Mutual information relevance networks: functional genomic clustering using pairwise entropy measurements.
Increasing numbers of methodologies are available to find functional genomic clusters in RNA expression data. We describe a technique that computes comprehensive pair-wise mutual information for all genes in such a data set. An association with a high mutual information means that one gene is non-randomly associated with another; we hypothesize this means the two are related biologically. By picking a threshold mutual information and using only associations at or above the threshold, we show how this technique was used on a public data set of 79 RNA expression measurements of 2,467 genes to construct 22 clusters, or Relevance Networks. The biological significance of each Relevance Network is explained.


Outcome of patients with end-stage renal disease admitted to the intensive care unit.
To describe the clinical course of patients with end-stage renal disease (ESRD) admitted to the intensive care unit (ICU) and to compare the performance of Acute Physiology and Chronic Health Evaluation (APACHE) III and Sequential Organ Failure Assessment (SOFA) in predicting their outcome. This retrospective cohort study consisted of patients with ESRD admitted to 3 ICUs between January 1, 1997, and November 30, 2002. Data on demographics, APACHE III score, SOFA score, development of sepsis and organ failure, use of mechanical ventilation, and mortality were collected. Of the 476 patients with ESRD who underwent dialysis during the study period, 93 (20%) required admission to the ICU. The most common ICU admission diagnosis was gastrointestinal bleeding. The first day median (Interquartile range) APACHE III score, SOFA score, and APACHE III predicted hospital mortality rate were 64 (47-79), 6 (5-8), and 12.9% (4.2%-30.8%), respectively. The observed ICU, hospital, and 30-day mortality rates were 9%, 16%, and 22%, respectively. Nonrenal organ failure developed in 48 patients (52%) and sepsis in 15 patients (16%). Mechanical ventilation was required In 26 patients (28%). The area under the receiver operating characteristic curve for the first-day APACHE III probability of hospital death in predicting 30-day mortality was 0.78 (95% confidence interval, 0.68-0.86) compared with 0.66 (95% confidence interval, 0.55-0.76) for the SOFA score (P = .16). The observed hospital mortality of patients with ESRD admitted to the ICU is relatively low. There is no statistically significant difference in the performance of APACHE III and SOFA prognostic models in discriminating between 30-day survivors and nonsurvivors.


Molecular interaction of a potent nonpeptide agonist with the chemokine receptor CCR8.
Most nonpeptide antagonists for CC-chemokine receptors share a common pharmacophore with a centrally located, positively charged amine that interacts with the highly conserved glutamic acid (Glu) located in position 6 of transmembrane helix VII (VII:06). We present a novel CCR8 nonpeptide agonist, 8-[3-(2-methoxyphenoxy)benzyl]-1-phenethyl-1,3,8-triaza-spiro[4.5]decan-4-one (LMD-009), that also contains a centrally located, positively charged amine. LMD-009 selectively stimulated CCR8 among the 20 identified human chemokine receptors. It mediated chemotaxis, inositol phosphate accumulation, and calcium release with high potencies (EC50 from 11 to 87 nM) and with efficacies similar to that of the endogenous agonist CCL1, and it competed for 125I-CCL1 binding with an affinity of 66 nM. A series of 29 mutations targeting 25 amino acids broadly distributed in the minor and major ligand-binding pockets of CCR8 uncovered that the binding of LMD-009 and of four analogs [2-(1-(3-(2-methoxyphenoxy)benzyl)-4-hydroxypiperidin-4-yl)benzoic acid (LMD-584), N-ethyl-2-4-methoxybenzenesulfonamide (LMD-902), N-(1-(3-(2-methoxyphenoxy)benzyl)piperidin-4-yl)-2-phenyl-4-(pyrrolidin-1yl)butanamide (LMD-268), and N-(1-(3-(2-methoxyphenoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydro-2-oxoquinoline-4-carboxamide (LMD-174)] included several key-residues for nonpeptide antagonists targeting CCR1, -2, and -5. It is noteworthy that a decrease in potency of nearly 1000-fold was observed for all five compounds for the Ala substitution of the anchor-point GluVII:06 (Glu(286)) and a gain-of-function of 19-fold was observed for LMD-009 (but not the four other analogs) for the Ala substitution of PheVI:16 (Phe(254)). These structural hallmarks were particularly important in the generation of a model of the molecular mechanism of action for LMD-009. In conclusion, we present the first molecular mapping of the interaction of a nonpeptide agonist with a chemokine receptor and show that the binding pocket of LMD-009 and of analogs overlaps considerably with the binding pockets of CC-chemokine receptor nonpeptide antagonists in general.


Clinical approach to the patient with acute gastrointestinal bleeding.
Gastrointestinal bleeding (GIB) is a very common condition at all ages, with high rates of morbidity and mortality, especially in case of acute presentation. The optimal management of acute GIB requires a timely overview of vital signs and clinical presentation to stabilize the patient if necessary and set up the most adequate diagnostic and therapeutic approach, based on the suspected etiology. Endoscopy plays a major role both in diagnosis and treatment of acute GIB, as allows the application of several hemostasis techniques during the diagnostic session, which should preferably be performed within 24 hours from the acute event. The hemostasis technique should be chosen based on type, etiology of the bleeding and the operator preference and expertise. Nevertheless, several challenging cases need the cooperation of radiology especially in the diagnostic phase, and even in the therapeutic phase for those bleedings in which medical and endoscopic techniques have failed. Imaging diagnostic techniques include mainly CT angiography, scintigraphy with labeled erythrocytes and arteriography. This last technique plays also a therapeutic role in case arterial embolization is needed. Only those patients in which the previous techniques have failed, both in diagnosis and treatment, are candidates for emergency surgery.


Flavanols and cardiovascular disease prevention.
Diet is a major lifestyle factor in the primary and secondary prevention of numerous chronic diseases, including myocardial infarction, stroke, and diabetes. Epidemiological studies suggest that the beneficial cardiovascular health effects of diets rich in fruits and vegetables are in part mediated by their flavonoid content, with particular benefits provided by one member of this family, the flavanols. This concept is supported by findings from small-scale intervention studies with surrogate endpoints including endothelium-dependent vasodilation, blood pressure, platelet function, and glucose tolerance. Mechanistically, short-term effects on endothelium-dependent vasodilation following the consumption of flavanol-rich foods, as well as purified flavanols, have been linked to an increased nitric oxide bioactivity in healthy humans, and those with increased cardiovascular risk. The critical biological target(s) for flavanols have yet to be identified and the extent to which these acute results are important in the context of long-term human health is unknown. While flavanols represent a promising class of food components with respect to their ability to lower cardiovascular risk the flavanol-rich foods used in many trials have been poorly defined with respect to their flavanol content and flavanol-isomer profile; several studies have lacked appropriate controls, and the long-term randomized controlled intervention trials with flavanol-rich foods are missing. Thus, while the literature regarding flavanols and vascular health is encouraging, more in-depth and well-controlled clinical and experimental studies are needed to better define the potential protective vascular effects of these nutrients and their therapeutic value in cardiovascular medicine.


Ionic liquid interface at an electrode: simulations of electrochemical properties using an asymmetric restricted primitive model.
We use Monte Carlo simulations of a coarse-grained model to investigate structure and electrochemical behaviours at an electrode immersed in room temperature ionic liquids (RTILs). The simple RTIL model, which we denote the asymmetric restricted primitive model (ARPM), is composed of monovalent hard-sphere ions, all of the same size, in which the charge is asymmetrically placed. Not only the hard-sphere size (d), but also the charge displacement (b), is identical for all species, i.e. the monovalent RTIL ions are fully described by only two parameters (d, b). In earlier work, it was demonstrated that the ARPM can capture typical static RTIL properties in bulk solutions with remarkable accuracy. Here, we investigate its behaviour at an electrode surface. The electrode is assumed to be a perfect conductor and image charge methods are utilized to handle polarization effects. We find that the ARPM of the ionic liquid reproduces typical (static) electrochemical properties of RTILs. Our model predicts a declining differential capacitance with increasing temperature, which is expected from simple physical arguments. We also compare our ARPM, with the corresponding RPM description, at an elevated temperature (1000 K). We conclude that, even though ion pairing occurs in the ARPM system, reducing the concentration of 'free' ions, it is still better able to screen charge than a corresponding RPM melt. Finally, we evaluate the option to coarse-grain the model even further, by treating the fraction of the ions that form ion pairs implicitly, only through the contribution to the dielectric constant of the corresponding dipolar (ion pair) fluid. We conclude that this primitive representation of ion pairing is not able to reproduce the structures and differential capacitances of the system with explicit ion pairs. The main problem seems to be due to a limited dielectric screening in a layer near the electrode surface, resulting from a combination of orientational restrictions and a depleted dipole density.


Stochastic detection of Pim protein kinases reveals electrostatically enhanced association of a peptide substrate.
In stochastic sensing, the association and dissociation of analyte molecules is observed as the modulation of an ionic current flowing through a single engineered protein pore, enabling the label-free determination of rate and equilibrium constants with respect to a specific binding site. We engineered sensors based on the staphylococcal α-hemolysin pore to allow the single-molecule detection and characterization of protein kinase-peptide interactions. We enhanced this approach by using site-specific proteolysis to generate pores bearing a single peptide sensor element attached by an N-terminal peptide bond to the trans mouth of the pore. Kinetics and affinities for the Pim protein kinases (Pim-1, Pim-2, and Pim-3) and cAMP-dependent protein kinase were measured and found to be independent of membrane potential and in good agreement with previously reported data. Kinase binding exhibited a distinct current noise behavior that forms a basis for analyte discrimination. Finally, we observed unusually high association rate constants for the interaction of Pim kinases with their consensus substrate Pimtide (~10(7) to 10(8) M(-1) · s(-1)), the result of electrostatic enhancement, and propose a cellular role for this phenomenon.


Diminished n1 auditory evoked potentials to oddball stimuli in misophonia patients.
Misophonia (hatred of sound) is a newly defined psychiatric condition in which ordinary human sounds, such as breathing and eating, trigger impulsive aggression. In the current study, we investigated if a dysfunction in the brain's early auditory processing system could be present in misophonia. We screened 20 patients with misophonia with the diagnostic criteria for misophonia, and 14 matched healthy controls without misophonia, and investigated any potential deficits in auditory processing of misophonia patients using auditory event-related potentials (ERPs) during an oddball task. Subjects watched a neutral silent movie while being presented a regular frequency of beep sounds in which oddball tones of 250 and 4000 Hz were randomly embedded in a stream of repeated 1000 Hz standard tones. We examined the P1, N1, and P2 components locked to the onset of the tones. For misophonia patients, the N1 peak evoked by the oddball tones had smaller mean peak amplitude than the control group. However, no significant differences were found in P1 and P2 components evoked by the oddball tones. There were no significant differences between the misophonia patients and their controls in any of the ERP components to the standard tones. The diminished N1 component to oddball tones in misophonia patients suggests an underlying neurobiological deficit in misophonia patients. This reduction might reflect a basic impairment in auditory processing in misophonia patients.


Novel technique for intraoperative sciatic nerve assessment in complex primary total hip arthroplasty: a pilot study.
Sciatic nerve injury (SNI) is a potentially devastating complication after total hip arthroplasty (THA). Intraoperative neural monitoring has been found in several studies to be useful in preventing SNI, but can be difficult to implement. In this study, we examine the results of using a handheld nerve stimulator for intraoperative sciatic nerve (SN) monitoring during complex THA requiring limb lengthening and/or significant manipulation of the SN. A consecutive series of 11 cases (9 patients, 11 hips) with either severe developmental dysplasia of the hip (Crowe 3-4) or other underlying conditions requiring complex hip reconstruction involving significant leg lengthening and/or nerve manipulation. SN function was monitored intraoperatively by obtaining pre- and post-reduction thresholds during component trialing. The results of nerve stimulation were then used to influence intraoperative decision-making. No permanent postoperative SN complications occurred, with an average increase of 28.5 mm in limb length, range (6-51 mm). In 2 out of 11 cases, a change in nerve response was identified after trial reduction, which resulted in an alternate surgical plan (femoral shortening osteotomy and downsizing femoral head). In the remaining cases, the stimulator demonstrated a response consistent with the baseline assessment, assuring that the appropriate lengthening was achieved without SNI. 1 patient had a transient motor and sensory peroneal nerve palsy, which resolved within 2 weeks. The intraoperative use of a handheld nerve stimulator facilitates surgical decision-making and can potentially prevent SNI. The real-time assessment of nerve function allows immediate corrective action to be taken before nerve injury occurs.


Associations of the perceived and objective neighborhood environment with physical activity and sedentary time in New Zealand adolescents.
There is accumulating evidence supporting the association between neighborhood built environments and adults' physical activity (PA) and sedentary time (ST); however, few studies have investigated these associations in adolescents. A better understanding of the features of the built environment that encourage PA or ST is therefore of critical importance to promote health and wellbeing in adolescents. The aim of this study was to estimate the associations of GIS-determined and perceived walkability components in individual residential buffer zones with accelerometer-assessed moderate-to-vigorous physical activity (MVPA) and ST in adolescents. The Built Environment in Adolescent New Zealanders (BEANZ) study was conducted in two cities (Auckland and Wellington) during the 2013-2014 academic school years. The exposure measures were subjective and objective environmental indices of activity-friendliness using four residential buffers. Road network buffers were calculated around participant's residential addresses using the sausage buffer approach at 250 m, 500 m, 1 km, and 2 km scales. A 25 m radius was used for the buffers. Data were analysed using Generalized Additive Mixed Models in R. Data were analysed from 524 participants (15.78 ± 1.62 years; 45% male). Participants accumulated ~114 min/day of moderate-to-vigorous PA (MVPA) and ~354 min/day of ST during accelerometer wear-time (~828 min/day). The estimated difference in MVPA between participants with the 1st and 3rd quartiles observed values on the composite subjective environmental index of activity-friendliness (perceived land use mix - diversity, street connectivity and aesthetics) was equivalent to ~8 min/day (~56 MVPA min/week) and for the objective environmental index of activity-friendliness (gross residential density and number of parks within 2 km distance from home) was ~6 min of MVPA/day (~45 MVPA min/week). When both indices were entered in a main-effect model, both indices remained significantly correlated with MVPA with sex as a moderator. The predicted difference in sedentary time between those with the minimum and maximum observed values on the subjective index of non-sedentariness was ~20 min/day. The combined assessment of the main effects of subjective and objective indices of activity-friendliness on NZ adolescents' PA and ST showed positive relationships with MVPA for the subjective index only. The subjective index was a significant correlate of PA in both girls and boys, while the objective index was significant only in boys when sex was entered as a moderator. Further research is warranted to understand the relationships of ST with the built environment.


Highly stable triple helix formation by homopyrimidine (L)-acyclic threoninol nucleic acids with single stranded DNA and RNA.
Acyclic (L)-threoninol nucleic acid (aTNA) containing thymine, cytosine and adenine nucleobases were synthesized and shown to form surprisingly stable triplexes with complementary single stranded homopurine DNA or RNA targets. The triplex structures consist of two (L)-aTNA strands and one DNA or RNA, and these triplexes are significantly stronger than the corresponding DNA or RNA duplexes as shown in competition experiments. As a unique property the (L)-aTNAs exclusively form triplex structures with DNA and RNA and no duplex structures are observed by gel electrophoresis. The results were compared to the known enantiomer (D)-aTNA, which forms much weaker triplexes depending upon temperature and time. It was demonstrated that (L)-aTNA triplexes are able to stop primer extension on a DNA template, showing the potential of (L)-aTNA for antisense applications.


Aetiology of uveitis in Sierra Leone, west Africa.
In 1992, non-onchocercal uveitis caused 9% of blindness, 8% of visual impairment, and 11% of uniocular blindness among patients visiting an eye hospital in Sierra Leone, west Africa. The aim of this study was to determine the aetiology of uveitis in this population. General and ophthalmic examination complemented by serum and aqueous humour analyses for various infectious agents was performed for 93 uveitis patients and compared with serum (n = 100) and aqueous humour (n = 9) analysis of endemic controls. At the initial examination, 45 patients (48%) proved to be severely visually handicapped. After clinical and laboratory analyses, an aetiological diagnosis was established for 49 patients (52%). Toxoplasma gondii was the most important cause of uveitis (40/93; 43%). Anti-toxoplasma IgM antibodies were detected in serum samples of seven of 93 patients (8%) compared with one of 100 controls (1%, p < 0.05). At least six patients (15%) with ocular toxoplasmosis had acquired the disease postnatally. Antibodies against Treponema pallidum were detected in 18 of 92 patients (20%) and in 21 controls (21%). Other causes of uveitis were varicella zoster virus (one patient), herpes simplex virus (two patients), and HLA-B27 positive acute anterior uveitis with ankylosing spondylitis (one patient), while one patient had presumed HTLV-I uveitis. In a hospital population in Sierra Leone, west Africa, uveitis was associated with severe visual handicap and infectious diseases. Toxoplasmosis proved to be the most important cause of the uveitis. Although the distribution of congenital versus acquired toxoplasmosis in this population could not be determined, the results indicate an important role of postnatally acquired disease. The results further suggested minor roles for HIV, tuberculosis, toxocariasis, and sarcoidosis as causes of uveitis in this population.


AphidBase: a database for aphid genomic resources.
AphidBase aims to (i) store recently acquired genomic resources on aphids and (ii) compare them to other insect resources as functional annotation tools. For that, the Drosophila melanogaster genome has been loaded in the database using the GMOD open source software for a comparison with the 17 069 pea aphid unique transcripts (contigs) and the 13 639 gene transcripts of the Anopheles gambiae. Links to FlyBase and A.gambiae Entrez databases allow a rapid characterization of the putative functions of the aphid sequences. Text mining of the D.melanogaster literature was performed to construct a network of co-cited gene or protein names, which should facilitate functional annotation of aphid homolog sequences. AphidBase represents one of the first genomic databases for a hemipteran insect. http://w3.rennes.inra.fr/AphidBase.


Radical debridement guided by advanced imaging and frequent monitoring is an effective approach for the treatment of odontogenic abscesses and jaw osteomyelitis in rabbits: a review of 200 cases (2018-2023).
To report the prevalence and document the treatment and outcome of odontogenic abscesses and associated jaw osteomyelitis in pet rabbits. 200 client-owned rabbits. Pet rabbits surgically treated using extraoral teeth extraction with marsupialization for abscesses of dental origin and jaw osteomyelitis were included in the study (February 2018 to February 2023). A case must have had pre- and postoperative computed tomographic study and a follow-up period of at least 4 months. In total, 113 male and 87 female rabbits were treated surgically. The mean age at the time of the diagnosis at the authors' clinic was 3 years and 11 months. Male rabbits suffered from odontogenic abscesses significantly more often than females. The mean surgical time varied from 25 to 95 minutes, based on the severity of the pathology and location. The wound healed completely in an average of 39.7 days (range, 14 to 145 days; 95% CI, 36.9 to 42.5 days). Major complications detected in 18.5% (37/200) cases were associated with prolonged healing time mostly due to the formation of a bone sequestrum and gingival suture failure. The disease-free time following abscess resolution was on average 29 months (range, 4 to 60 months). The recurrence of the odontogenic infection was 8% (16/200 cases). The radical surgical technique with the extraction of all the infected teeth with the removal of all affected tissue and osteomyelitic bone and regular follow-up wound management is an effective method for the treatment of odontogenic abscesses with jaw osteomyelitis.


Phylogenetic and environmental context of a Tournaisian tetrapod fauna.
The end-Devonian to mid-Mississippian time interval has long been known for its depauperate palaeontological record, especially for tetrapods. This interval encapsulates the time of increasing terrestriality among tetrapods, but only two Tournaisian localities previously produced tetrapod fossils. Here we describe five new Tournaisian tetrapods (Perittodus apsconditus, Koilops herma, Ossirarus kierani, Diploradus austiumensis and Aytonerpeton microps) from two localities in their environmental context. A phylogenetic analysis retrieved three taxa as stem tetrapods, interspersed among Devonian and Carboniferous forms, and two as stem amphibians, suggesting a deep split among crown tetrapods. We also illustrate new tetrapod specimens from these and additional localities in the Scottish Borders region. The new taxa and specimens suggest that tetrapod diversification was well established by the Tournaisian. Sedimentary evidence indicates that the tetrapod fossils are usually associated with sandy siltstones overlying wetland palaeosols. Tetrapods were probably living on vegetated surfaces that were subsequently flooded. We show that atmospheric oxygen levels were stable across the Devonian/Carboniferous boundary, and did not inhibit the evolution of terrestriality. This wealth of tetrapods from Tournaisian localities highlights the potential for discoveries elsewhere.


High throughput screening of complex biological samples with mass spectrometry - from bulk measurements to single cell analysis.
High throughput screening (HTS) of molecular analytes is in high demand from and implemented in many areas of chemistry, medicine and industrial biotechnology including the discovery of biomarkers and the development of new chemical entities. Despite its prevalence, technical challenges remain in many of the new application areas of HTS which require rapid results from complex mixtures, for example in: screening biotransformations; targeted metabolomics; and in locating drugs and/or metabolites in biological matrices. Common to all of these are lengthy and costly sample preparation stages, involving recovery from cell cultures, extractions followed by low throughput LC-MS/MS methods or specific fluorescence measurements. In the latter the target molecules need to be inherently fluorescent or to include a fluorescent label or tag which can adversely influence a cellular system. Direct infusion mass spectrometry coupled with robotic sample infusion is a viable contender for information rich HTS with sub-second analysis times, and recent developments in ambient ionisation have heralded a new era where screening can be performed on crude cell lysates or even from live cells. Besides commercially available technologies such as RapidFire, Acoustic Mist Ionisation, and the TriVersa ChipMate there are promising new developments from academic groups. Novel applications using desorption electrospray ionisation, microfluidics, rapid LC-separation and 'one cell' direct infusion methods offer much potential for increasing throughput from 'messy' complex samples and for significantly reducing the amount of material that needs to be analysed. Here we review recent advances in HTS coupled with MS with an emphasis on methods that reduce or remove all sample preparation and will facilitate single cell screening approaches.


"I did not intend to stop. I just could not stand cigarettes any more." A qualitative interview study of smoking cessation among the elderly.
Every year, more than 650,000 Europeans die because they smoke. Smoking is considered to be the single most preventable factor influencing health. General practitioners (GP) are encouraged to advise on smoking cessation at all suitable consultations. Unsolicited advice from GPs results in one of 40-60 smokers stopping smoking. Smoking cessation advice has traditionally been given on an individual basis. Our aim was to gain insights that may help general practitioners understand why people smoke, and why smokers stop and then remain quitting and, from this, to find fruitful approaches to the dialogue about stopping smoking. Interviews with 18 elderly smokers and ex-smokers about their smoking and decisions to smoke or quit were analysed with qualitative content analysis across narratives. A narrative perspective was applied. Six stages in the smoking story emerged, from the start of smoking, where friends had a huge influence, until maintenance of the possible cessation. The informants were influenced by "all the others" at all stages. Spouses had vital influence in stopping, relapses and continued smoking. The majority of quitters had stopped by themselves without medication, and had kept the tobacco handy for 3-6 months. Often smoking cessation seemed to happen unplanned, though sometimes it was planned. With an increasingly negative social attitude towards smoking, the informants became more aware of the risks of smoking. "All the others" is a clue in the smoking story. For smoking cessation, it is essential to be aware of the influence of friends and family members, especially a spouse. People may stop smoking unplanned, even when motivation is not obvious. Information from the community and from doctors on the negative aspects of smoking should continue. Eliciting life-long smoking narratives may open up for a fruitful dialogue, as well as prompting reflection about smoking and adding to the motivation to stop.


The Royal College experience and plans for the maintenance of certification program.
The Royal College of Physicians and Surgeons of Canada, in 2001, implemented a mandatory maintenance of certification (MOC) program that is required for fellows to maintain membership and fellowship. Participation in the MOC program is one of the recognized pathways approved by provincial medical regulatory authorities in Canada by which specialists can demonstrate their commitment to continued competent performance in practice. This article traces the historical beginnings of the MOC program, highlighting the educational foundation and scientific evidence that influenced its philosophy, goals, and strategic priorities. The MOC program has evolved into a complex system of continuing professional development to facilitate and enable a "cultural shift'' in how we conceptualize and support the continuing professional development (CPD) of specialists. The MOC program is an educational strategy that supports a learning culture where specialists are able to design, implement and document their accomplishments from multiple learning activities to build evidence-informed practices. In the future, the MOC Program must evolve from assisting fellows to use effective educational resources "for credit" to enable fellows, leveraging a competency-based CPD model, to demonstrate their capacity to continuously improve practice. This will require innovative methods to capture learning and practice improvements in real time, integrate learning during the delivery of health care, expand automation of reporting strategies, and facilitate new sociocultural methods of emergent learning and practice change. Collectively, these directions will require a research agenda that will generate evidence for how transformative cultural change in continuing professional education of the profession can be realized.


The governance of integrated health and social care in England since 2010: great expectations not met once again?
Integrating health and social care has long been a goal of policy-makers and practitioners. Yet, this aim has remained elusive, partly due to conflicting definitions and a weak evidence base. As part of a special edition exploring the use of the TAPIC (transparency, accountability, participation, integrity and capability) framework in different national contexts and inter-agency settings, this article examines the governance of integrated care in England since 2010, focusing on the extent to which thesefive governance attributes are applicable to integrated care in England. The plethora of English policy initiatives on integrated care (such as the 'Better Care Fund', personal health budgets, and 'Sustainability and Transformation Plans') mostly shows signs of continuity over time although the barriers to integrated care often persist. The article concludes that the contribution of integrated care to improved outcomes remains unclear and yet it remains a popular policy goal. Whilst some elements of the TAPIC framework fit less well than others to the case of integrated care, the case of integrated care can be better understood and explained through this lens.


Quantitative CT Imaging of Ventral Hernias: Preliminary Validation of an Anatomical Labeling Protocol.
We described and validated a quantitative anatomical labeling protocol for extracting clinically relevant quantitative parameters for ventral hernias (VH) from routine computed tomography (CT) scans. This information was then used to predict the need for mesh bridge closure during ventral hernia repair (VHR). A detailed anatomical labeling protocol was proposed to enable quantitative description of VH including shape, location, and surrounding environment (61 scans). Intra- and inter-rater reproducibilities were calculated for labeling on 18 and 10 clinically acquired CT scans, respectively. Preliminary clinical validation was performed by correlating 20 quantitative parameters derived from anatomical labeling with the requirement for mesh bridge closure at surgery (26 scans). Prediction of this clinical endpoint was compared with similar models fit on metrics from the semi-quantitative European Hernia Society Classification for Ventral Hernia (EHSCVH). High labeling reproducibilities were achieved for abdominal walls (±2 mm in mean surface distance), key anatomical landmarks (±5 mm in point distance), and hernia volumes (0.8 in Cohen's kappa). 9 out of 20 individual quantitative parameters of hernia properties were significantly different between patients who required mesh bridge closure versus those in whom fascial closure was achieved at the time of VHR (p<0.05). Regression models constructed by two to five metrics presented a prediction with 84.6% accuracy for bridge requirement with cross-validation; similar models constructed by EHSCVH variables yielded 76.9% accuracy. Reproducibility was acceptable for this first formal presentation of a quantitative image labeling protocol for VH on abdominal CT. Labeling-derived metrics presented better prediction of the need for mesh bridge closure than the EHSCVH metrics. This effort is intended as the foundation for future outcomes studies attempting to optimize choice of surgical technique across different anatomical types of VH.


Extended pleurectomy decortication for malignant pleural mesothelioma in the elderly: the need for an inclusive yet selective approach.
The median age at diagnosis of patients with pleural mesothelioma in the UK is 73 years. Recent series have shown the feasibility of extended pleurectomy decortication in the elderly, but with continuing debate about the efficacy of this treatment, we reviewed our experience to identify more detailed selection criteria. We reviewed prospectively collected data on all patients from 1999 to 2016 undergoing extended pleurectomy decortication. We compared clinical and pathological outcomes and survival data from patients 70 years and older (≥70 years) with those younger than 70 years (<70 years). Eighty-two of the 300 (27.3%) patients were ≥70 years of age at the time of surgery. More patients in the elderly group required intensive care postoperatively (6.2 vs 16.7%, P = 0.01) and developed atrial fibrillation (14.4 vs 24.4%, P = 0.05). There was no intergroup difference in length of hospital stay or in in-hospital, 30-day or 90-day mortality. Elderly patients were less likely to receive neoadjuvant (<70 years 21.2%, ≥70 years 11.0%; P = 0.045) or adjuvant chemotherapy (<70 years 45.4%, ≥70 years 29.3%; P = 0.04). Median overall survival was similar: <70 years 14.0 months, ≥70 years 10.3 months; P = 0.29. However, in node-positive patients, survival was poorer in the elderly (13.0 vs 9.1 months, P = 0.05), particularly in those with non-epithelioid tumours (3.8 vs 6.7 months, P = 0.04). On multivariable analysis, age was not a significant prognostic factor, although lack of adjuvant therapy (P = 0.001) and admission to the intensive care unit (P < 0.001) remained poor prognostic factors. Although age in isolation should not be an exclusion criterion for extended pleurectomy decortication for mesothelioma, in the elderly, a more rigorous preoperative evaluation of nodal disease and an additional assessment of fitness for adjuvant chemotherapy are recommended.


Predicting red meat yields in carcasses from beef-type and calf-fed Holstein steers using the United States Department of Agriculture calculated yield grade.
Analyses were conducted to evaluate the ability of the USDA yield grade equation to detect differences in subprimal yield of beef-type steers and calf-fed Holstein steers that had been fed zilpaterol hydrochloride (ZH; Intervet Inc., Millsboro, DE) as well as those that had not been fed ZH. Beef-type steer (n = 801) and calf-fed Holstein steer (n = 235) carcasses were fabricated into subprimal cuts and trim. Simple correlations between calculated yield grades and total red meat yields ranged from -0.56 to -0.62 for beef-type steers. Reliable correlations from calf-fed Holstein steers were unobtainable; the probability of a type I error met or exceeded 0.39. Linear models were developed for the beef-type steers to predict total red meat yield based on calculated USDA yield grade within each ZH duration. At an average calculated USDA yield grade of 2.9, beef-type steer carcasses that had not been fed ZH had an estimated 69.4% red meat yield, whereas those fed ZH had an estimated 70.7% red meat yield. These results indicate that feeding ZH increased red meat yield by 1.3% at a constant calculated yield grade. However, these data also suggest that the calculated USDA yield grade score is a poor and variable estimator (adjusted R(2) of 0.31 to 0.38) of total red meat yield of beef-type steer carcasses, regardless of ZH feeding. Moreover, no relationship existed (adjusted R(2) of 0.00 to 0.01) for calf-fed Holstein steer carcasses, suggesting the USDA yield grade is not a valid estimate of calf-fed Holstein red meat yield.


Field trial of 1% niclosamide as a topical antipenetrant to Schistosoma mansoni cercariae.
A randomized, double-blind, placebo-controlled field trial of a topical antipenetrant lotion, 1% niclosamide, applied daily to the upper and lower limbs of farmers occupationally exposed to Schistosoma mansoni cercarial-infested water, was conducted in the Nile Delta to assess its safety and efficacy in preventing reinfection. Farmers aged 18-40 years were treated to cure their S. mansoni infections three months prior to the onset of the trial. Subjects were randomly assigned to receive niclosamide or placebo lotion that was self-applied daily for five months. A total of 186 subjects met the inclusion criteria and completed the trial. The exposure to schistosomal-infested water occurred during routine irrigation activities from June to November 1991. Stool specimens were evaluated monthly during and for two months following the lotion application period. The subjects applying the niclosamide lotion were comparable to those applying placebo lotion in age (mean 30 years for both), total water contact (184.5 hr versus 173.8 hr), reported lotion application compliance (88% versus 92%), and reported water contact involving skin exposure other than upper and lower limbs (23% versus 27%). The schistosomal reinfection rate was lower in the niclosamide group (53.3%) compared with the placebo lotion group (71.3%), (P < 0.02). Increased protection might be obtained with total body application for shorter, less intense, water contact exposures.


On the relative significance of bacteria for the distribution of polychlorinated biphenyls in Arctic Ocean surface waters.
This study presents the first field observations of polychlorinated biphenyls (PCB) in bacteria in oceanic waters. To contribute to the limited knowledge of what role bacteria play in the dynamics of hydrophobic organic contaminants (HOCs) in surface seawater, PCB concentrations were measured in bacteria (0.2-2 microm) collected at seven stations in the northern Barents Sea marginal ice zone (MIZ) and the central Arctic Ocean. Concentrations of individual PCB congeners in bacteria were 0.5-5 ng/g oc (organic carbon), which was as high as or higher than PCB concentrations in bulk particulate organic carbon (POC, "phytoplankton"; > 0.7 microm). Considering the relative biomasses of phytoplankton and bacteria, the amount of PCB in bacteria was generally 5-20% of that in phytoplankton, but at two stations the bacterial biomass contained more PCBs than the phytoplankton pool. This study further showed that efficient PCB uptake in bacteria may be described by an apparent equilibrium partitioning model with linear regressions between the organic-carbon-normalized partition coefficient and the octanol-water partition coefficient (log K(bact-oc)-log K(ow)).


Nucleotide excision repair of oxidised genomic DNA is not a source of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine.
Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) is a widely measured biomarker of oxidative stress. It has been commonly assumed to be a product of DNA repair, and therefore reflective of DNA oxidation. However, the source of urinary 8-oxodGuo is not understood, although potential confounding contributions from cell turnover and diet have been ruled out. Clearly it is critical to understand the precise biological origins of this important biomarker, so that the target molecule that is oxidised can be identified, and the significance of its excretion can be interpreted fully. In the present study we aimed to assess the contributions of nucleotide excision repair (NER), by both the global genome NER (GG-NER) and transcription-coupled NER (TC-NER) pathways, and sanitisation of the dGTP pool (e.g. via the activity of the MTH1 protein), on the production of 8-oxodGuo, using selected genetically-modified mice. In xeroderma pigmentosum A (XPA) mice, in which GG-NER and TC-NER are both defective, the urinary 8-oxodGuo data were unequivocal in ruling out a contribution from NER. In line with the XPA data, the production of urinary 8-oxodGuo was not affected in the xeroderma pigmentosum C mice, specifically excluding a role of the GG-NER pathway. The bulk of the literature supports the mechanism that the NER proteins are responsible for removing damage to the transcribed strand of DNA via TC-NER, and on this basis we also examined Cockayne Syndrome mice, which have a functional loss of TC-NER. These mice showed no difference in urinary 8-oxodGuo excretion, compared to wild type, demonstrating that TC-NER does not contribute to urinary 8-oxodGuo levels. These findings call into question whether genomic DNA is the primary source of urinary 8-oxodGuo, which would largely exclude it as a biomarker of DNA oxidation. The urinary 8-oxodGuo levels from the MTH1 mice (both knock-out and hMTH1-Tg) were not significantly different to the wild-type mice. We suggest that these findings are due to redundancy in the process, and that other enzymes substitute for the lack of MTH1, however the present study cannot determine whether or not the 2'-deoxyribonucleotide pool is the source of urinary 8-oxodGuo. On the basis of the above, urinary 8-oxodGuo is most accurately defined as a non-invasive biomarker of oxidative stress, derived from oxidatively generated damage to 2'-deoxyguanosine.


From pituitary expansion to empty sella: disease progression in a mouse model of autoimmune hypophysitis.
Lymphocytic hypophysitis has a variable clinical course, where a swelling of the pituitary gland at presentation is thought to be followed by pituitary atrophy and empty sella. Data in patients, however, are scanty and contradictory. To better define the course of hypophysitis, we used an experimental model based on the injection of pituitary proteins into SJL mice. A cohort of 33 mice was divided into three groups: 18 cases were immunized with pituitary proteins emulsified in complete Freund's adjuvant; six controls were injected with adjuvant only; and nine controls were left untreated. Mice were followed by cranial magnetic resonance imaging (MRI) for up to 300 d, for a total of 106 MRI scans, and killed at different time points to correlate radiological and pathological findings. Empty sella was defined as a reduction in pituitary volume greater than 2 sd below the mean volume. All immunized mice showed by MRI a significant expansion of pituitary volume during the early phases of the disease. The volume then decreased gradually in the majority of cases (14 of 18, 78%), reaching empty sella values by d 300 after immunization. In a minority of cases (four of 18, 22%), the decrease was so rapid and marked to induce a central area of necrosis accompanied by hemorrhages, mimicking the condition known in patients as pituitary apoplexy. No radiological or pathological changes were observed in controls. Overall, these findings indicate that the evolution of hypophysitis is complex but can lead, through different routes, to the development of empty sella.


Effects of Plantago major L. leaf extracts on oral epithelial cells in a scratch assay.
The present study was undertaken to evaluate the effects from different leaf extracts of the traditional medicinal herb Plantago major L. (plantain) on cell proliferation and migration in vitro, as a test for potential wound healing properties. Water and ethanol-based extracts were prepared from Plantago major fresh and dried leaves, and tested in vitro in a scratch assay with oral epithelial cells. The scratch assay produced reliable results after 18 h. Most of the tested extracts increased the proliferation/migration of the oral epithelial cells compared to the negative control. A concentration of 1.0 mg/mL (on dry weight basis) appears to be optimal regardless of type of extract, and among the alternatives, 0.1 mg/mL was always better than 10 mg/mL. Ethanol-based extracts with a concentration of 10 mg/mL had very detrimental effects on cell proliferation/migration. At the other two concentrations, ethanol-based extracts had the most beneficial effect, followed by water extracts of fresh leaves, ethanol plus water extracts of dried leaves and, finally, water extracts of dried leaves. This study suggests that both the water extracts and the more polyphenol-rich ethanol-based extracts of Plantago major leaves have medicinal properties. Further research is, however, needed to determine what compounds are responsible for the wound healing effects.


Inverse association between prostate cancer and the use of calcium channel blockers.
Calcium channel blockers block calcium signal-mediated apoptosis. It is hypothesized that the use of these drugs may be associated with the development of cancer. This study investigated the association between daily use of calcium channel blockers and prostate cancer in a community-based cohort of men who participated in a longitudinal study of lower urinary tract symptoms. Study subjects were men ages 40 to 79 years by January 1, 1990, and were randomly selected from Olmsted County in Minnesota. At baseline, participants underwent an interview to determine all medications taken on a daily basis, including calcium channel blockers and to elicit a family history of prostate cancer. During follow-up, all men with a histological diagnosis of prostate cancer were identified through patient self-report and by a review of the complete medical record. Over 12,668 person years of follow-up, 15 (6.8%) of 220 calcium channel blocker users and 120 (10.5%) of 1142 nonusers developed prostate cancer (P = 0.09; odds ratio, 0.62; 95% confidence interval, 0.36-1.10). With adjustment for age and family history of prostate cancer, the risk (odds ratio, 95% confidence interval) of prostate cancer was 0.55 (0.31-0.97) in calcium channel blocker users compared with nonusers. In analyses stratified by family history of prostate cancer, the risk of prostate cancer was 0.45 (0.23-0.88) in men without a family history and 2.64 (0.82-8.47) in men with a family history of prostate cancer (P = 0.006). These findings suggest an association between prostate cancer and daily use of calcium channel blockers that varies by family history of prostate cancer.


Association of Torulopsis glabrata infections with fluconazole prophylaxis in neutropenic bone marrow transplant patients.
Because the use of fluconazole prophylaxis had been associated with an increased rate of Candida krusei infections at The John Hopkins Oncology Center, early empiric amphotericin B plus flucytosine were given to febrile neutropenic patients colonized by C. krusei. By this practice, the proportion of fungemias attributable to C. krusei was low (12.5%) in patients receiving fluconazole over a 6-month interval. However, Torulopsis (Candida) glabrata assumed a much higher proportion of fungemias (75%) among patients receiving fluconazole. In vitro susceptibility testing combined with this clinical experience suggests that some T. glabrata isolates are not susceptible to fluconazole and can cause breakthrough infections in patients receiving fluconazole.


Conversion of dihydroceramide into ceramide: involvement of a desaturase.
Ceramide has been suggested to be a potent bioactive lipid involved in cell growth, differentiation and apoptosis. Its precursor, dihydroceramide, does not affect these processes. The truncated dihydroceramide analogues N-hexanoyl-[4,5-3H]-d-erythro-sphinganine and N-[1-14C]-hexanoyl-d-erythro-sphinganine were used to study the conversion of dihydroceramide into ceramide by rat hepatocytes. The formation of tritiated water after the addition of the tritiated substrate to intact and permeabilized rat hepatocytes was followed to measure enzyme activity. Desaturation was severely depressed in permeabilized hepatocytes, suggesting loss of cofactors. Of a variety of cofactors tested in the permeabilized cells, NADPH appeared to be stimulatory, pointing to the involvement of a desaturase. In agreement with this, the addition of inhibitors and redox effectors known to affect Delta9-stearoyl-CoA desaturase and Delta1-plasmanyl-ethanolamine desaturase to intact cells resulted in severe inhibition of the desaturation. When added to permeabilized cells fortified with NADPH, these compounds counteracted the NADPH stimulation. The enzyme system was further studied in broken cells. On cell fractionation, the activity was recovered in the microsomal fraction. The results indicate that the conversion of dihydroceramide into ceramide is ctalysed by a desaturase and not by a dehydrogenase or an oxidase as was generally believed.


Effects of metoprolol on mortality and late infarction in diabetics with suspected acute myocardial infarction. Retrospective data from two large studies.
From two large scale studies in patients with suspected acute myocardial infarction we report the outcome in diabetics after treatment with either metoprolol or placebo. In the Göteborg Metoprolol Trial mortality at 3 months was reduced by metoprolol from 17.9% to 7.5% and late infarction was reduced from 16.4% to 3.8%. In the MIAMI Trial, mortality was decreased by metoprolol from 11.3% to 5.7% and the occurrence of late infarction was decreased from 4.5% to 3.1% during 15-day follow-up. Compared with the overall results, the effect of metoprolol on mortality appears particularly impressive in diabetics.


Benefit-Risk Assessment of Obesity Drugs: Focus on Glucagon-like Peptide-1 Receptor Agonists.
The prevalence of obesity and related comorbidities is increasing worldwide. Furthermore, clinically meaningful body weight losses has proven difficult to achieve and especially to maintain through sustained lifestyle change in the form of diet and exercise. Pharmacotherapy against obesity is a non-invasive treatment as an adjunct to lifestyle changes, but approved anti-obesity drugs are currently few. This article reviews the major anti-obesity drugs and the benefit-risk profiles of the long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and semaglutide (a modified version of liraglutide with longer half-life and tripled receptor affinity). Generally, GLP-1 RAs are well tolerated and induce significant weight loss and lowering of comorbidities. Studies with liraglutide 3.0 mg/day have shown an average placebo-subtracted weight loss of 5.5 kg (range 4.6-5.9) in 1- to 3-year duration trials. One trial using semaglutide 0.4 mg once daily reported an average weight loss of 11.6% (~ 13.1 kg) after 1 year. Furthermore, semaglutide induced a ~ 6 percentage point larger placebo-subtracted body weight loss in a head-to-head comparison with liraglutide (11.6 vs. 5.5% weight loss, respectively). The safety profiles for both drugs were similar, with transient gastrointestinal disorders being the most commonly reported adverse events. The longest running trial and the most recent trials have not raised any new safety concerns. Long-term trials and post-marketing surveillance is warranted to fully assess both long-term efficacy and safety. Future combinational therapies of mimicked gut hormones involved in regulation of energy homeostasis and/or additional lifestyle change in the form of exercise might further improve efficacy.


Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator.
Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. The polymorphism rs10490924 in the ARMS2 gene is highly associated with AMD and linked to an indel mutation (del443ins54), the latter inducing mRNA instability. At present, the function of the ARMS2 protein, the exact cellular sources in the retina and the biological consequences of the rs10490924 polymorphism are unclear. Recombinant ARMS2 was expressed in Pichia pastoris, and protein functions were studied regarding cell surface binding and complement activation in human serum using fluoresence-activated cell sorting (FACS) as well as laser scanning microscopy (LSM). Biolayer interferometry defined protein interactions. Furthermore, endogenous ARMS2 gene expression was studied in human blood derived monocytes and in human induced pluripotent stem cell-derived microglia (iPSdM) by PCR and LSM. The ARMS2 protein was localized in human genotyped retinal sections and in purified monocytes derived from AMD patients without the ARMS2 risk variant by LSM. ARMS2 expression in monocytes under oxidative stress was determined by Western blot analysis. Here, we demonstrate for the first time that ARMS2 functions as surface complement regulator. Recombinant ARMS2 binds to human apoptotic and necrotic cells and initiates complement activation by recruiting the complement activator properdin. ARMS2-properdin complexes augment C3b surface opsonization for phagocytosis. We also demonstrate for the first time expression of ARMS2 in human monocytes especially under oxidative stress and in microglia cells of the human retina. The ARMS2 protein is absent in monocytes and also in microglia cells, derived from patients homozygous for the ARMS2 AMD risk variant (rs10490924). ARMS2 is likely involved in complement-mediated clearance of cellular debris. As AMD patients present with accumulated proteins and lipids on Bruch's membrane, ARMS2 protein deficiency due to the genetic risk variant might be involved in drusen formation.


Traced on the Timeline: Discovery of Acetylcholine and the Components of the Human Cholinergic System in a Primitive Unicellular Eukaryote Acanthamoeba spp.
Acetylcholine (ACh) is the neurotransmitter of cholinergic signal transduction that affects the target cells via muscarinic (mAChR) and nicotinic (nAChR) cholinergic receptors embedded in the cell membrane. Of the cholinergic receptors that bind to ACh, the mAChRs execute several cognitive and metabolic functions in the human central nervous system (CNS). Very little is known about the origins and autocrine/paracrine roles of the ACh in primitive life forms. With the recent report of the evidence of an ACh binding mAChR1 like receptor in Acanthamoeba spp., it was tempting to investigate the origin and functional roles of cholinergic G-Protein coupled receptors (GPCRs) in the biology of eukaryotes. We inferred the presence of ACh, its synthetic, degradation system, and a signal transduction pathway in an approximately ∼2.0 billion year old primitive eukaryotic cell Acanthamoeba castellanii. Bioinformatics analysis, ligand binding prediction, and docking methods were used to establish the origins of enzymes involved in the synthesis and degradation of ACh. Notably, we provide evidence of the presence of ACh in A. castellanii by colorimetric analysis, which to date is the only report of its presence in this primitive unicellular eukaryote. We show the evidence for the presence of homology of evolutionary conserved key enzymes of the cholinergic system like choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in A. castellanii spp., which were found to be near identical to their human counterparts. Tracing the origin, functions of ACh, and primeval mAChRs in primitive eukaryotic cells has the potential of uncovering covert cholinergic pathways that can be extended to humans in order to understand the states of cholinergic deficiency in neurodegenerative diseases (ND).


Surveillance to Track Progress Toward Polio Eradication - Worldwide, 2016-2017.
Global efforts to eradicate polio began in 1988, and four of the six World Health Organization (WHO) regions currently have achieved poliofree certification. Within the remaining two regions with endemic poliomyelitis (African and Eastern Mediterranean), Afghanistan, Nigeria, and Pakistan have never interrupted transmission of wild poliovirus (WPV). The primary means of detecting poliovirus transmission is surveillance for acute flaccid paralysis (AFP) among children aged <15 years, combined with collection and testing of stool specimens for detection of WPV and vaccine-derived polioviruses (VDPVs)* in WHO-accredited laboratories within the Global Polio Laboratory Network (GPLN) (1,2). AFP surveillance is supplemented by environmental surveillance for polioviruses in sewage from selected locations. Genomic sequencing of isolated polioviruses enables the mapping of transmission by time and place, assessment of potential gaps in surveillance, and identification of the emergence of VDPVs (3). This report presents poliovirus surveillance data from 2016-2017, with particular focus on six countries in the Eastern Mediterranean Region (EMR) and 20 countries in the African Region (AFR) that reported WPV or circulating VDPVs (cVDPVs) during 2011-2017. Included in the 20 AFR countries are the three most affected by the 2014-2015 Ebola virus disease (Ebola) outbreak (Guinea, Liberia, and Sierra Leone), even though only one (Guinea) reported WPV or cVDPVs during the surveillance period. During 2017, a total of 14 (70%) of the 20 AFR countries and five (83%) of the six EMR countries met both surveillance quality indicators at the national level; however, provincial-level variation was seen. Surveillance strengthening activities are needed in specific countries of these regions to provide evidence supporting ultimate certification of the interruption of poliovirus circulation.


Feasibility and acceptability of two incentive-based implementation strategies for mental health therapists implementing cognitive-behavioral therapy: a pilot study to inform a randomized controlled trial.
Informed by our prior work indicating that therapists do not feel recognized or rewarded for implementation of evidence-based practices, we tested the feasibility and acceptability of two incentive-based implementation strategies that seek to improve therapist adherence to cognitive-behavioral therapy for youth, an evidence-based practice. This study was conducted over 6 weeks in two community mental health agencies with therapists (n = 11) and leaders (n = 4). Therapists were randomized to receive either a financial or social incentive if they achieved a predetermined criterion on adherence to cognitive-behavioral therapy. In the first intervention period (block 1; 2 weeks), therapists received the reward they were initially randomized to if they achieved criterion. In the second intervention period (block 2; 2 weeks), therapists received both rewards if they achieved criterion. Therapists recorded 41 sessions across 15 unique clients over the project period. Primary outcomes included feasibility and acceptability. Feasibility was assessed quantitatively. Fifteen semi-structured interviews were conducted with therapists and leaders to assess acceptability. Difference in therapist adherence by condition was examined as an exploratory outcome. Adherence ratings were ascertained using an established and validated observational coding system of cognitive-behavioral therapy. Both implementation strategies were feasible and acceptable-however, modifications to study design for the larger trial will be necessary based on participant feedback. With respect to our exploratory analysis, we found a trend suggesting the financial reward may have had a more robust effect on therapist adherence than the social reward. Incentive-based implementation strategies can be feasibly administered in community mental health agencies with good acceptability, although iterative pilot work is essential. Larger, fully powered trials are needed to compare the effectiveness of implementation strategies to incentivize and enhance therapists' adherence to evidence-based practices such as cognitive-behavioral therapy.


Detection of σ-alkane complexes of manganese by NMR and IR spectroscopy in solution: (η5-C5H5)Mn(CO)2(ethane) and (η5-C5H5)Mn(CO)2(isopentane).
Irradiation of CpMn(CO)3 in liquid ethane at 135 K at 355 nm yields a photoproduct that exhibits ν(CO) bands in the IR spectrum shifted to low wavenumber with respect to CpMn(CO)3 that are indicative of a Mn(i) dicarbonyl. Parallel experiments employing in situ irradiation within an NMR probe (133 K, 355 nm photolysis) reveal the 1H NMR signals of this product and confirm its formulation as the σ-ethane complex CpMn(CO)2(η2-C1-H-ethane). The resonance of its coordinated C-H group is observed at δ -5.84 and decays with lifetime of ca. 360 s. Analogous photolysis experiments in isopentane solution with IR detection produce CpMn(CO)2(η2-C-H-isopentane) with similar IR bands to those of CpMn(CO)2(η2-C-H-ethane). 1H NMR spectra of the same species were obtained by irradiation of CpMn(CO)3 in a 60 : 40 mixture of propane and isopentane; three isomers of CpMn(CO)2(η2-C-H-isopentane) were detected with coordination of manganese at the two inequivalent methyl positions and at the methylene group, respectively. The lifetimes of these isomers are ca. 380 ± 20 s at 135 K and do not vary significantly from each other. These σ-complexes of manganese are far more reactive than those of related CpRe(CO)2(alkane) complexes which are stable in solution at 170-180 K. The room temperature lifetimes of CpMn(CO)2(η2-C-H-ethane) and CpMn(CO)2(η2-C-H-isopentane), as determined by TRIR spectroscopy, are 2.0 ± 0.1 and 28 ± 1 μs, respectively.


Pathological effects of Arcobacter cryaerophilus infection in rainbow trout (Oncorhynchus mykiss Walbaum).
Arcobacter cryaerophilus was isolated from naturally infected rainbow trout (Oncorhynchus mykiss Walbaum), and its pathogenicity was tested by intramuscular injection into 40 healthy 1-year-old rainbow trout at 16 degrees C. The lethal dosage of 50% end point (LD50) for A. cryaerophilus was calculated 2.25 x 10(4) viable cells. Experimental infection caused deaths with gross clinical abnormalities such as degenerated opercula and gills, liver damage, haemorrhagic kidney and serous fluid in swollen intestines. The counts of A. cryaerophilus in kidney, liver and gills of experimentally infected fish ranged from 1.59 x 10(10) colony forming units (cfu)/g to 7.41 x 10(12) cfu/g. The means of erythrocyte (RBC) count, haematocrit level, serum cholesterol, triglyceride, albumin and total protein concentrations in the blood of the experimentally infected rainbow trout group were significantly lower than in the healthy fish. Leukocyte (WBC) counts of the experimentally infected rainbow trout were significantly higher than those of healthy fish. The present work shows that the selected blood characteristics may be good indicators of response to infections in rainbow trout.


Inbreeding and outbreeding depression in Caenorhabditis nematodes.
The nematode Caenorhabditis elegans reproduces primarily by self-fertilization of hermaphrodites, yet males are present at low frequencies in natural populations (androdioecy). The ancestral state of C. elegans was probably gonochorism (separate males and females), as in its relative C. remanei. Males may be maintained in C. elegans because outcrossed individuals escape inbreeding depression. The level of inbreeding depression is, however, expected to be low in such a highly selfing species, compared with an outcrosser like C. remanei. To investigate these issues, we measured life-history traits in the progeny of inbred versus outcrossed C. elegans and C. remanei individuals derived from recently isolated natural populations. In addition, we maintained inbred lines of C. remanei through 13 generations of full-sibling mating. Highly inbred C. remanei showed dramatic reductions in brood size and relative fitness compared to outcrossed individuals, with evidence of both direct genetic and maternal-effect inbreeding depression. This decline in fitness accumulated over time, causing extinction of nearly 90% of inbred lines, with no evidence of purging of deleterious mutations from the remaining lines. In contrast, pure strains of C. elegans performed better than crosses between strains, indicating outbreeding depression. The results are discussed in relation to the evolution of androdioecy and the effect of mating system on the level of inbreeding depression.


Physiological vagility affects population genetic structure and dispersal and enables migratory capacity in vertebrates.
Vagility is defined as the relative capacity for movement. We developed previously a quantitative metric in vertebrates for physiological vagility (PV), the speed at which an animal can move sustainably, incorporating aerobic capacity, body size, body temperature, and transport costs, allowing quantitative tests of whether PV can explain variation in interclass population genetic structure and behaviors involved in dispersal. We found that PV increased with body mass, correlated with maximal dispersal distances, and was inversely related to genetic structure in multiple vertebrate groups. Here we review these relationships and expand our analysis to include additional groups; we also suggest that PV may be utilized to partially explain variation in migratory capacity between groups. We show a positive correlation between PV and maximum migration distance (MMAX) in most groups that reflects many of the relationships observed between PV and dispersal. Flying birds, marine mammals, and large terrestrial mammals display the greatest MMAX and each of these groups has the highest PV among vertebrate groups, while reptiles and small terrestrial mammals had the lowest PV and MMAX. By contrast, marine turtles have exceptional MMAX but do not possess high PV. We suggest that PV is an important mechanism enabling both dispersal and migratory capacity, and affects genetic structure, but that other life history characteristics also need to be considered.


Human impacts on regional avian diversity and abundance.
Patterns of association between humans and biodiversity typically show positive, negative, or negative quadratic relationships and can be described by 3 hypotheses: biologically rich areas that support high human population densities co-occur with areas of high biodiversity (productivity); biodiversity decreases monotonically with increasing human activities (ecosystem stress); and biodiversity peaks at intermediate levels of human influence (intermediate disturbance). To test these hypotheses, we compared anthropogenic land cover and housing units, as indices of human influence, with bird species richness and abundance across the Midwestern United States. We modeled richness of native birds with 12 candidate models of land cover and housing to evaluate the empirical evidence. To assess which species were responsible for observed variation in richness, we repeated our model-selection analysis with relative abundance of each native species as the response and then asked whether natural-history traits were associated with positive, negative, or mixed responses. Native avian richness was highest where anthropogenic land cover was lowest and housing units were intermediate based on model-averaged predictions among a confidence set of candidate models. Eighty-three of 132 species showed some pattern of association with our measures of human influence. Of these species approximately 40% were negatively associated, approximately 6% were positively associated, and approximately 7% showed evidence of an intermediate relationship with human influence measures. Natural-history traits were not closely related to the direction of the relationship between abundance and human influence. Nevertheless, pooling species that exhibited any relationship with human influence and comparing them with unrelated species indicated they were significantly smaller, nested closer to the ground, had shorter incubation and fledging times, and tended to be altricial. Our results support the ecosystem-stress hypothesis for the majority of individual species and for overall species diversity when focusing on anthropogenic land cover. Nevertheless, the great variability in housing units across the land-cover gradient indicates that an intermediate-disturbance relationship is also supported. Our findings suggest preemptive conservation action should be taken, whereby areas with little anthropogenic land cover are given conservation priority. Nevertheless, conservation action should not be limited to pristine landscapes because our results showed that native avian richness and the relative abundance of many species peaked at intermediate housing densities and levels of anthropogenic land cover.


The Effect of Increasing Donor Age on Myocardial Ischemic Tolerance in a Rodent Model of Donation After Circulatory Death.
Hearts from older donors or procured via donation after circulatory death (DCD) can alleviate transplant waitlist; however, these hearts are particularly vulnerable to injury caused by warm ischemic times (WITs) inherent to DCD. This study investigates how the combination of increasing donor age and pharmacologic supplementation affects the ischemic tolerance and functional recovery of DCD hearts and how age impacts cardiac mitochondrial respiratory capacity and oxidative phosphorylation. Wistar rats (12-, 18-, and 24-mo-old) were subjected to DCD with 20-min fixed WIT. Hearts were procured, instrumented onto a Langendorff perfusion circuit, flushed with Celsior preservation solution with or without supplementation (glyceryl trinitrate [GTN]/erythropoietin [EPO]/zoniporide [Z]) and perfused (Krebs-Henseleit buffer, 37°C Langendorff 30-min, working 30-min). Cardiac functional recovery of aortic flow (AF), coronary flow (CF), cardiac output (CO), and lactate dehydrogenase release were measured. Native heart tissue (3-, 12-, and 24-mo) were assessed for mitochondrial respiratory capacity. Unsupplemented 18- and 24-month DCD hearts showed a 6-fold decrease in AF recovery relative to unsupplemented 12-month DCD hearts. GTN/EPO/Z supplementation significantly increased AF and CO recovery of 18-month DCD hearts to levels comparable to supplemented 12-month hearts; however, GTN/EPO/Z did not improve 24-month DCD heart recovery. Compared to 12-month heart tissue, 24-month hearts exhibited significantly impaired mitochondrial oxygen flux at complex I, II, and uncoupled maximal respiration stage. Reduced ischemic tolerance after DCD was associated with increasing age. Pharmacologic supplementation improves functional recovery of rat DCD hearts but only up to age 18 months, possibly attributed to a decline in mitochondrial respiratory capacity with increasing age.


Unemployment and mental health scarring during the life course.
There has been little research on the long-term relationship between unemployment experiences and mental health over the life course. This article investigates the relationship between youth unemployment as well as that of unemployment experiences during later periods and mental health at ages 16, 21, 30 and 42 years. The study makes use of the 'Northern Swedish Cohort' (NSC), a 27-year prospective cohort study. The cohort, investigated at ages 16, 18, 21, 30 and 42 years, consisted of all graduates from compulsory school in an industrial town in Sweden. Of the original 1083 participants, 94.3% of those still alive were still participating at the 27-year follow up. Mental health, measured through a three-item index of nervous symptoms, depressive symptoms and sleeping problems, was analysed using a repeated measures linear mixed models approach using ages 16, 21, 30 and 43 years. Unemployment exposure was measured as exposure to at least a 6-month spell during three periods; 18-21, 21-30 and 30-42 years. Youth unemployment was shown to be significantly connected with poorer mental health at all three target ages, 21, 30 and 42 years. Later singular unemployment experiences did not appear to have the same long-term negative effects. There was however an accumulation in poorer mental health among respondents with unemployment experiences during two, and even more so three, of the periods. There are long-term mental health scarring effects of exposure to youth unemployment and multiple exposure to unemployment during the life course.


Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity.
Diabetes and its complications are caused by chronic glucotoxicity driven by persistent hyperglycemia. In this article, we review the mechanisms of diabetic glucotoxicity by focusing mainly on hyperglycemic stress and carbon stress. Mechanisms of hyperglycemic stress include reductive stress or pseudohypoxic stress caused by redox imbalance between NADH and NAD(+) driven by activation of both the polyol pathway and poly ADP ribose polymerase; the hexosamine pathway; the advanced glycation end products pathway; the protein kinase C activation pathway; and the enediol formation pathway. Mechanisms of carbon stress include excess production of acetyl-CoA that can over-acetylate a proteome and excess production of fumarate that can over-succinate a proteome; both of which can increase glucotoxicity in diabetes. For hyperglycemia stress, we also discuss the possible role of mitochondrial complex I in diabetes as this complex, in charge of NAD(+) regeneration, can make more reactive oxygen species (ROS) in the presence of excess NADH. For carbon stress, we also discuss the role of sirtuins in diabetes as they are deacetylases that can reverse protein acetylation thereby attenuating diabetic glucotoxicity and improving glucose metabolism. It is our belief that targeting some of the stress pathways discussed in this article may provide new therapeutic strategies for treatment of diabetes and its complications.


Immunohistochemical marker panels for distinguishing between epithelioid mesothelioma and lung adenocarcinoma.
The distinction between epithelioid mesothelioma and lung adenocarcinoma remains an important diagnostic challenge for surgical pathologists. The aim of the present study was to select a limited and appropriate panel of antibodies that can differentiate between epithelioid mesothelioma and lung adenocarcinoma. Specimens of 90 epithelioid mesotheliomas and 51 lung adenocarcinomas obtained from Japanese cases were examined using calretinin, WT1, AE1/AE3, CAM5.2, cytokeratin (CK) 5/6, vimentin, epithelial membrane antigen (EMA), thrombomodulin, CEA, CA19-9, and CA125. Ninety-six percent of epithelioid mesotheliomas were positive for calretinin; 99% for WT1; 100% for AE1/AE; 97% for CAM5.2; 70% for CK 5/6; 91% for vimentin; 96% for EMA; 71% for thrombomodulin; 77% for mesothelin; 7% for CEA; 17% for CA19-9; and 85% for CA125. In contrast, 33% of lung adenocarcinomas were positive for calretinin; 16% for WT1; 100% for AE1/AE3, CAM5.2, and EMA; 41% for CK 5/6; 47% for vimentin; 20% for thrombomodulin; 69% for mesothelin; 98% for CEA; 73% for CA19-9; and 80% for CA125. For distinguishing between epithelioid mesothelioma and lung adenocarcinoma, the combination of CEA, calretinin and each WT1 or thrombomodulin was suggested to be the best panel of immunohistochemical markers.


Sleep and movement differentiates actions of two types of somatostatin-expressing GABAergic interneuron in rat hippocampus.
Neuropeptides acting on pre- and postsynaptic receptors are coreleased with GABA by interneurons including bistratified and O-LM cells, both expressing somatostatin but innervating segregated dendritic domains of pyramidal cells. Neuropeptide release requires high-frequency action potentials, but the firing patterns of most peptide/GABA-releasing interneurons during behavior are unknown. We show that behavioral and network states differentiate the activities of bistratified and O-LM cells in freely moving rats. Bistratified cells fire at higher rates during sleep than O-LM cells and, unlike O-LM cells, strongly increase spiking during sharp wave-associated ripples (SWRs). In contrast, O-LM interneurons decrease firing during sleep relative to awake states and are mostly inhibited during SWRs. During movement, both cell types fire cooperatively at the troughs of theta oscillations but with different frequencies. Somatostatin and GABA are differentially released to distinct dendritic zones of CA1 pyramidal cells during sleep and wakefulness to coordinate segregated glutamatergic inputs from entorhinal cortex and CA3.


Noncovalent tagging of siRNA with steroids for transmembrane delivery.
Short interfering RNA (siRNA) has broad applications in biology and medicine, and holds tremendous potential to become a new class of therapeutics for many diseases. As a highly anionic macrobiomolecule, its cytosolic delivery, however, has been a major roadblock in translation. Here, we report the development of small, bifunctional chemical tags capable of transporting siRNA directly into the cytosol. The bifunctional tags consist of a siRNA-binding moiety that interacts with siRNA non-covalently, and a steroid domain that readily fuses with the mammalian cell membrane. In contrast to the conventional covalently conjugated siRNA-steroid that enters cells largely via endocytosis which substantially limits siRNA bioavailability, the non-covalently tagged siRNA is cell membrane-permeant, avoiding the endocytic pathway. This new methodology enables effective RNA interference (RNAi) without the need of cationic transfection or endosomolytic agents, opening a new avenue for intracellular delivery of native biologics.


Replication checkpoint kinase Cds1 regulates Mus81 to preserve genome integrity during replication stress.
The replication checkpoint kinase Cds1 preserves genome integrity by stabilizing stalled replication forks. Cds1 targets substrates through its FHA domain. The Cds1 FHA domain interacts with Mus81, a subunit of the Mus81-Eme1 structure-specific endonuclease. We report here that Mus81 and Rhp51 are required for generating deletion mutations in fission yeast replication mutants that experience replication stress. A mutation in the Mus81 FHA-binding motif eliminates its Cds1-binding and Cds1-dependent phosphorylation. Furthermore, this mutation exacerbates the deletion mutator phenotype of a replication mutant, and induces a hyper-recombination phenotype in hydroxyurea-treated cells. In unperturbed cells, Mus81 associates with chromatin throughout S phase. In replication mutants grown at semipermissive temperature, Mus81 undergoes minor Cds1-dependent phosphorylation, remains chromatin-associated, generates deletion mutations, and maintains cell growth. Upon S-phase arrest by acute hydroxyurea treatment, Mus81 is not required for cell viability but is essential for recovery from replication fork collapse. Moreover, Mus81 undergoes extensive Cds1-dependent phosphorylation and dissociates from chromatin in hydroxyurea-arrested cells, thereby preventing it from cleaving stalled replication forks that could lead to fork breakage and chromosomal rearrangement. These results provide novel insights into how Cds1 regulates Mus81 accordingly when cells experience different replication stress to preserve genome integrity.


Compounded Low-dose Naltrexone for the Treatment of Guttate Psoriasis: A Case Report.
The ancient autoimmune skin condition psoriasis is still ubiquitous worldwide, produces the same, often-intolerable effects noted in its earliest recorded descriptions, and remains without cure. Management options designed to resolve the itchy, scaly, weeping, erythematous, and often widespread lesions of that disorder are now available, but they vary in efficacy, most are associated with the development of severe adverse effects, and many are prohibitively expensive. In this article, we describe the successful use of a compounded formulation of oral low-dose naltrexone to manage guttate psoriasis in a 75-year-old white male patient. That therapy produced only 1 adverse effect (dry skin near the lesions on the patient's arms and legs) and was relatively inexpensive. The formulation for that preparation and comments from the patient, the pharmacist who suggested its use, the prescriber, and the compounder who prepared it are included. Many clinicians are unaware of the benefits of compounded low-dose naltrexone in treating autoimmune diseases. We hope that this case report will encourage compounding pharmacists to consider and suggest it as an alternative therapy for patients who cannot tolerate or afford manufactured medications to treat psoriasis.


A methodology for generating a tailored implementation blueprint: an exemplar from a youth residential setting.
Tailored implementation approaches are touted as more likely to support the integration of evidence-based practices. However, to our knowledge, few methodologies for tailoring implementations exist. This manuscript will apply a model-driven, mixed methods approach to a needs assessment to identify the determinants of practice, and pilot a modified conjoint analysis method to generate an implementation blueprint using a case example of a cognitive behavioral therapy (CBT) implementation in a youth residential center. Our proposed methodology contains five steps to address two goals: (1) identify the determinants of practice and (2) select and match implementation strategies to address the identified determinants (focusing on barriers). Participants in the case example included mental health therapists and operations staff in two programs of Wolverine Human Services. For step 1, the needs assessment, they completed surveys (clinician N = 10; operations staff N = 58; other N = 7) and participated in focus groups (clinician N = 15; operations staff N = 38) guided by the domains of the Framework for Diffusion [1]. For step 2, the research team conducted mixed methods analyses following the QUAN + QUAL structure for the purpose of convergence and expansion in a connecting process, revealing 76 unique barriers. Step 3 consisted of a modified conjoint analysis. For step 3a, agency administrators prioritized the identified barriers according to feasibility and importance. For step 3b, strategies were selected from a published compilation and rated for feasibility and likelihood of impacting CBT fidelity. For step 4, sociometric surveys informed implementation team member selection and a meeting was held to identify officers and clarify goals and responsibilities. For step 5, blueprints for each of pre-implementation, implementation, and sustainment phases were generated. Forty-five unique strategies were prioritized across the 5 years and three phases representing all nine categories. Our novel methodology offers a relatively low burden collaborative approach to generating a plan for implementation that leverages advances in implementation science including measurement, models, strategy compilations, and methods from other fields.


Block response-adaptive randomization in clinical trials with binary endpoints.
In a clinical trial, response-adaptive randomization (RAR) uses accumulating data to weigh the randomization of remaining patients in favour of the better performing treatment. The aim is to reduce the number of failures within the trial. However, many well-known RAR designs, in particular, the randomized play-the-winner-rule (RPWR), have a highly myopic structure which has sometimes led to unfortunate randomization sequences when used in practice. This paper introduces random permuted blocks into two RAR designs, the RPWR and sequential maximum likelihood estimation, for trials with a binary endpoint. Allocation ratios within each block are restricted to be one of 1:1, 2:1 or 3:1, preventing unfortunate randomization sequences. Exact calculations are performed to determine error rates and expected number of failures across a range of trial scenarios. The results presented show that when compared with equal allocation, block RAR designs give similar reductions in the expected number of failures to their unmodified counterparts. The reductions are typically modest under the alternative hypothesis but become more impressive if the treatment effect exceeds the clinically relevant difference.


Distant positioning of proteasomal proteolysis relative to actively transcribed genes.
While it is widely acknowledged that the ubiquitin-proteasome system plays an important role in transcription, little is known concerning the mechanistic basis, in particular the spatial organization of proteasome-dependent proteolysis at the transcription site. Here, we show that proteasomal activity and tetraubiquitinated proteins concentrate to nucleoplasmic microenvironments in the euchromatin. Such proteolytic domains are immobile and distinctly positioned in relation to transcriptional processes. Analysis of gene arrays and early genes in Caenorhabditis elegans embryos reveals that proteasomes and proteasomal activity are distantly located relative to transcriptionally active genes. In contrast, transcriptional inhibition generally induces local overlap of proteolytic microdomains with components of the transcription machinery and degradation of RNA polymerase II. The results establish that spatial organization of proteasomal activity differs with respect to distinct phases of the transcription cycle in at least some genes, and thus might contribute to the plasticity of gene expression in response to environmental stimuli.


What Is Time Good for in Working Memory?
Giving people more time to process information in working memory improves their performance on working memory tasks. It is often assumed that free time given after presentation of an item enables maintenance processes to counteract forgetting of this item, suggesting that time has a retroactive benefit. Two other hypotheses-short-term consolidation and temporal distinctiveness-entail a local effect of time on immediately preceding and following items. Here, we show instead a novel global and proactive benefit of time in working memory. In three serial-recall experiments (Ns = 21, 25, and 26 young adults, respectively), we varied the position and duration of the free time within a seven-item list of consonants. Experiment 1 showed that the effect is global and not local. Experiments 2a and 2b showed that increased interitem time benefited performance only for the subsequent items, implying a proactive benefit. This finding rules out maintenance processes, short-term consolidation, and temporal distinctiveness as explanations of the free-time benefit but is consistent with the proposal of a gradually recovering encoding resource.


Anthropometric measures and the risk of endometrial cancer, overall and by tumor microsatellite status and histological subtype.
Obesity is an established risk factor for endometrial cancer, but this association is not well understood for subtypes of endometrial cancer. We evaluated the association of recent and adult-life obesity with subtypes of endometrial cancer based on microsatellite status (microsatellite-stable (MSS) vs. microsatellite-instable (MSI)) and histology (type I vs. type II). Analyses were based on a population-based case-control study (524 cases and 1,032 controls) conducted in Alberta, Canada (2002-2006) and included the following groupings of subtypes: MSS = 337 and MSI = 130; type I = 458 and type II = 66. Logistic and polytomous logistic regression were used to estimate odds ratios and 95% confidence intervals for overall endometrial cancer and subtypes of endometrial cancer, respectively. The risks of all subtypes of endometrial cancer, except type II, increased with an increase in all of the anthropometric characteristics examined. The risks for MSI tumors were suggestively stronger than those for MSS tumors; the risk with high (≥30) body mass index (weight (kg)/height (m)(2)) was significantly stronger for MSI tumors (odds ratio = 4.96, 95% confidence interval: 2.76, 8.91) than for MSS tumors (odds ratio = 2.33, 95% confidence interval: 1.66, 3.28) (P-heterogeneity = 0.02). Obesity is associated with most subtypes of endometrial cancer, and further studies are warranted to elucidate the biological mechanisms underlying the stronger risk for the MSI subtype with a high body mass index.


Delirium after elective surgery among elderly patients taking statins.
Postoperative delirium after elective surgery is frequent and potentially serious. We sought to determine whether the use of statin medications was associated with a higher risk of postoperative delirium than other medications that do not alter microvascular autoregulation. We conducted a retrospective cohort analysis of 284 158 consecutive patients in Ontario aged 65 years and older who were admitted for elective surgery. We identified exposure to statins from outpatient pharmacy records before admission. We identified delirium by examining hospital records after surgery. About 7% (n = 19 501) of the patients were taking statins. Overall, 3195 patients experienced postoperative delirium; the rate was significantly higher among patients taking statins (14 per 1000) than among those not taking statins (11 per 1000) (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.15-1.47, p < 0.001). The increased risk of postoperative delirium persisted after we adjusted for multiple demographic, medical and surgical factors (OR 1.28, 95% CI 1.12-1.46) and exceeded the increased risk of delirium associated with prolonging surgery by 30 minutes (OR 1.20, 95% CI 1.19-1.21). The relative risk associated with statin use was somewhat higher among patients who had noncardiac surgery than among those who had cardiac surgery (adjusted OR 1.33, 95% CI 1.16-1.53), and extended to more complicated cases of delirium. We did not observe an increased risk of delirium with 20 other cardiac or noncardiac medications. The use of statins is associated with an increased risk of postoperative delirium among elderly patients undergoing elective surgery.


Self-reported pain perception of patients after mucosal graft harvesting in the palatal area.
To evaluate the patient-reported pain perception after palatal graft harvesting during a 4 weeks healing period Ninety patients, scheduled for different periodontal and peri-implant plastic surgeries requiring palatal mucosal graft harvesting, were consecutively recruited. Mucosal thickness was measured at the donor sites with an ultrasonic device prior to the surgeries. Graft thickness, length, and width were assessed after harvesting, and the wound areas were calculated. Based on a Visual Analogue Scale (VAS), the patients were asked to report their perceived pain after the intervention and 1, 3, 7, 14, 21 and 28 days thereafter. Pain was most pronounced on the first postoperative day and decreased within the course of time. Graft thickness directly correlated with the amount of pain perceived while increased palatal mucosal thickness before and after graft harvesting decreased pain levels. The denuded wound surface area, however, did not influence the perceived pain level. The wound depth at the donor site (graft thickness) was positively correlated with the patient's perception for pain. The wound surface area, however, did not influence the perceived pain level.


Should plasma be transfused prophylactically before invasive procedures?
Plasma transfusion to correct abnormal coagulation test results prior to an invasive procedure is a common clinical practice; however, there are no evidence-based guidelines. This review aims to analyze the most recent publications to either support or disprove such practice. Due to heightened awareness of transfusion-related acute lung injury and volume overload in susceptible patients, clinicians are increasingly questioning the validity of prophylactic plasma transfusion. Recently, several articles, reviews and clinical studies (although small and poorly designed) have shown no benefit of prophylactic plasma transfusion in either correcting abnormal coagulation tests or reducing perceived risk of hemorrhage. The use of sensitive reagents (especially for prothrombin time) has resulted in increased incidence of abnormal preprocedure coagulation screening test results - tests that are not designed to assess risk of bleeding in patients without a history of bleeding. Transfusion of plasma prior to an invasive procedure to correct mild to moderate abnormal test results neither corrects the abnormality nor reduces the perceived bleeding risk.


Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet.
In 2003, an international working group last reported on recommendations for diagnosis, response assessment, and treatment outcomes in acute myeloid leukemia (AML). Since that time, considerable progress has been made in elucidating the molecular pathogenesis of the disease that has resulted in the identification of new diagnostic and prognostic markers. Furthermore, therapies are now being developed that target disease-associated molecular defects. Recent developments prompted an international expert panel to provide updated evidence- and expert opinion-based recommendations for the diagnosis and management of AML, that contain both minimal requirements for general practice as well as standards for clinical trials. A new standardized reporting system for correlation of cytogenetic and molecular genetic data with clinical data is proposed.


Isoflavones, equol and cardiovascular disease: pharmacological and therapeutic insights.
Isoflavones are an important class of phytoestrogens that are found at extrememly high levels in soy. Up until recently, daidzein and genistein were considered to be the most important and hence most studied isoflavones, however more recently attention has shifted to isoflavone metabolies. Equol represents the main active product of daidzein metabolism, produced via specific microflora in the gut. It has a longer half life and greater biological activity, including superior antioxidant activity. Yet, whilst the majority of animals produce equol following soy consumption, as much as 30-50 % of the adult human population cannot. This inability to produce equol in as much as half the population is thought to provide some explanation for the failure of soy to reveal any substantial health benefits in clinical studies. This article will comprehensively review literature investigating the potential cardiovascular benefits of daidzein and its metabolites, paying particular attention to equol. It will focus on the relative vasorelaxant activity, effects on nitric oxide synthase (NOS), antioxidant activity and potential for the treatment and prevention of hypertension and stroke. Findings obtained in both animal and human studies will be reviewed with the hope of gaining an insight into the experimental and clinical importance of equol to the cardiovascular benefits of soy.


Investigating the Evidence of Behavioral, Cognitive, and Psychiatric Endophenotypes in Autism: A Systematic Review.
Substantial evidence indicates that parents of autistic individuals often display milder forms of autistic traits referred to as the broader autism phenotype (BAP). To determine if discrete endophenotypes of autism can be identified, we reviewed the literature to assess the evidence of behavioral, cognitive, and psychiatric profiles of the BAP. A systematic review was conducted using EMBASE, MEDLINE, PsycINFO, PsycEXTRA, and Global Health. Sixty papers met our inclusion criteria and results are discussed according to the proportion of studies that yield significant deficits per domain. The behavioral, cognitive, and psychiatric endophenotypes in parents of autistic probands are still not clarified; however, evidence suggests mild social/communication deficits, rigid/aloof personality traits, and pragmatic language difficulties as the most useful sociobehavioral candidate endophenotype traits. The existence of deficits in the cognitive domain does suggest familial vulnerability for autism. Furthermore, increased depressed mood and anxiety can also be useful markers; however, findings should be interpreted with caution because of the small number of studies in such heterogeneously broad domains and several methodological limitations.


Treatment of Ocular Pyogenic Granuloma With Topical Timolol.
Pyogenic granulomas, acquired vascular lesions, form on the ocular or palpebral surface related to inflammation from chalazia, trauma, or surgery. They can be unsightly, spontaneously bleed, and cause irritation to patients. A case series is presented of 4 consecutive children with acquired ocular surface pyogenic granulomas treated at Boston Children's Hospital from 2014 to 2016 with only topical timolol, 0.5%, twice daily for a minimum of 21 days. In all cases, complete resolution occurred within the treatment period with no recurrence for at least 3 months. There were no adverse effects from the timolol during follow-up. This case series of 4 children, while limited to no greater than 12 weeks of follow-up and without control children, suggests that ocular surface pyogenic granulomas respond to topical timolol treatment, which has a lower adverse-effect profile than conventional topical steroid treatments or other medical or surgical therapies. If confirmed in larger studies with longer follow-up and controls, this may be the desired treatment modality.