreme isolation between spectator qubit memories and qubits associated with the photonic interface. We achieve this isolation by cotrapping ^{171}Yb^{+} and ^{138}Ba^{+} qubits. We further demonstrate the ingredients of a scalable ion trap network node with two distinct experiments that consist of entangling the mixed species qubit pair through their collective motion and entangling a ^{138}Ba^{+} qubit with an emitted visible photon.


Across Multiple Species, Phytochemical Diversity and Herbivore Diet Breadth Have Cascading Effects on Herbivore Immunity and Parasitism in a Tropical Model System.
Terrestrial tri-trophic interactions account for a large part of biodiversity, with approximately 75% represented in plant-insect-parasitoid interactions. Herbivore diet breadth is an important factor mediating these tri-trophic interactions, as specialisation can influence how herbivore fitness is affected by plant traits. We investigated how phytochemistry, herbivore immunity, and herbivore diet breadth mediate plant-caterpillar-parasitoid interactions on the tropical plant genus Piper (Piperaceae) at La Selva Biological station in Costa Rica and at Yanayacu Biological Station in Ecuador. We collected larval stages of one Piper generalist species, Quadrus cerealis, (Lepidoptera: Hesperiidae) and 4 specialist species in the genus Eois (Lepidoptera: Geometridae) from 15 different species of Piper, reared them on host leaf material, and assayed phenoloxidase activity as a measure of potential larval immunity. We combined these data with parasitism and caterpillar species diet breadth calculated from a 19-year database, as well as established values of phytochemical diversity calculated for each plant species, in order to test specific hypotheses about how these variables are related. We found that phytochemical diversity was an important predictor for herbivore immunity, herbivore parasitism, and diet breadth for specialist caterpillars, but that the direction and magnitude of these relationships differed between sites. In Costa Rica, specialist herbivore immune function was negatively associated with the phytochemical diversity of the Piper host plants, and rates of parasitism decreased with higher immune function. The same was true for Ecuador with the exception that there was a positive association between immune function and phytochemical diversity. Furthermore, phytochemical diversity did not affect herbivore immunity and parasitism for the more generalised herbivore. Results also indicated that small differences in herbivore diet breadth are an important factor mediating herbivore immunity and parasitism success for Eois at both sites. These patterns contribute to a growing body of literature that demonstrate strong cascading effects of phytochemistry on higher trophic levels that are dependent on herbivore specialisation and that can vary in space and time. Investigating the interface between herbivore immunity, plant chemical defence, and parasitoids is an important facet of tri-trophic interactions that can help to explain the enormous amount of biodiversity found in the tropics.


Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection.
Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 in Saudi Arabia and has caused over 2400 cases and more than 800 deaths. Epidemiological studies identified diabetes as the primary comorbidity associated with severe or lethal MERS-CoV infection. Understanding how diabetes affects MERS is important because of the global burden of diabetes and pandemic potential of MERS-CoV. We used a model in which mice were made susceptible to MERS-CoV by expressing human DPP4, and type 2 diabetes was induced by administering a high-fat diet. Upon infection with MERS-CoV, diabetic mice had a prolonged phase of severe disease and delayed recovery that was independent of virus titers. Histological analysis revealed that diabetic mice had delayed inflammation, which was then prolonged through 21 days after infection. Diabetic mice had fewer inflammatory monocyte/macrophages and CD4+ T cells, which correlated with lower levels of Ccl2 and Cxcl10 expression. Diabetic mice also had lower levels of Tnfa, Il6, Il12b, and Arg1 expression and higher levels of Il17a expression. These data suggest that the increased disease severity observed in individuals with MERS and comorbid type 2 diabetes is likely due to a dysregulated immune response, which results in more severe and prolonged lung pathology.


Sociodemographic Characteristics, Financial Worries and Serious Psychological Distress in U.S. Adults.
Economic recessions have been well studied in relationship to poor mental health. However, subjective financial worries have not been examined relative to serious psychological distress (SPD), a measure of poor mental health. Adults 18 to 64 years in the cross-sectional 2016 National Health Interview Survey (n = 24,126) were examined for worries about paying for bills, serious medical events, expected medical costs, retirement, children's college tuition and maintaining a standard of living; by sociodemographic such as sex and race/ethnicity. Over 50% of adults reported two or more financial worries. In multivariate models, financial worries were associated with SPD. White adults at the lowest education level had the greatest proportion with SPD compared with all other race/ethnic groups. Women had greater risk for SPD and for each financial worry compared with men. Financial worries were prevalent in U.S. adults, were associated with increased risk for SPD, and varied by sex.


Research data management in academic institutions: A scoping review.
The purpose of this study is to describe the volume, topics, and methodological nature of the existing research literature on research data management in academic institutions. We conducted a scoping review by searching forty literature databases encompassing a broad range of disciplines from inception to April 2016. We included all study types and data extracted on study design, discipline, data collection tools, and phase of the research data lifecycle. We included 301 articles plus 10 companion reports after screening 13,002 titles and abstracts and 654 full-text articles. Most articles (85%) were published from 2010 onwards and conducted within the sciences (86%). More than three-quarters of the articles (78%) reported methods that included interviews, cross-sectional, or case studies. Most articles (68%) included the Giving Access to Data phase of the UK Data Archive Research Data Lifecycle that examines activities such as sharing data. When studies were grouped into five dominant groupings (Stakeholder, Data, Library, Tool/Device, and Publication), data quality emerged as an integral element. Most studies relied on self-reports (interviews, surveys) or accounts from an observer (case studies) and we found few studies that collected empirical evidence on activities amongst data producers, particularly those examining the impact of research data management interventions. As well, fewer studies examined research data management at the early phases of research projects. The quality of all research outputs needs attention, from the application of best practices in research data management studies, to data producers depositing data in repositories for long-term use.


Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities.
Primary familial brain calcification (PFBC, OMIM#213600), also known as Fahr's disease, is a rare autosomal dominant or recessive neurodegenerative disorder characterized by bilateral and symmetrical microvascular calcifications affecting multiple brain regions, particularly the basal ganglia (globus pallidus, caudate nucleus, and putamen) and thalamus. The most common clinical manifestations include cognitive impairment, neuropsychiatric signs, and movement disorders. Loss-of-function mutations in SLC20A2 are the major genetic causes of PFBC. This study aimed to investigate whether Slc20a2 knockout mice could recapitulate the dynamic processes and patterns of brain calcification and neurological symptoms in patients with PFBC. We comprehensively evaluated brain calcifications and PFBC-related behavioral abnormalities in Slc20a2-deficient mice. Brain calcifications were analyzed using classic calcium-phosphate staining methods. The Morris water maze, Y-maze, and fear conditioning paradigms were used to evaluate long-term spatial learning memory, working memory, and episodic memory, respectively. Sensorimotor gating was mainly assessed using the prepulse inhibition of the startle reflex program. Spontaneous locomotor activity and motor coordination abilities were evaluated using the spontaneous activity chamber, cylinder test, accelerating rotor-rod, and narrowing balance beam tests. Slc20a2 homozygous knockout (Slc20a2-HO) mice showed congenital and global developmental delay, lean body mass, skeletal malformation, and a high proportion of unilateral or bilateral eye defects. Brain calcifications were detected in the hypothalamus, ventral thalamus, and midbrain early at postnatal day 80 in Slc20a2-HO mice, but were seldom found in Slc20a2 heterozygous knockout (Slc20a2-HE) mice, even at extremely old age. Slc20a2-HO mice exhibited spatial learning memory impairments and sensorimotor gating deficits while exhibiting normal working and episodic memories. The general locomotor activity, motor balance, and coordination abilities were not statistically different between Slc20a2-HO and wild-type mice after adjusting for body weight, which was a major confounding factor in our motor function evaluations. The human PFBC-related phenotypes were highly similar to those in Slc20a2-HO mice. Therefore, Slc20a2-HO mice might be suitable for the future evaluation of neuropharmacological intervention strategies targeting cognitive and neuropsychiatric impairments.


Rescuing defective vesicular trafficking protects against alpha-synuclein toxicity in cellular and animal models of Parkinson's disease.
Studies in yeast are providing critical insights into the mechanisms of neurodegeneration in Parkinson's disease (PD). A recent study shows that disruption of vesicular trafficking between the endoplasmic reticulum (ER) and the Golgi, caused by the overexpression and/or aggregation of alpha-synuclein, is linked to degeneration of dopamine neurons. Overexpression of proteins that are known to enhance ER-to-Golgi transport rescue defective trafficking in yeast, worm, fly, and cellular models of PD.


Diverse environmental stresses elicit distinct responses at the level of pre-mRNA processing in yeast.
Gene expression in eukaryotic cells is profoundly influenced by the post-transcriptional processing of mRNAs, including the splicing of introns in the nucleus and both nuclear and cytoplasmic degradation pathways. These processes have the potential to affect both the steady-state levels and the kinetics of changes to levels of intron-containing transcripts. Here we report the use of a splicing isoform-specific microarray platform to investigate the effects of diverse stress conditions on pre-mRNA processing. Interestingly, we find that diverse stresses cause distinct patterns of changes at this level. The responses we observed are most dramatic for the RPGs and can be categorized into three major classes. The first is characterized by accumulation of RPG pre-mRNA and is seen in multiple types of amino acid starvation regimes; the magnitude of splicing inhibition correlates with the severity of the stress. The second class is characterized by a rapid decrease in both pre- and mature RPG mRNA and is seen in many stresses that inactivate the TORC1 kinase complex. These decreases depend on nuclear turnover of the intron-containing pre-RNAs. The third class is characterized by a decrease in RPG pre-mRNA, with only a modest reduction in the mature species; this response is observed in hyperosmotic and cation-toxic stresses. We show that casein kinase 2 (CK2) makes important contributions to the changes in pre-mRNA processing, particularly for the first two classes of stress responses. In total, our data suggest that complex post-transcriptional programs cooperate to fine-tune expression of intron-containing transcripts in budding yeast.


Improved potency of escitalopram on the human serotonin transporter: demonstration of an ex vivo assay technique.
The potency of escitalopram ("Lexapro," s-citalopram, LU-26-054) was compared with that of racemic citalopram ("Celexa") using plasma samples from drug-treated normal controls applied to an assay of human serotonin [5-hydroxytryptamine (5-HT)] transport inhibition in blood platelets. Samples were available for both 4-hour and 24-day drug administration. The data indicated that 5-HT transport inhibition was fully manifest for each drug within 4 hours of administration, without significant increase in platelet transport inhibition by 24-day treatment. In addition, a dose-response relationship could be seen for escitalopram and citalopram with increasing 5-HT transport inhibition observed with increasing dose. It was evident from the data that escitalopram was significantly more potent than its racemate in inhibiting human platelet 5-HT transport. Thirty milligrams of escitalopram approximated the effect of 60 mg of racemic citalopram, and similarly, 10 mg of escitalopram approximated that of 20 mg of its racemate. This is the first demonstration of escitalopram's pharmacodynamic effect on the human 5-HT transporter. The results demonstrate its superior potency at the human 5-HT transporter site.


The connectivity domain: Analyzing resting state fMRI data using feature-based data-driven and model-based methods.
Spontaneous fluctuations of resting state functional MRI (rsfMRI) have been widely used to understand the macro-connectome of the human brain. However, these fluctuations are not synchronized among subjects, which leads to limitations and makes utilization of first-level model-based methods challenging. Considering this limitation of rsfMRI data in the time domain, we propose to transfer the spatiotemporal information of the rsfMRI data to another domain, the connectivity domain, in which each value represents the same effect across subjects. Using a set of seed networks and a connectivity index to calculate the functional connectivity for each seed network, we transform data into the connectivity domain by generating connectivity weights for each subject. Comparison of the two domains using a data-driven method suggests several advantages in analyzing data using data-driven methods in the connectivity domain over the time domain. We also demonstrate the feasibility of applying model-based methods in the connectivity domain, which offers a new pathway for the use of first-level model-based methods on rsfMRI data. The connectivity domain, furthermore, demonstrates a unique opportunity to perform first-level feature-based data-driven and model-based analyses. The connectivity domain can be constructed from any technique that identifies sets of features that are similar across subjects and can greatly help researchers in the study of macro-connectome brain function by enabling us to perform a wide range of model-based and data-driven approaches on rsfMRI data, decreasing susceptibility of analysis techniques to parameters that are not related to brain connectivity information, and evaluating both static and dynamic functional connectivity of the brain from a new perspective.


Leflunomide, a Reversible Monoamine Oxidase Inhibitor.
A screening study aimed at identifying inhibitors of the enzyme, monoamine oxidase (MAO), among clinically used drugs have indicated that the antirheumatic drug, leflunomide, is an inhibitor of both MAO isoforms. Leflunomide inhibits human MAO-A and MAO-B and exhibits IC50 values of 19.1 μM and 13.7 μM, respectively. The corresponding Ki values are 17.7 μM (MAO-A) and 10.1 μM (MAO-B). Dialyses of mixtures of the MAO enzymes and leflunomide show that inhibition of the MAOs by leflunomide is reversible. The principal metabolite of leflunomide, teriflunomide (A77 1726), in contrast is not an MAO inhibitor. This study concludes that, although leflunomide is only moderately potent as an MAO inhibitor, isoxazole derivatives may represent a general class of MAO inhibitors and this heterocycle may find application in MAO inhibitor design. In this respect, MAO inhibitors are used in the clinic for the treatment of depressive illness and Parkinson's disease, and are under investigation as therapy for certain types of cancer, Alzheimer's disease and age-related impairment of cardiac function.


Multiobjective satisfaction within an interactive evolutionary design environment.
The paper introduces the concept of an Interactive Evolutionary Design System (IEDS) that supports the engineering designer during the conceptual/preliminary stages of the design process. Requirement during these early stages relates primarily to design search and exploration across a poorly defined space as the designer's knowledge base concerning the problem area develops. Multiobjective satisfaction plays a major role, and objectives are likely to be ill-defined and their relative importance uncertain. Interactive evolutionary search and exploration provides information to the design team that contributes directly to their overall understanding of the problem domain in terms of relevant objectives, constraints, and variable ranges. This paper describes the development of certain elements within an interactive evolutionary conceptual design environment that allows off-line processing of such information leading to a redefinition of the design space. Such redefinition may refer to the inclusion or removal of objectives, changes concerning their relative importance, or the reduction of variable ranges as a better understanding of objective sensitivity is established. The emphasis, therefore, moves from a multiobjective optimization over a preset number of generations to a relatively continuous interactive evolutionary search that results in the optimal definition of both the variable and objective space relating to the design problem at hand. The paper describes those elements of the IEDS relating to such multiobjective information gathering and subsequent design space redefinition.


Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model for ABCA4-mediated retinal dystrophies following Vitamin A supplementation.
Dietary supplementation with vitamin A is sometimes prescribed as a treatment for retinitis pigmentosa, a group of inherited retinal degenerations that cause progressive blindness. Loss-of-function mutations in the ABCA4 gene are responsible for a subset of recessive retinitis pigmentosa. Other mutant alleles of ABCA4 cause the related diseases, recessive cone-rod dystrophy, and recessive Stargardt macular degeneration. Mice with a knockout mutation in the abca4 gene massively accumulate toxic lipofuscin pigments in the retinal pigment epithelium. Treatment of these mice with fenretinide, an inhibitor of vitamin A delivery to the eye, blocks formation of these toxic pigments. Here the authors tested the hypothesis that dietary supplementation with vitamin A may accelerate lipofuscin pigment formation in abca4(-/-) mice. Wild-type and abca4(-/-) mice were fed normal or vitamin A-supplemented diets. Tissues from these mice were analyzed biochemically for retinoids and lipofuscin pigments. Eyes from these mice were analyzed morphologically for lipofuscin in the retinal pigment epithelium and for degeneration of photoreceptors. Visual function in these mice was analyzed by electroretinography. Mice that received vitamin A supplementation had dramatically higher levels of retinyl esters in the liver and retinal pigment epithelium. Lipofuscin pigments were significantly increased by biochemical and morphologic analysis in wild-type and abca4(-/-) mice fed the vitamin A-supplemented diet. Photoreceptor degeneration was observed in 11-month-old albino, but not pigmented, abca4(-/-) mice on both diets. Vitamin A supplementation should be avoided in patients with ABCA4 mutations or other retinal or macular dystrophies associated with lipofuscin accumulation in the retinal pigment epithelium.


Independent External Validation of a Score Predicting Survival After Radiotherapy for Bone Metastases and Expansion to Patients Treated With Single Fraction Radiotherapy.
Recently a prognostic score that predicts 12-month survival in patients treated with fractionated radiotherapy for painful bone metastases has been developed. Fractionated radiotherapy might cause unnecessary burden for patients with limited survival, thus estimation of survival is clinically relevant. The purpose of the present study was independent external validation of the new score and, in addition, its application in patients who received single fraction irradiation, a convenient option currently endorsed in several guidelines. We conducted a retrospective analysis of 270 patients, including 24% who had received single fraction irradiation. The three-tiered score was assigned as described in the development study, and included age, performance status and primary tumor type. Additional prognostic factors not studied in the development cohort, such as the Glasgow prognostic score (GPS) and presence of liver metastases, were included in this validation study. The three-tiered score was valid in this independent cohort (12-month survival rates were 7%, 30% and 71%, respectively, P = 0.0001). Its performance and validity were also confirmed in the single fraction radiotherapy group. Three additional prognostic factors were significant in the multivariate analysis and may therefore contribute to decision making. Irrespective of fractionation, the score based on age, performance status and primary tumor type provides a readily available estimate of 12-month survival.


The value of social attributes of stimuli for promoting engagement in persons with dementia.
The present study examined the impact of different attributes of social stimuli using the stimulus attributes aspect of the Comprehensive Process Model of Engagement ( Am J Geriatr Psychiatry. 17:299-307). Participants were 193 residents of 7 Maryland nursing homes with a diagnosis of dementia. Stimuli were chosen to represent different levels of the following social attributes: social versus not social, realistic versus not realistic, animated versus nonanimated, human versus nonhuman, and alive versus not alive. Participants had significantly longer engagement, were significantly more attentive, and displayed a significantly more positive attitude with social stimuli than with nonsocial stimuli. Longer durations and higher ratings of attention and attitude were seen with realistic and animated stimuli as compared to their counterparts. Human and live stimuli resulted in significantly more engagement than their counterparts. Giving any social stimulus to the residents is preferable to providing none, and the social attributes of stimuli should be maximized.


Working memory load-dependent brain response predicts behavioral training gains in older adults.
In the domain of working memory (WM), a sigmoid-shaped relationship between WM load and brain activation patterns has been demonstrated in younger adults. It has been suggested that age-related alterations of this pattern are associated with changes in neural efficiency and capacity. At the same time, WM training studies have shown that some older adults are able to increase their WM performance through training. In this study, functional magnetic resonance imaging during an n-back WM task at different WM load levels was applied to compare blood oxygen level-dependent (BOLD) responses between younger and older participants and to predict gains in WM performance after a subsequent 12-session WM training procedure in older adults. We show that increased neural efficiency and capacity, as reflected by more "youth-like" brain response patterns in regions of interest of the frontoparietal WM network, were associated with better behavioral training outcome beyond the effects of age, sex, education, gray matter volume, and baseline WM performance. Furthermore, at low difficulty levels, decreases in BOLD response were found after WM training. Results indicate that both neural efficiency (i.e., decreased activation at comparable performance levels) and capacity (i.e., increasing activation with increasing WM load) of a WM-related network predict plasticity of the WM system, whereas WM training may specifically increase neural efficiency in older adults.


"If there is a tension about something, I can solve it": A qualitative investigation of change processes in a trial of brief problem-solving interventions for common adolescent mental health problems in India.
There is limited understanding of change processes and long-term effects of low-intensity psychosocial interventions. We investigated these aspects in two brief problem-solving intervention formats for adolescents with elevated mental health symptoms and associated distress/impairment. This qualitative study was nested within a school-based randomized controlled trial in New Delhi, India, which compared two problem-solving intervention formats: a lay counsellor-led format supported by printed materials (intervention arm) and printed problem-solving materials alone ("bibliotherapy" control arm). A total of 32 participants, ranging in age from 14 to 20 years (mean = 16.4 years, SD = 1.9) and comprising 21 males and 11 females, were interviewed across both trial arms at 12-month follow-up. Five themes were derived using thematic framework analysis. The "impacts on symptoms and functioning" theme described symptomatic improvements and functional gains. "Processes underlying problem solving" reflected changes in positive beliefs, attitudes and emotions when confronted with problems, and the use of a more effective problem-solving coping style. "Experiences of problem-solving materials" covered benefits (e.g. access to relatable stories and readymade solutions) and limitations (e.g. diminishing use over time) of printed problem-solving handouts. "Role of supporting figures" accounted for the facilitating roles played by counsellors and trusted others. There were also accounts of researchers functioning as de facto counsellors in the bibliotherapy arm. "Recommended modifications for intervention delivery" included more flexible and private ways to access the interventions, greater personalization of the counselling process, more engaging and relevant supporting materials, and suggestions for widening access to the interventions in schools and community settings. We infer from our qualitative analysis that changes in problem-solving style and problem orientation underpinned long-term symptomatic and functional improvements. Participants in the counsellor-led intervention appeared better able to sustain the use of problem-solving skills and generalize this approach beyond the original presenting problems. We attribute the differences between arms to the influence of direct advice and supportive interactions with counsellors. Practice implications are discussed.


Reuniting perception and conception.
Work in philosophy and psychology has argued for a dissociation between perceptually-based similarity and higher-level rules in conceptual thought. Although such a dissociation may be justified at times, our goal is to illustrate ways in which conceptual processing is grounded in perception, both for perceptual similarity and abstract rules. We discuss the advantages, power and influences of perceptually-based representations. First, many of the properties associated with amodal symbol systems can be achieved with perceptually-based systems as well (e.g. productivity). Second, relatively raw perceptual representations are powerful because they can implicitly represent properties in an analog fashion. Third, perception naturally provides impressions of overall similarity, exactly the type of similarity useful for establishing many common categories. Fourth, perceptual similarity is not static but becomes tuned over time to conceptual demands. Fifth, the original motivation or basis for sophisticated cognition is often less sophisticated perceptual similarity. Sixth, perceptual simulation occurs even in conceptual tasks that have no explicit perceptual demands. Parallels between perceptual and conceptual processes suggest that many mechanisms typically associated with abstract thought are also present in perception, and that perceptual processes provide useful mechanisms that may be co-opted by abstract thought.


Binding of anti-platelet factor 4/heparin antibodies depends on the thermodynamics of conformational changes in platelet factor 4.
The chemokine platelet factor 4 (PF4) undergoes conformational changes when complexing with polyanions. This can induce the antibody-mediated adverse drug effect of heparin-induced thrombocytopenia (HIT). Understanding why the endogenous protein PF4 becomes immunogenic when complexing with heparin is important for the development of other negatively charged drugs and may also hint toward more general mechanisms underlying the induction of autoantibodies to other proteins. By circular dichroism spectroscopy, atomic force microscopy, and isothermal titration calorimetry we characterized the interaction of PF4 with unfractionated heparin (UFH), its 16-, 8-, and 6-mer subfractions, low-molecular-weight heparin (LMWH), and the pentasaccharide fondaparinux. To bind anti-PF4/heparin antibodies, PF4/heparin complexes require (1) an increase in PF4 antiparallel β-sheets exceeding ∼30% (achieved by UFH, LMWH, 16-, 8-, 6-mer), (2) formation of multimolecular complexes (UFH, 16-, 8-mer), and (3) energy (needed for a conformational change), which is released by binding of ≥11-mer heparins to PF4, but not by smaller heparins. These findings may help to synthesize safer heparins. Beyond PF4 and HIT, the methods applied in the current study may be relevant to unravel mechanisms making other endogenous proteins more vulnerable to undergo conformational changes with little energy requirement (eg, point mutations and post-translational modifications) and thereby predisposing them to become immunogenic.


Influence of self-reported work conditions and health on full, partial and no return to work after long-term sickness absence.
This study aimed at describing the frequency of full, partial, and no return to work after long-term sick leave and at ascertaining the influence of psychosocial work conditions, work ability and health, reported before the onset of sick leave, on full and partial return to work. Altogether 853 public-sector employees in Sweden, mainly women, with at least one sick leave lasting > or = 28 days, were studied. The outcome was the level of sick leave 2 years after the sick leave began. Potential predictors were self-rated health, work ability, and psychosocial work conditions assessed by questionnaire before the sick leave. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated by multinomial regression analyses. Altogether 41% of the participants went directly from full sick leave to full return to work; 21% had periods of partial return to work, but, at the 2-year follow-up, were fully back to work; 15% had partial return to work; and 23% were still not working. A relaxed work situation, a combination of low demands and high decision latitude, increased the odds for full (OR 2.72, 95% CI 1.60-4.62) and partial (OR 2.42, 95% CI 1.21-4.85) return to work. Negative consequences of organizational changes were associated with decreased odds for full return to work (OR 0.54, 95% CI 0.38-0.77). Good self-rated health and work ability were associated with full return to work. Partial return to work often precedes full return to work, but also operates as a long-term solution for remaining occupationally active. Promoting relatively low demands and high decision latitude at work may support both full and partial return to work after long sick leaves.


Mental Health Costs of Inflammatory Bowel Diseases.
Mental health diagnoses (MHDs) were identified as significant drivers of inflammatory bowel disease (IBD)-related costs in an analysis titled "Cost of Care Initiative" supported by the Crohn's & Colitis Foundation. In this subanalysis, we sought to characterize and compare IBD patients with and without MHDs based on insurance claims data in terms of demographic traits, medical utilization, and annualized costs of care. We analyzed the Optum Research Database of administrative claims from years 2007 to 2016 representing commercially insured and Medicare Advantage insured IBD patients in the United States. Inflammatory bowel disease patients with and without an MHD were compared in terms of demographics (age, gender, race), insurance type, IBD-related medical utilization (ambulatory visits, emergency department [ED] visits, and inpatient hospitalizations), and total IBD-related costs. Only patients with costs >$0 in each of the utilization categories were included in the cost estimates. Of the total IBD study cohort of 52,782 patients representing 179,314 person-years of data, 22,483 (42.6%) patients had at least 1 MHD coded in their claims data with a total of 46,510 person-years in which a patient had a coded MHD. The most commonly coded diagnostic categories were depressive disorders, anxiety disorders, adjustment disorders, substance use disorders, and bipolar and related disorders. Compared with patients without an MHD, a significantly greater percentage of IBD patients with MHDs were female (61.59% vs 48.63%), older than 75 years of age (9.59% vs 6.32%), white (73.80% vs 70.17%), and significantly less likely to be younger than 25 years of age (9.18% vs 11.39%) compared with those without mental illness (P < 0.001). Patients with MHDs had significantly more ED visits (14.34% vs 7.62%, P < 0.001) and inpatient stays (19.65% vs 8.63%, P < 0.001) compared with those without an MHD. Concomitantly, patients with MHDs had significantly higher ED costs ($970 vs $754, P < 0.001) and inpatient costs ($39,205 vs $29,550, P < 0.001) compared with IBD patients without MHDs. Patients with MHDs also had significantly higher total annual IBD-related surgical costs ($55,693 vs $40,486, P < 0.001) and nonsurgical costs (medical and pharmacy) ($17,220 vs $11,073, P < 0.001), and paid a larger portion of the total out-of-pocket cost for IBD services ($1017 vs $905, P < 0.001). Patients whose claims data contained both IBD-related and MHD-related diagnoses generated significantly higher costs compared with IBD patients without an MHD diagnosis. Based on these data, we speculate that health care costs might be reduced and the course of patients IBD might be improved if the IBD-treating provider recognized this link and implemented effective behavioral health screening and intervention as soon as an MHD was suspected during management of IBD patients. Studies investigating best screening and intervention strategies for MHDs are needed.


Addressing the structural drivers of HIV: a luxury or necessity for programmes?
The social, economic, political and environmental structural factors that increase susceptibility to HIV infection and undermine prevention and treatment efforts continue to pose a challenge. The papers in this series highlight the importance of sustaining those efforts to address the structural drivers of the HIV epidemic, and that initiatives to achieve HIV elimination will only come about through a comprehensive HIV response, that includes meaningful responses to the social, political, economic and environmental factors that affect HIV risk and vulnerability. In the context of declining resources for HIV/AIDS, the papers speak to the need to integrate responses to the structural drivers of HIV/AIDS into future HIV investments, with both initiatives to integrate HIV into broader gender and development initiatives, as well as adaptations of current service models, to ensure that they are sensitive to and able to respond to the broader economic and social responsibilities that their clients face.


Job seeking, reemployment, and mental health: a randomized field experiment in coping with job loss.
Cognitive theories of adherence to difficult courses of action and findings from previous survey research on coping with a major life event--job loss--were used to generate a preventive intervention, tested by a randomized field experiment. The aim was to prevent poor mental health and loss of motivation to seek reemployment among those who continued to be unemployed and to promote high-quality reemployment. Ss were 928 recently unemployed adults from southeastern Michigan, representing a broad range of demographic characteristics; they were randomly assigned to either the experimental or control condition. The experimental intervention included training in job seeking with a problem-solving process emphasizing inoculation against setbacks and positive social reinforcement. A pretest was administered, followed by posttests 1 and 4 months after the experiment. The experimental condition yielded higher quality reemployment in terms of earnings and job satisfaction, and higher motivation among those who continued to be unemployed.


A national survey of self-injurious behavior in American prisons.
This study sought information about the prevalence, epidemiology, and management of self-injurious behavior by inmates in U.S. prison systems. Although self-injurious behavior has long been the source of significant challenges in correctional settings, limited research is available on this topic. Mental health directors in all 51 state and federal prison systems were invited to respond to a 30-item questionnaire available online or in hard copy. Univariate statistics were used to describe significant aspects of the national experience with self-injurious behavior, and bivariate statistics were used to examine relationships between variables. Thirty-nine systems (77%) responded to the survey. Responses indicated that <2% of inmates per year engage in self-injurious behavior, but such events were reported to occur at least weekly in 85% of systems, with occurrences more than once daily in some systems, thus causing substantial disruptions to operations and draining resources. The highest rates of occurrence of these behaviors were in maximum-security and lockdown units and most often involved inmates with axis II disorders. Despite the seriousness of the problem, systems typically collect few, if any, data on self-injurious behaviors, and management approaches to dealing with them lack consistency within and across systems. Eighty-four percent of respondents expressed interest in participating in further studies on this topic. The survey responses indicated the disruptive effects of self-injurious behavior in the nation's prisons, a need for better epidemiologic monitoring and data on such behavior, and the importance of developing and widely using effective interventions. The high response rate and expressed interest in follow-up projects suggest that state and federal correctional mental health directors see a need for better information and management in this area.