Self-administered Expanded Disability Status Scale with functional system scores correlates well with a physician-administered test.
Patient-administered measures are needed to assess disability cost-effectively in large epidemiological studies. An outpatient clinic in a large multiple sclerosis center. A self-administered EDSS questionnaire was developed (EDSS-S). Consecutive patients with clinically definite multiple sclerosis completed the EDSS-S (n=95). During the same visit, a physician completed an EDSS (EDSS-P). Scores below 4.0 were determined using functional system (FS) scores. Scores above 4.0 were calculated by two methods, using gait alone and using gait and functional system scores combined. EDSS-P scores ranged from 0-9.5 (mean 5.1, median 5.0, 78% female, age 17-78, mean age 45). Mean EDSS-P, EDSS-S and intraclass correlation coefficients of agreement were: EDSS using ambulation alone (4.6, 5.1, 0.89), EDSS using ambulation and FS scores (4.6, 5.3, 0.87), bowel/bladder FS scores (1.6, 1.7, 0.79), pyramidal FS scores (2.1, 2.4, 0.67), sensory FS scores (1.6, 2.1, 0.60), cerebellar FS scores (1.1, 1.6, 0.55), brainstem FS scores (0.5, 1.2, 0.45), vision FS scores (1.9, 1.3, 0.38), cerebral FS scores (0.6, 2.3, 0.27). Very good correlation was seen between patient and physician scores for EDSS and the bowel/bladder FS score. Four other FS scores correlated moderately. In general, patients scored themselves more disabled than physicians.


Juvenile Justice, Mental Health, and the Transition to Adulthood: A Review of Service System Involvement and Unmet Needs in the U.S.
Although adolescents are the primary focus of juvenile justice, a significant number of young people involved with this system are considered transition age youth (i.e., 16-25 years of age). The aim of this review is to summarize the specific needs of transition age youth with mental health conditions involved with the juvenile justice system, identify the multiple service systems relevant to this group, and offer recommendations for policies and practice. A comprehensive search strategy was used to identify and synthesize the literature. Findings highlight the paucity of research specific to transition age youth. Thus, we also summarized relevant research on justice-involved adolescents, with a focus evaluating its potential relevance in the context of the unique milestones of the transition age, including finishing one's education, setting and working towards vocational goals, and transitioning from ones' family of origin to more independent living situations. Existing programs and initiatives relevant to transition age youth with mental health conditions are highlighted, and nine specific recommendations for policy and practice are offered.


Using pravastatin to improve the vascular reactivity in a mouse model of soluble fms-like tyrosine kinase-1-induced preeclampsia.
To estimate the effects of pravastatin on the altered vascular function in a mouse model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase-1 (sFlt-1). Pregnant CD1 mice, at day 8 of gestation, were randomly allocated to injection using the tail vein of the adenovirus carrying sFlt-1 (10 plaque-forming units in 100 microliters; sFlt-1 group) or mFc (10 plaque-forming units) as virus control, and then to receive pravastatin (Pra; 5 mg/kg/d) dissolved in drinking water or control. The mice in four groups (sFlt-1, sFlt-1-pravastatin, mFc, and mFc-pravastatin; n=4-6 per group) were killed at day 18 of gestation and 2-mm segments of carotid artery were used for vascular reactivity studies. Serum sFlt-1 levels were also measured by enzyme-linked immunosorbent assay. Mice in the sFlt-1 group had the highest responses to phenylephrine. Treatment with pravastatin decreased the contractile responses to phenylephrine (maximal effect [mean+/-standard error of the mean] 137.35+/- 27.70 compared with 42.24+/-8.76; P=.006) for sFlt-1 compared with sFlt-1-pravastatin, respectively. There were no differences in the contractile responses to thromboxane A2. The vasorelaxant responses to acetylcholine were significantly highest in the mFc-pravastatin group, with a maximal effect of 108.37+/-5.25 compared with 89.77+/-3.96 in the mFc group (P=.008), and those with sodium nitroprusside were not different across the four groups. Serum sFlt-1 levels were not different at baseline (day 8) but were significantly lower in sFlt-1-pravastatin compared with sFlt-1 at day 18 (59.42+/-5.31 compared with 102.59+/-15.15 ng/mL; P=.01). Pravastatin improved the vascular reactivity in this murine model of preeclampsia by decreasing sFlt-1 levels. Statins should be evaluated for the prevention of the vascular abnormalities of preeclampsia.


Feasibility Study: Colombian Caribbean Folk Dances to Increase Physical Fitness and Health-Related Quality of Life in Older Women.
The objectives of the study were to describe the feasibility of an intervention in older women based on folk dances of the Colombian Caribbean region, and to analyze the effects of the intervention on physical fitness and health-related quality of life (HRQoL). A pilot study was conducted in a sample of 27 participants, 15 in the intervention group (IG) and 12 in the comparison group (CG). Caribbean Colombian dance rhythms were introduced as an intervention that lasted 12 weeks. Recruitment and retention was not optimal. Treatment fidelity components indicated that intervention was administered as intended. IG participants showed positive and statistically significant changes in some components of physical fitness. No significant changes were observed in HRQoL indicators for either group. In conclusion, the intervention was feasible, but recruitment and retention was challenging. Folk dances of the Colombian Caribbean region provoked significant results in physical fitness but not in HRQoL.


Systematics of the ant genus Proceratium Roger (Hymenoptera, Formicidae, Proceratiinae) in China - with descriptions of three new species based on micro-CT enhanced next-generation-morphology.
The genus Proceratium Roger, 1863 contains cryptic, subterranean ants that are seldom sampled and rare in natural history collections. Furthermore, most Proceratium specimens are extremely hairy and, due to their enlarged and curved gaster, often mounted suboptimally. As a consequence, the poorly observable physical characteristics of the material and its scarcity result in a rather challenging alpha taxonomy of this group. In this study, the taxonomy of the Chinese Proceratium fauna is reviewed and updated by combining examinations of traditional light microscopy with x-ray microtomography (micro-CT). Based on micro-CT scans of seven out of eight species, virtual 3D surface models were generated that permit in-depth comparative analyses of specimen morphology in order to overcome the difficulties to examine physical material of Proceratium. Eight Chinese species are recognized, of which three are newly described: Proceratium bruelheidei Staab, Xu & Hita Garcia, sp. n. and P. kepingmaisp. n. belong to the P. itoi clade and have been collected in the subtropical forests of southeast China, whereas P. shoheisp. n. belongs to the P. stictum clade and it is only known from a tropical forest of Yunnan Province. Proceratium nujiangense Xu, 2006 syn. n. is proposed as a junior synonym of P. zhaoi Xu, 2000. These taxonomic acts raise the number of known Chinese Proceratium species to eight. In order to integrate the new species into the existing taxonomic system and to facilitate identifications, an illustrated key to the worker caste of all Chinese species is provided, supplemented by species accounts with high-resolution montage images and still images of volume renderings of 3D models based on micro-CT. Moreover, cybertype datasets are provided for the new species, as well as digital datasets for the remaining species that include the raw micro-CT scan data, 3D surface models, 3D rotation videos, and all light photography and micro-CT still images. These datasets are available online (Dryad, Staab et al. 2018, http://dx.doi.org/10.5061/dryad.h6j0g4p).


Seasonal baseline of nutrients and stable isotopes in a saline lake of Argentina: biogeochemical processes and river runoff effects.
The seasonal variability of inorganic and organic nutrients and stable isotopes and their relations with plankton and environmental conditions were monitored in Lake Chasicó. Principal component analysis evidenced the strong influence of the river runoff on several biogeochemical variables. Silicate concentrations were controlled by diatom biomass and river discharge. Higher values of nitrate and soluble reactive phosphorus (SRP) indicated agricultural uses in the river basin. Elevated pH values (∼ 9) inhibiting nitrification in the lake explained partially the dominance of ammonium: ∼ 83 % of dissolved inorganic nitrogen (DIN). The low DIN/SRP ratio inferred nitrogen limitation, although the hypotheses of iron and CO2 limitation are relevant in alkaline lakes. Particulate organic matter (POM) and dissolved organic matter (DOM) were mainly of autochthonous origin. The main allochthonous input was imported by the river as POM owning to the arid conditions. Dissolved organic carbon was likely top-down regulated by the bacterioplankton grazer Brachionus plicatilis. The δ(13)C signature was a good indicator of primary production and its values were influenced probably by CO2 limitation. The δ(15)N did not evidence nitrogen fixation and suggested the effects of anthropogenic activities. The preservation of a good water quality in the lake is crucial for resource management.


Isoliquiritigenin attenuates spinal tuberculosis through inhibiting immune response in a New Zealand white rabbit model.
Spinal tuberculosis (ST) is the tuberculosis caused by Mycobacterium tuberculosis (Mtb) infections in spinal curds. Isoliquiritigenin 4,2',4'-trihydroxychalcone, ISL) is an anti-inflammatory flavonoid derived from licorice (Glycyrrhiza uralensis), a Chinese traditional medicine. In this study, we evaluated the potential of ISL in treating ST in New Zealand white rabbit models. In the model, rabbits (n=40) were infected with Mtb strain H37Rv or not in their 6th lumbar vertebral bodies. Since the day of infection, rabbits were treated with 20 mg/kg and 100 mg/kg of ISL respectively. After 10 weeks of treatments, the adjacent vertebral bone tissues of rabbits were analyzed through Hematoxylin-Eosin staining. The relative expression of Monocyte chemoattractant protein-1 (MCP-1/CCL2), transcription factor κB (NF-κB) p65 in lymphocytes were verified through reverse transcription quantitative real-time PCR (RT-qPCR), western blotting and enzyme-linked immunosorbent assays (ELISA). The serum level of interleukin (IL)-2, IL-4, IL-10 and interferon γ (IFN-γ) were evaluated through ELISA. The effects of ISL on the phosphorylation of IκBα, IKKα/β and p65 in NF-κB signaling pathways were assessed through western blotting. In the results, ISL has been shown to effectively attenuate the granulation inside adjacent vertebral tissues. The relative level of MCP-1, p65 and IL-4 and IL-10 were retrieved. NF-κB signaling was inhibited, in which the phosphorylation of p65, IκBα and IKKα/β were suppressed whereas the level of IκBα were elevated. In conclusion, ISL might be an effective drug that inhibited the formation of granulomas through downregulating MCP-1, NF-κB, IL-4 and IL-10 in treating ST.


Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging.
Diabetes and aging are commonly accompanied by arterio- and atherosclerosis. Infiltration of the arterial subendothelial intima by macrophages/monocytes is an important early event preceding the development of atheromatous lesions; these macrophages are known to produce mitogenic factors in early atherosclerotic lesions. It has been previously shown that, over time, vascular matrix accumulates proteins nonenzymatically modified by advanced glycosylation end products (AGEs). In view of the fact that macrophages/monocytes have AGE-specific receptors associated with the expression of several growth factors, we investigated the possibility that AGEs mediate initial monocyte-vessel wall interactions that occur before overt formation of vascular lesions. This study demonstrates that (i) in vitro- and in vivo-formed AGEs are chemotactic for human blood monocytes, (ii) sub-endothelial AGEs can selectively induce monocyte migration across an intact endothelial cell monolayer, and (iii) subsequent monocyte interaction with AGE-containing matrix results in the expression of platelet-derived growth factor. These results support the existing hypothesis that in vivo-forming glucose-derived protein adducts can act as signals for the normal turnover of senescent tissue protein by means of the AGE-specific receptor system. Time-dependent glucose-induced deposition of AGEs on matrix proteins may promote monocyte infiltration into the subendothelium. Subsequent AGE-triggered macrophage activation and consequent elaboration of proliferative factors may normally coordinate remodeling but may also lead to the diverse pathogenic changes typical of arterio- and atherosclerosis in diabetic or aging populations.


FDG PET Imaging of the Pain Matrix in Neuropathic Pain Model Rats.
Pain is an unpleasant subjective experience that is usually modified by complex multidimensional neuropsychological processes. Increasing numbers of neuroimaging studies in humans have characterized the hierarchical brain areas forming a pain matrix, which is involved in the different dimensions of pain components. Although mechanistic investigations have been performed extensively in rodents, the homologous brain regions involved in the multidimensional pain components have not been fully understood in the rodent brain. Herein, we successfully identified several brain regions activated in response to mechanical allodynia in neuropathic pain rat models using an alternative neuroimaging method based on 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG PET) scanning. Regions such as the medial prefrontal cortex, primary somatosensory cortex hindlimb region, and the centrolateral thalamic nucleus were identified. Moreover, brain activity in these regions was positively correlated with mechanical allodynia-related behavioral changes. These results suggest that FDG PET imaging in neuropathic pain model rats enables the evaluation of regional brain activity encoding the multidimensional pain aspect. It could thus be a fascinating tool to bridge the gap between preclinical and clinical investigations.


Salvage surgery for local recurrence after carbon ion radiotherapy for patients with lung cancer.
Carbon ion radiotherapy (CIRT) has been expected to be an alternative for surgery for early-stage non-small-cell lung cancer (NSCLC) and adopted as the second-best choice even in operable patients although local recurrence after CIRT is sometimes experienced. The purpose of this study was to investigate the demographic data, perioperative courses and therapeutic outcomes of patients who underwent salvage resection for local recurrence after CIRT. From November 1994 to February 2012, CIRT was applied for 602 c-T1/T2/T3N0M0 NSCLC lesions of 599 patients at the National Institute of Radiological Science. A total of 95 (16%) patients were diagnosed as having local recurrence, of whom 12 underwent salvage surgeries. The medical records were retrospectively reviewed. There were 7 men and 5 women (mean age, 63 ± 7.4 years). The clinical stages upon initial presentation with NSCLC were as follows: 4 IA, 7 IB and 1 IIB. All the patients were operable, but refused surgery and underwent CIRT. The median progression-free survival time after CIRT was 20 months (range, 7.1-77 months), and salvage surgery was performed at a median of 24 months (range, 9-78 months) after CIRT. All surgeries were successfully performed without any significant CIRT-related adhesions during the surgery, resulting in no mortality or Clavien-Dindo grade 3-4 postoperative complications. However, the distribution of pathological stages was as follows: 4 IA, 3 IB, 2 IIB, 2 IIIA and 1 IV, which included 6 upstages from the clinical stages before CIRT. The Kaplan-Meier estimate of overall survival after the salvage surgery showed that the 3-year survival rate was 82%. The dose intensity of CIRT spared the hilum of the lungs and parietal pleura, none of the patients developed adhesions outside of the radiation field, such that the salvage surgeries for local recurrence after CIRT were safe and feasible.


Protected areas as frontiers for human migration.
Causes of human population growth near protected areas have been much debated. We conducted 821 interviews in 16 villages around Budongo Forest Reserve, Masindi district, Uganda, to explore the causes of human migration to protected areas and to identify differences in forest use between migrant and nonmigrant communities. We asked subjects for information about birthplace, migration, household assets, household activities, and forest use. Interview subjects were categorized as nonmigrants (born in one of the interview villages), socioeconomic migrants (chose to emigrate for economic or social reasons) from within Masindi district (i.e., local migrants) and from outside the Masindi district (i.e., regional migrants), or forced migrants (i.e., refugees or internally displaced individuals who emigrated as a result of conflict, human rights abuses, or natural disaster). Only 198 respondents were born in interview villages, indicating high rates of migration between 1998 and 2008. Migrants were drawn to Budongo Forest because they thought land was available (268 individuals) or had family in the area (161 individuals). A greater number of regional migrants settled in villages near Lake Albert than did forced and local migrants. Migration category was also associated with differences in sources of livelihood. Of forced migrants 40.5% earned wages through labor, whereas 25.5% of local and 14.5% of regional migrants engaged in wage labor. Migrant groups appeared to have different effects on the environment. Of respondents that hunted, 72.7% were regional migrants. Principal component analyses indicated households of regional migrants were more likely to be associated with deforestation. Our results revealed gaps in current models of human population growth around protected areas. By highlighting the importance of social networks and livelihood choices, our results contribute to a more nuanced understanding of causes of migration and of the environmental effects of different migrant groups.


Liver fat content determined by magnetic resonance imaging and spectroscopy.
Hepatic steatosis as the most prevalent liver disorder can either be related to alcoholic liver disease (ALD) or non-alcoholic fatty liver disease (NAFLD). In both conditions, hepatocytes excessively accumulate fat-containing vacuoles within their cytoplasm, which is the key histological feature. In contrast to ALD, NAFLD is commonly associated with metabolic syndrome, obesity and insulin resistance. To determine increased liver fat content, liver biopsy is currently considered the gold standard. Besides the invasive technique, various other non-invasive techniques have been developed, such as ultrasound, computed tomography (CT), magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) based methods. Among these techniques, ultrasound and CT provide only qualitative information about hepatic steatosis, whereas MRS- or MRI-based methods are able to determine even small amounts of fat accurately. These non-invasive magnetic resonance techniques have already proven their great potential, especially in longitudinal and cross-sectional studies regarding various metabolic conditions and medical treatment regimens. In this review, the most common, non-invasive MRS/MRI techniques for assessment of intrahepatic lipid content are described with their inherent advantages and limitations.


Development of the pattern of photoreceptors in the chick retina.
The various classes of photoreceptor cells found in vertebrate retinae are organized in specific patterns, which are important for visual function. It is not known how these patterns are achieved during development. The chick retina provides an excellent model system in which to investigate this issue, containing cone opsins red, green, blue, and violet, as well as the rod-specific opsin rhodopsin. In this study, whole-mount in situ hybridization has revealed striking differences among opsins in both spatial and temporal aspects of expression. The long-wavelength cone opsins, red and green, were first detected in a small spot within the area centralis at embryonic day 14 (E14). In contrast, the short-wavelength cone opsins, blue and violet, were not detected until 2 d later and showed domains of expression both within the area centralis and in temporal retina. The first rhodopsin transcripts were seen at E15 in inferior retina. When opsin expression was first detected, there were differences in the localization of RNA within the inner segment of cone photoreceptors, suggesting that morphological differentiation preceded the expression of photopigment molecules. Marked differences in the distribution of rods and cones were also found. Within the area centralis, a circular rod-free zone bisected by a narrow rod-sparse region along the nasal-temporal axis was evident as soon as rhodopsin RNA could be detected. Such specialized regions appear to be set aside soon after photoreceptor cells become postmitotic, as evidenced by a spatially restricted pattern of visinin RNA observed at E7. The onset of particular opsins in restricted regions of the retina suggest an underlying pattern related to visual function in the chick.


Monitoring alkylphenols in water using the polar organic chemical integrative sampler (POCIS): Determining sampling rates via the extraction of PES membranes and Oasis beads.
Polar organic chemical integrative samplers (POCIS) have previously been used to monitor alkylphenol (AP) contamination in water and produced water. However, only the sorbent receiving phase of the POCIS (Oasis beads) is traditionally analyzed, thus limiting the use of POCIS for monitoring a range of APs with varying hydrophobicity. Here a "pharmaceutical" POCIS was calibrated in the laboratory using a static renewal setup for APs (from 2-ethylphenol to 4-n-nonylphenol) with varying hydrophobicity (log Kow between 2.47 and 5.76). The POCIS sampler was calibrated over its 28 day integrative regime and sampling rates (Rs) were determined. Uptake was shown to be a function of AP hydrophobicity where compounds with log Kow < 4 were preferentially accumulated in Oasis beads, and compounds with log Kow > 5 were preferentially accumulated in the PES membranes. A lag phase (over a 24 h period) before uptake in to the PES membranes occurred was evident. This work demonstrates that the analysis of both POCIS phases is vital in order to correctly determine environmentally relevant concentrations owing to the fact that for APs with log Kow ≤ 4 uptake, to the PES membranes and the Oasis beads, involves different processes compared to APs with log Kow ≥ 4. The extraction of both the POCIS matrices is thus recommended in order to assess the concentration of hydrophobic APs (log Kow ≥ 4), as well as hydrophilic APs, most effectively.


Ciliopathy is differentially distributed in the brain of a Bardet-Biedl syndrome mouse model.
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous inherited human disorder displaying a pleotropic phenotype. Many of the symptoms characterized in the human disease have been reproduced in animal models carrying deletions or knock-in mutations of genes causal for the disorder. Thinning of the cerebral cortex, enlargement of the lateral and third ventricles, and structural changes in cilia are among the pathologies documented in these animal models. Ciliopathy is of particular interest in light of recent studies that have implicated primary neuronal cilia (PNC) in neuronal signal transduction. In the present investigation, we tested the hypothesis that areas of the brain responsible for learning and memory formation would differentially exhibit PNC abnormalities in animals carrying a deletion of the Bbs4 gene (Bbs4-/-). Immunohistochemical localization of adenylyl cyclase-III (ACIII), a marker restricted to PNC, revealed dramatic alterations in PNC morphology and a statistically significant reduction in number of immunopositive cilia in the hippocampus and amygdala of Bbs4-/- mice compared to wild type (WT) littermates. Western blot analysis confirmed the decrease of ACIII levels in the hippocampus and amygdala of Bbs4-/- mice, and electron microscopy demonstrated pathological alterations of PNC in the hippocampus and amygdala. Importantly, no neuronal loss was found within the subregions of amygdala and hippocampus sampled in Bbs4-/- mice and there were no statistically significant alterations of ACIII immunopositive cilia in other areas of the brain not known to contribute to the BBS phenotype. Considered with data documenting a role of cilia in signal transduction these findings support the conclusion that alterations in cilia structure or neurochemical phenotypes may contribute to the cognitive deficits observed in the Bbs4-/- mouse mode.


Engineered Illumination Devices for Optogenetic Control of Cellular Signaling Dynamics.
Spatially and temporally varying patterns of morphogen signals during development drive cell fate specification at the proper location and time. However, current in vitro methods typically do not allow for precise, dynamic spatiotemporal control of morphogen signaling and are thus insufficient to readily study how morphogen dynamics affect cell behavior. Here, we show that optogenetic Wnt/β-catenin pathway activation can be controlled at user-defined intensities, temporal sequences, and spatial patterns using engineered illumination devices for optogenetic photostimulation and light activation at variable amplitudes (LAVA). By patterning human embryonic stem cell (hESC) cultures with varying light intensities, LAVA devices enabled dose-responsive control of optoWnt activation and Brachyury expression. Furthermore, time-varying and spatially localized patterns of light revealed tissue patterning that models the embryonic presentation of Wnt signals in vitro. LAVA devices thus provide a low-cost, user-friendly method for high-throughput and spatiotemporal optogenetic control of cell signaling for applications in developmental and cell biology.


Muscle fiber characteristics in patients with peripheral arterial disease.
There have been conflicting reports of muscle fiber type changes in patients with peripheral arterial disease (PAD). The purpose of this study was to examine the myosin heavy chain (MHC) expression as well as histochemical changes in the gastrocnemius muscle in patients with symptomatic PAD. Needle biopsy specimens were obtained from the medial gastrocnemius of 14 subjects with PAD (mean age (+/- SD), 69.7 +/- 4.8 yr) and eight activity-matched control subjects (mean age, 65.1 +/- 6.6 yr). Ankle-brachial index was assessed using Doppler ultrasound to determine the hemodynamic status of the patients, and maximal walking performance was determined during a graded treadmill test. Expression of MHC isoforms was determined by SDS-PAGE. The proportion of MHC I was significantly smaller in PAD than in the controls (45.6 +/- 9.1% vs 58.8 +/- 15.0%). The proportion of MHC IIx was also larger in the subjects with PAD compared with the controls (22.9 +/- 9.1% vs 16.0 +/- 11.3%). In addition, there was a significant decrease in the cross-sectional area of the type I and type IIA fibers in the subjects with PAD as well as enhanced capillary density. This study showed a significant modification in the expression of MHC isoforms and muscle fiber type in the gastrocnemius in patients with symptomatic PAD. These results suggest that muscle ischemia resulting from PAD is an important factor in causing the adaptations in the contractile apparatus of the muscle.


(-)-hydroxycitrate ingestion increases fat oxidation during moderate intensity exercise in untrained men.
We examined the effects of (-)-Hydroxycitrate (HCA) ingestion on fat oxidation during moderate intensity exercise in untrained men. Six subjects ingested 500 mg of HCA or a placebo for 5 days and did endurance exercise. Blood FFA concentrations were significantly increased and respiratory exchange ratio (RER) decreased by HCA ingestion. These results suggested short-term HCA ingestion increases fat oxidation in untrained men.


Insufficient access to oral paediatric medicines in Ghana: A descriptive study.
Among the most vulnerable people in society are children and this is especially so in their access to health care Off-label prescription of paediatric medicines is known to be associated with safety outcomes some of which may be serious. This study identifies frequently prescribed children's medicines that are not readily available in Ghana and are prepared extemporaneously. All prescriptions for extemporaneous oral preparations for children presented to the local production unit of the Korle-Bu Teaching Hospital from November, 2013 were eligible for the study. Information from such prescriptions was recorded in a systematic format. Presence of the prescribed medicine on the World Health Organization Children's Medicine List was ascertained in addition to the anatomical and therapeutic classification code. The registration of the prescribed medicine for paediatric use by the Food and Drugs Authority, Ghana was also checked. Descriptive statistics of the data was presented. In all 622 prescriptions for 35 different paediatric formulations were served. Prescriptions from several health facilities including government hospitals (6.6 %, N = 622), private hospitals (2.4 %, N = 622) and the University of Ghana hospital (1.1 %, N = 622) were all honoured. Some of the prescribed medicines (Baclofen, Clonazepam, Hydroxyurea and Lamotrigine) were neither on the World Health Organization Children's Medicine list nor registered with the Food and Drugs Authority, Ghana. Most prescribed medicines (88.6 %, N = 35) were for non-communicable diseases. Paediatric prescriptions including off-label medicines are prescribed and formulated extemporaneously in this setting. Steps should be taken to improve access and monitor benefit-risk profiles of paediatric medicines in order to improve treatment outcomes among children.


Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.
Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. PROSPERO Identifier: CRD42021230155.


A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling.
Lysine methylation of histones is recognized as an important component of an epigenetic indexing system demarcating transcriptionally active and inactive chromatin domains. Trimethylation of histone H3 lysine 4 (H3K4me3) marks transcription start sites of virtually all active genes. Recently, we reported that the WD40-repeat protein WDR5 is important for global levels of H3K4me3 and control of HOX gene expression. Here we show that a plant homeodomain (PHD) finger of nucleosome remodelling factor (NURF), an ISWI-containing ATP-dependent chromatin-remodelling complex, mediates a direct preferential association with H3K4me3 tails. Depletion of H3K4me3 causes partial release of the NURF subunit, BPTF (bromodomain and PHD finger transcription factor), from chromatin and defective recruitment of the associated ATPase, SNF2L (also known as ISWI and SMARCA1), to the HOXC8 promoter. Loss of BPTF in Xenopus embryos mimics WDR5 loss-of-function phenotypes, and compromises spatial control of Hox gene expression. These results strongly suggest that WDR5 and NURF function in a common biological pathway in vivo, and that NURF-mediated ATP-dependent chromatin remodelling is directly coupled to H3K4 trimethylation to maintain Hox gene expression patterns during development. We also identify a previously unknown function for the PHD finger as a highly specialized methyl-lysine-binding domain.


Measuring cognitive load: mixed results from a handover simulation for medical students.
The application of cognitive load theory to workplace-based activities such as patient handovers is hindered by the absence of a measure of the different load types. This exploratory study tests a method for measuring cognitive load during handovers. The authors developed the Cognitive Load Inventory for Handoffs (CLI4H) with items for intrinsic, extraneous, and germane load. Medical students completed the measure after participating in a simulated handover. Exploratory factor and correlation analyses were performed to collect evidence for validity. Results yielded a two-factor solution for intrinsic and germane load that explained 50 % of the variance. The extraneous load items performed poorly and were removed from the model. The score for intrinsic load correlated with the Paas Cognitive Load scale (r = 0.31, p = 0.004) and was lower for students with more prior handover training (p = 0.036). Intrinsic load did not, however, correlate with performance. Germane load did not correlate with the Paas Cognitive Load scale but did correlate as expected with performance (r = 0.30, p = 0.005) and was lower for those students with more prior handover training (p = 0.03). The CLI4H yielded mixed results with some evidence for validity of the score from the intrinsic load items. The extraneous load items performed poorly and the use of only a single item for germane load limits conclusions. The instrument requires further development and testing. Study results and limitations provide guidance to future efforts to measure cognitive load during workplace-based activities, such as handovers.


There Is an "Eye" in Team: Exploring the Interplay Between Emotion, Gaze Behavior, and Collective Efficacy in Team Sport Settings.
Little is understood about the attentional mechanisms that lead to perceptions of collective efficacy. This paper presents two studies that address this lack of understanding. Study one examined participant's (N = 59) attentional processes relating to positive, neutral, or negative emotional facial photographs, when instructed to select their "most confident" or "least confident" team. Eye gaze metrics of first fixation duration (FFD), fixation duration (FD), and fixation count (FC) were measured alongside individual perceptions of collective efficacy and emotional valence of the teams selected. Participants had shorter FFD, longer FD, and more FC on positive faces when instructed to select their most confident team (p < 0.05). Collective efficacy and emotional valence were significantly greater when participants selected their most confident team (p < 0.05). Study two explored the influence of video content familiarity of team-based observation interventions on attentional processes and collective efficacy in interdependent team-sport athletes (N = 34). When participants were exposed to familiar (own team/sport) and unfamiliar (unknown team/sport) team-based performance video, eye tracking data revealed similar gaze behaviors for the two conditions in terms of areas of interest. However, collective efficacy increased most for the familiar condition. Study one results indicate that the emotional expressions of team members influence both where and for how long we look at potential team members, and that conspecifics' emotional expression impacts on our perceptions of collective efficacy. For Study two, given the apparent greater increase in collective efficacy for the familiar condition, the similar attentional processes evident for familiar and unfamiliar team footage suggests that differences in meaning of the observed content dictates collective efficacy perceptions. Across both studies, the findings indicate the importance of positive emotional vicarious experiences when using team-based observation interventions to improve collective efficacy in teams.


Deciphering the dynamics of star molecules in shear flow.
This work analyses the rotation of star polymers under shear flow, in melts, and in good solvent dilute solution. The latter is modeled by single molecule Brownian hydrodynamics, while melts are modeled using non-equilibrium molecular dynamics in closed (periodic) boxes and in open boundaries. A Dissipative Particle Dynamics (DPD) thermostat introduces pairwise monomer friction in melts at will, in directions normal and tangent to the monomer-monomer vectors. Although tangential friction is seldom modeled, we show that it is essential to control hydrodynamic effects in melts. We analyze the different sources of molecular angular momentum in solution and melts and distinguish three dynamic regimes as the shear rate [small gamma, Greek, dot above] is increased. These dynamic regimes are related with the disruption of the different relaxation mechanisms of the star in equilibrium. Although strong differences are found between harmonic springs and finitely extensible bonds, above a critical shear rate the star molecule has a "breathing" mode with successive elongations and contractions in the flow direction with frequency Ω. The force balance in the flow direction unveils a relation between Ω and the orientation angle. Using literature results for the tumbling of rings and linear chains, either in melt or in solution, we show that the relation is general. A different "tank-treading" dynamics determines the rotation of monomers around the center of mass of the molecule. We show that the tank-treading frequency does not saturate but keeps increasing with [small gamma, Greek, dot above]. This is at odds with previous studies which erroneously calculated the molecular angular frequency, used as a proxy for tank-treading.


Microbiologic and Clinical Findings of Implants in Healthy Condition and with Peri-Implantitis.
To compare implants in healthy conditions and implants with peri-implantitis with regard to their clinical parameters and the microbiologic composition at the peri-implant sulcus, inside the implant connection, and the gingival sulcus of neighboring teeth. A cross-sectional study was performed including consecutive patients with implants in healthy conditions and with peri-implantitis. Clinical parameters for which patients were screened included bleeding on probing, pocket depth, and plaque index at six sites. Samples for microbiologic analysis were obtained from three locations: the peri-implant sulcus, inside the implant connection, and the gingival sulcus of neighboring teeth. Quantitative real-time polymerase chain reaction (PCR) was carried out for total counts of 10 microorganisms: Aggregatibacter actinomycetemcomitans, Porphyromona gingivalis, Tanerella forsythia, Tanerella denticola, Prevotela intermedia, Peptostreptococcus micros, Fusobacterium nucleatum, Campylobacter rectus, Eikenella corrodens, and Candida albicans. The response variables were the percentage of positive sites and total bacterial counts. One hundred twenty-two implants in 57 patients were analyzed in the healthy group and 113 implants in 53 patients in the peri-implantitis group. Differences between the groups were statistically significant for bruxism, probing pocket depth, bleeding on probing, and radiographic bone level. Orange complex species (P intermedia, P micros, F nucleatum) were the most prevalent in the three types of sites for both groups, and prevalence values were higher in the peri-implantitis group. Differences in prevalence between groups were more marked inside the connection than in the peri-implant sulcus. Absolute loads of most microbes and total bacterial counts were higher for the peri-implantitis group in the three locations. Again, differences were bigger inside the connection than at the peri-implant sulcus. Significant interactions were found for prevalence and absolute microbial loads between groups and locations, and for the interaction of group × location. Clinical and microbiologic differences were observed between healthy subjects and those with peri-implantitis. Microbiologic differences between groups were more marked inside the connection than in the peri-implant sulcus. The potential role of the implant connection as a microbial reservoir for peri-implant diseases and in the outcome of their treatment should be confirmed with further studies.


T cell clones specific for IgG2a of the a allotype: direct evidence for presentation of endogenous antigen.
T cell clones specific for IgG2a of the alpha allotype have been isolated from C57BL/6J mice. Antigenic determinants recognized by these clones were localized by using a panel of hybrid IgG2b-IgG2a myeloma proteins. These experiments provide evidence for two distinct antigenic sites, one located in a segment encompassing the hinge region and most of the CH2 domain, and the other in a segment spanning the CH3 domain and the C-terminal eight residues of the CH2 domain. As judged by their failure to respond in the presence of B6.C-H-2bm12 spleen cells, all the clones recognize determinants created, in part, by the I-A beta chain. A strong proliferative response was observed in the presence of spleen cells from several H-2b strains, including C3H.SW, A.BY, D1.LP, and BALB.B. Experiments testing reactivity directed toward spleen cells from appropriate allotype-congenic mouse strains demonstrated that this response was controlled by Igh-linked genes. These results clearly indicated 1) that Igh-1a-specific T cell clones are stimulated by endogenously synthesized IgG2a, and 2) these T cells recognize shared determinants expressed on IgG2a molecules of various strains. These experiments thus provide strong evidence for presentation of self antigens under normal physiological conditions.


Investigating lithium-ion battery materials during overcharge-induced thermal runaway: an operando and multi-scale X-ray CT study.
Catastrophic failure of lithium-ion batteries occurs across multiple length scales and over very short time periods. A combination of high-speed operando tomography, thermal imaging and electrochemical measurements is used to probe the degradation mechanisms leading up to overcharge-induced thermal runaway of a LiCoO2 pouch cell, through its interrelated dynamic structural, thermal and electrical responses. Failure mechanisms across multiple length scales are explored using a post-mortem multi-scale tomography approach, revealing significant morphological and phase changes in the LiCoO2 electrode microstructure and location dependent degradation. This combined operando and multi-scale X-ray computed tomography (CT) technique is demonstrated as a comprehensive approach to understanding battery degradation and failure.


App-assisted external ventricular drain insertion.
The freehand technique for insertion of an external ventricular drain (EVD) is based on fixed anatomical landmarks and does not take individual variations into consideration. A patient-tailored approach based on augmented-reality techniques using devices such as smartphones can address this shortcoming. The Sina neurosurgical assist (Sina) is an Android mobile device application (app) that was designed and developed to be used as a simple intraoperative neurosurgical planning aid. It overlaps the patient's images from previously performed CT or MRI studies on the image seen through the device camera. The device is held by an assistant who aligns the images and provides information about the relative position of the target and EVD to the surgeon who is performing EVD insertion. This app can be used to provide guidance and continuous monitoring during EVD placement. The author describes the technique of Sina-assisted EVD insertion into the frontal horn of the lateral ventricle and reports on its clinical application in 5 cases as well as the results of ex vivo studies of ease of use and precision. The technique has potential for further development and use with other augmented-reality devices.


Generating superpositions of higher-order Bessel beams.
We report the first experimental generation of the superposition of higher-order Bessel beams, by means of a spatial light modulator (SLM) and a ring slit aperture. We present illuminating a ring slit aperture with light which has an azimuthal phase dependence, such that the field produced is a superposition of two or more higher-order Bessel beams. The experimentally produced fields are in good agreement with those calculated theoretically. The significance of these fields is that even though one is able to generate fields which carry zero orbital angular momentum, a rotation in the field's intensity profile as it propagates is observed.


Complex histories of repeated gene flow in Cameroon crater lake cichlids cast doubt on one of the clearest examples of sympatric speciation.
One of the most celebrated examples of sympatric speciation in nature are monophyletic radiations of cichlid fishes endemic to Cameroon crater lakes. However, phylogenetic inference of monophyly may not detect complex colonization histories involving some allopatric isolation, such as double invasions obscured by genome-wide gene flow. Population genomic approaches are better suited to test hypotheses of sympatric speciation in these cases. Here, we use comprehensive sampling from all four sympatric crater lake cichlid radiations in Cameroon and outgroups across Africa combined with next-generation sequencing to genotype tens of thousands of SNPs. We find considerable evidence of gene flow between all four radiations and neighboring riverine populations after initial colonization. In a few cases, some sympatric species are more closely related to outgroups than others, consistent with secondary gene flow facilitating their speciation. Our results do not rule out sympatric speciation in Cameroon cichlids, but rather reveal a complex history of speciation with gene flow, including allopatric and sympatric phases, resulting in both reproductively isolated species and incipient species complexes. The best remaining non-cichlid examples of sympatric speciation all involve assortative mating within microhabitats. We speculate that this feature may be necessary to complete the process of sympatric speciation in nature.


Watershed boundaries and geographic isolation: patterns of diversification in cutthroat trout from western North America.
For wide-ranging species, intraspecific variation can occur as a result of reproductive isolation from local adaptive differences or from physical barriers to movement. Cutthroat trout (Oncorhynchus clarkii), a widely distributed fish species from North America, has been divided into numerous putative subspecies largely based on its isolation in different watersheds. In this study, we examined mtDNA sequence variation of cutthroat trout to determine the major phylogenetic lineages of this polytypic species. We use these data as a means of testing whether geographic isolation by watershed boundaries can be a primary factor organizing intraspecific diversification. We collected cutthroat trout from locations spanning almost the entire geographic range of this species and included samples from all major subspecies of cutthroat trout. Based on our analyses, we reveal eight major lineages of cutthroat trout, six of which correspond to subspecific taxonomy commonly used to describe intraspecific variation in this species. The Bonneville cutthroat trout (O. c. utah) and Yellowstone cutthroat trout (O. c. bouvieri) did not form separate monophyletic lineages, but instead formed an intermixed clade. We also document the geographic distribution of a Great Basin lineage of cutthroat trout; a group typically defined as Bonneville cutthroat trout, but it appears more closely related to the Colorado River lineage of cutthroat trout. Our study indicates that watershed boundaries can be an organizing factor isolating genetic diversity in fishes; however, historical connections between watersheds can also influence the template of isolation. Widely distributed species, like cutthroat trout, offer an opportunity to assess where historic watershed connections may have existed, and help explain the current distribution of biological diversity across a landscape.


Direct and cluster-assisted dehydrogenation of methane by Nb+ and Ta+: a theoretical investigation.
DFT calculations have been performed to examine both direct and cluster-assisted methane C-H bond activation by Nb+ and Ta+ cations. The commonly accepted dehydrogenation pathways, that are oxidative addition and reductive elimination, have been studied in detail for methane ligated clusters M(CH4)n+ (M = Nb, Ta and n = 1-4). For the second H atom transfer to the metal in the presence of additional CH4 molecules (n > 1) two alternative routes have been explored. Energy profiles for ground quintet and excited triplet and singlet spin states of both Nb+ and Ta+ cations have been calculated. Spin crossings occur for all the examined pathways. Clustering of methane ligands appears to favorably affect the process stabilizing all the intercepted minima and transition states and bringing all the calculated PESs below the reference energy of the separated reactants. The direct activation of methane (n = 1) can proceed efficiently only for Ta+, whereas dehydrogenation is endothermic for Nb+ by 9.0 kcal mol-1. When assisted by additional methane ligands, the dehydrogenation process becomes exothermic for both cations whatever the number of coordinated molecules.


First Report of Heterobasidion annosum on Pinus pinaster in Spain.
The basidiomycete Heterobasidion annosum (Fr.) Bref. (=Fomes annosus (Fr.) Cooke), one of the most important pathogens in coniferous forests in Europe, Asia, and North America, causes root and butt rot. H. annosum was first recorded on Pinus pinaster Ait. (commonly known as Maritime pine) in France and Great Britain in 1961 (4) and Portugal in 1986 (2). P. pinaster is the most widespread conifer in Spain, with more than 700,000 and 600,000 ha in pure and mixed stands, respectively. Over the last few years, P. pinaster decline was observed in several stands in the center of the Iberian Peninsula. Unusual crown transparency, small needles, foliage discoloration, and early tree death are characteristic decline symptoms associated with the high mortality rate on this species. In June of 2010, 11 trees (40 to 60 years old) with a different degree of decline were felled in two zones (42°2'41″N, 3°18'14″W, elevation 1,096 m and 41°55'40″N, 3°12'3″W, elevation 1,128 m) and cut into sections (stump height, breast height, and near the top). Wood slices were removed from each section and taken to the laboratory. Samples were placed in moist chambers with optimal conditions of humidity and temperature to enhance pathogen growth. After 20 days of incubation in darkness at 25°C, H. annosum (anamorph Spiniger meineckellum [A. Olson] Stalpers) occurred on most of these slices. Conidiophores with subglobose to pyriform conidia (5.8 × 4.2 μm) were observed with a compound microscope. The fungus was isolated to extract DNA by disruption of the mycelium followed by washes with phenol/chloroform/isoamyl alcohol solution (25:24:1). DNA was precipitated with 20% polyethylene glycol solution. PCR was carried out according to the instructions of the manufacturer of Dynazyme II DNA polymerase (Finnzymes Ltd, Espoo, Finland) with ITS primers, 1F (5'-CTTGGTCATTTAGAGGAAGTAA-3') and 4 (5'-TCCTCCGCTTATTGATATGC-3'). After DNA purification, samples were sequenced (SECUGEN, Madrid, Spain) and aligned and corrected with Geneious Pro 5.3 to obtain the consensus sequences. Resulting DNA sequences of two isolates were deposited in GenBank (Nos. FR850494 and FR850495), and compared with a Blastn search at GenBank showing 100% identity and 100% coverage with H. annosum sensu stricto, former ISG-P (intersterility group of pines). For pathogenicity tests, 10 seedlings (2 year old) were inoculated with autoclaved P. pinaster wood chips colonized by H. annosum, and 10 control seedlings were inoculated with noncolonized wood chips. Inoculums were prepared by growing H. annosum on 4-mm-diameter wood chips placed on potato dextrose agar media for 3 weeks. The wood chips were put inside an oblique incision made at 6 cm above the soil line and wrapped with Parafilm. After 8 weeks in a growth chamber at 22.5°C with a 14-h photoperiod, the inoculated seedlings showed typical symptoms and 3 seedlings of 10 were dead. H. annosum was previously recorded on P. sylvestris in central Spain (1), causing needle drop, swelling at the stump height, and presence of dead trees by circular areas. This pathogen was also reported on P. nigra in northeastern Spain, associated with defoliation and mortality (3). To our knowledge, this is the first record of H. annosum on P. pinaster in Spain. References: (1) J. Benito-Martínez. An. Jardín Bot. Madrid 3:23, 1943. (2) N. Neves et al. EPPO Bull. 16:505, 1986. (3) J. Oliva et al. Bol. Sanidad Vegetal. Plagas. 34:415, 2008. (4) P. Spaulding. US Dep. Agric. Agric. Handb. 197:100, 1961.


Concentration-dependent regulation of thyrotropin receptor function by thyroid-stimulating antibody.
Thyrotropin receptor (TSHR) Ab's of the stimulating variety are the cause of hyperthyroid Graves disease. MS-1 is a hamster mAb with TSHR-stimulating activity. To examine the in vivo biological activity of MS-1, mice were treated with purified MS-1 intraperitoneally and the thyroid response evaluated. MS-1 induced a dose-dependent increase in serum thyroxine (T4), with a maximum effect after 10 proportional, variant g of MS-1 was administered. MS-1-secreting hybridoma cells were then transferred into the peritoneum of nude mice to study chronic thyroid stimulation. Serum MS-1 levels detected after 2 weeks were approximately 10-50 proportional, variant g/ml, and the serum TSH was suppressed in all animals. Serum triiodothyronine levels were elevated, but only in animals with low serum MS-1 concentrations. In addition, there was a negative correlation between serum T4 and the serum MS-1 concentrations. These in vivo studies suggested a partial TSHR inactivation induced by excessive stimulation by MS-1. We confirmed this inactivation by demonstrating MS-1 modulation of TSHR function in vitro as evidenced by downregulation and desensitization of the TSHR at concentrations of MS-1 achieved in the in vivo studies. Thus, inactivation of the TSHR by stimulating TSHR autoantibodies (TSHR-Ab's) in Graves disease patients may provide a functional explanation for the poor correlation between thyroid function and serum TSHR-Ab concentrations.


MAP2d promotes bundling and stabilization of both microtubules and microfilaments.
Two low molecular weight MAP2 variants have been described, MAP2c and MAP2d. These variants are produced from a single gene by alternative splicing, and in their C-terminal regions contain, respectively, 3 and 4 tandem repeats, some of which are known to be involved in binding to microtubules. Substantial differences in the developmental expression pattern of MAP2c and MAP2d suggest they have different functions in neural cells. In order to investigate the respective roles of these MAP2 variants, we have analyzed the effects of MAP2c and MAP2d expression on microtubule and microfilament organization in transiently transfected cells. Our results show that both variants stabilize microtubules, but only MAP2d stabilizes microfilaments.


More adverse renal prognosis of autosomal dominant polycystic kidney disease in families with primary hypertension.
Marked variability of age at renal death is noted in autosomal dominant polycystic kidney disease (ADPKD). The hypothesis that the coexistence of primary hypertension and ADPKD within families is associated with earlier renal death was tested. Of a total of 162 ADPKD patients treated in one Austrian and three German centers, 57 propositi were identified whose families provided (1) information concerning blood pressure; (2) documented presence of ADPKD (by sonography or autopsy) in one parent; and (3) age at renal death in the propositus. Hypertension of the unaffected parent was defined as blood pressure above 140/90 mm Hg or antihypertensive treatment before age 60 yr. Age at renal death in the propositus was defined as the start of renal replacement therapy. Median age at renal death of 23 offspring (11 male, 12 female) from families with a history of primary hypertension of the nonaffected parent was lower than that of 34 offspring (16 male, 18 female) from families without a known history of primary hypertension of the nonaffected parent, i.e., 49 yr (26 to 64) versus 54 yr (28 to 82) (P < 0.03). The data are consistent with the notion that genetic predisposition to primary hypertension is associated with an earlier onset of terminal renal failure in families with ADPKD.


Cardiac transplantation. University of Miami/Jackson Memorial Hospital experience.
Cardiac transplantation at the University of Miami/Jackson Memorial Medical Center began in November 1986. Up to April 1993, 220 potential recipients were evaluated and 84 accepted. Sixty-three patients received transplants while 14 died awaiting a donor heart. Within six years, the average recipient age has increased from 40 to 59 years. The overall one, two, and five-year survival rates (including operative deaths) are 89.5%, 82%, and 76%, respectively. Postoperative complications and mortality were related to infection or rejection frequently encountered within the first 28 months; thereafter the actuarial survival curve showed minimal decay and the complication rate declined. One or more hospital readmissions were needed in 38 of 57 (67%) survivors. Among the 50 long-term survivors, 42% are working and 84% are in New York Heart Association functional Class I.


Open issues in Mucopolysaccharidosis type I-Hurler.
Mucopolysaccharidosis I-Hurler (MPS I-H) is the most severe form of a metabolic genetic disease caused by mutations of IDUA gene encoding the lysosomal α-L-iduronidase enzyme. MPS I-H is a rare, life-threatening disease, evolving in multisystem morbidity including progressive neurological disease, upper airway obstruction, skeletal deformity and cardiomyopathy. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the gold standard for the treatment of MPS I-H in patients diagnosed and treated before 2-2.5 years of age, having a high rate of success. Beyond the child's age, other factors influence the probability of treatment success, including the selection of patients, of graft source and the donor type employed. Enzyme replacement therapy (ERT) with human recombinant laronidase has also been demonstrated to be effective in ameliorating the clinical conditions of pre-transplant MPS I-H patients and in improving HSCT outcome, by peri-transplant co-administration. Nevertheless the long-term clinical outcome even after successful HSCT varies considerably, with a persisting residual disease burden. Other strategies must then be considered to improve the outcome of these patients: one is to pursue early pre-symptomatic diagnosis through newborn screening and another one is the identification of novel treatments. In this perspective, even though newborn screening can be envisaged as a future attractive perspective, presently the best path to be pursued embraces an improved awareness of signs and symptoms of the disorder by primary care providers and pediatricians, in order for the patients' timely referral to a qualified reference center. Furthermore, sensitive new biochemical markers must be identified to better define the clinical severity of the disease at birth, to support clinical judgement during the follow-up and to compare the effects of the different therapies. A prolonged neuropsychological follow-up of post-transplant cognitive development of children and residual disease burden is needed. In this perspective, the reference center must guarantee a multidisciplinary follow-up with an expert team. Diagnostic and interventional protocols of reference centers should be standardized whenever possible to allow comparison of clinical data and evaluation of results. This review will focus on all these critical issues related to the management of MPS I-H.


Evidence on multimorbidity from definition to intervention: An overview of systematic reviews.
The increasing challenge of multiple chronic diseases (multimorbidity) requires more evidence-based knowledge and effective practice. In order to better understand the existing evidence on multimorbidity, we performed a systematic review of systematic reviews on multimorbidity with pre-established search strategies and exclusion criteria by searching multiple databases and grey literature. Of 8006 articles found, 53 systematic reviews (including meta-analysis and qualitative research synthesis performed in some reviews) that stated multimorbidity as the main focus were included, with 79% published during 2013-2016. Existing evidence on definition, measurement, prevalence, risk factors, health outcomes, clinical practice and medication (polypharmacy), and intervention and management were identified and synthesised. There were three major definitions from three perspectives. Seven studies on prevalence reported a range from 3.5% to 100%. As six studies showed, depression, hypertension, diabetes, arthritis, asthma, and osteoarthritis were prone to be comorbid with other conditions. Four groups of risk factors and eight multimorbidity associated outcomes were explored by five and six studies, respectively. Nine studies evaluated interventions, which could be categorized into either organizational or patient-oriented, the effects of these interventions were varied. Self-management process, priority setting and decision making in multimorbidity were synthesised by evidence from 4 qualitative systematic reviews. We were unable to draw solid conclusions from this overview due to the heterogeneity in methodology and inconsistent findings among included reviews. As suggested by all included studies, there is a need for prospective research, especially longitudinal cohort studies and randomized control trials, to provide more definitive evidence on multimorbidity.


Musculoskeletal Disorders and Working Posture among Dental and Oral Health Students.
The prevalence of musculoskeletal disorders (MSD) in the dental professions has been well established, and can have detrimental effects on the industry, including lower productivity and early retirement. There is increasing evidence that these problems commence during undergraduate training; however, there are still very few studies that investigate the prevalence of MSD or postural risk in these student groups. Thus, the aim of this study was to determine the prevalence of MSD and conduct postural assessments of students studying oral health and dentistry. A previously validated self-reporting questionnaire measuring MSD prevalence, derived from the Standardised Nordic Questionnaire, was distributed to students. Posture assessments were also conducted using a validated Posture Assessment Instrument. MSD was highly prevalent in all student groups, with 85% reporting MSD in at least one body region. The neck and lower back were the most commonly reported. The final year dental students had the highest percentage with poor posture (68%), while the majority of students from other cohorts had acceptable posture. This study supports the increasing evidence that MSD could be developing in students, before the beginning of a professional career. The prevalence of poor posture further highlights the need to place further emphasis on ergonomic education.


The prevalence of pain in pediatric human immunodeficiency virus/acquired immunodeficiency syndrome as reported by participants in the Pediatric Late Outcomes Study (PACTG 219).
As the life expectancy of children with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) increases, quality-of-life outcomes are of increasing concern. The prevalence of pain in adults with AIDS ranges from 40% to 60%, depending on stage of illness. There is limited research concerning pain in HIV-infected children and youth. The General Health Assessment for Children was administered to caregivers of HIV-infected children and youth enrolled in the Pediatric Late Outcomes Study (PACTG 219), a prospective cohort study. Pain is assessed over the previous month with 7 questions. For the purpose of this analysis, we defined pain as the presence of pain of at least moderate intensity. Participants were observed from January 1, 1996, to December 31, 1999. A total of 985 HIV-positive participants had a baseline pain evaluation in 1995. The prevalence of pain remained relatively constant during each year of observation, averaging 20%. Lower CD4+ T-lymphocyte percentage, female gender, and an HIV/AIDS-related diagnosis were highly associated with an increased risk of reported pain. Pain was also independently associated with increased risk of death. After adjusting for CD4 percentage, use of combination therapy including protease inhibitors, comorbid diagnoses, and other sociodemographic characteristics, individuals reporting pain were over 5 times more likely to die than those not reporting pain (hazard ratio = 5.07; 95% confidence interval = 3.23-7.95). Pain is a frequently encountered symptom in children and youth with HIV disease and is also associated with increased mortality. These findings emphasize the importance of pain management in this population.


Evaluation of hamstring muscle strength and morphology after anterior cruciate ligament reconstruction.
This study aimed to clarify the relationship between knee flexor strength and hamstring muscle morphology after anterior cruciate ligament (ACL) reconstruction using the semitendinosus (ST) tendon and to determine the causative factors of decreased knee flexor muscle strength. Fourteen male and ten female patients who resumed sports activities after surgery participated in the experiment. Isometric knee flexion torque was measured at 30°, 45°, 60°, 90°, and 105° of knee flexion. Magnetic resonance imaging (MRI) was used to calculate ST muscle length and hamstring muscle volume, and to confirm the status of ST tendon regeneration. The correlation between the MRI findings and flexor strength was analyzed. Regenerated ST tendon was confirmed in 21 of the 24 patients, but muscle volume (87.6%) and muscle length (74.5%) of the ST in the operated limb were significantly smaller than those in the normal limb. The percentage of the knee flexion torque of the operated limb compared with that of the normal was apparently lower at 105° (69.1%) and 90° (68.6%) than at 60° (84.4%). Tendon regeneration, ST muscle shortening, and ST muscle atrophy correlated with decreased knee flexion torque. These results indicated that preserving the morphology of the ST muscle-tendon complex is important.


Using administrative data to estimate time to breast cancer diagnosis and percent of screen-detected breast cancers – a validation study in Alberta, Canada.
Appropriate use of administrative data enables the assessment of care quality at the population level. Our objective was to develop/validate methods for assessing quality of breast cancer diagnostic care using administrative data, specifically by identifying relevant medical tests to estimate the percentage screen/symptom-detected cancers and time to diagnosis. Two databases were created for all women diagnosed with a first-ever breast cancer in years 2007-2010 in Alberta, Canada, with dates of medical tests received in years 2006-2010. One purchased database had test results and was used to determine the 'true' first relevant test of a cancer diagnosis. The other free administrative database had test types but no test results. Receiver operating characteristic curves and concordance rates were used to assess estimates of percent screen/symptom-detected breast cancers; Log-rank test was used to assess time to diagnosis obtained from the two databases. Using a look-back period of 4-6 months from cancer diagnosis to identify relevant tests resulted in over 94% concordance, sensitivity and specificity for classifying patients into screen/symptom-detected group; good agreement between the distributions of time to diagnosis was also achieved. Our findings support the use of administrative data to accurately identify relevant tests for assessing the quality of breast cancer diagnostic care.


Complementary activities of TPX2 and chTOG constitute an efficient importin-regulated microtubule nucleation module.
Spindle assembly and function require precise control of microtubule nucleation and dynamics. The chromatin-driven spindle assembly pathway exerts such control locally in the vicinity of chromosomes. One of the key targets of this pathway is TPX2. The molecular mechanism of how TPX2 stimulates microtubule nucleation is not understood. Using microscopy-based dynamic in vitro reconstitution assays with purified proteins, we find that human TPX2 directly stabilizes growing microtubule ends and stimulates microtubule nucleation by stabilizing early microtubule nucleation intermediates. Human microtubule polymerase chTOG (XMAP215/Msps/Stu2p/Dis1/Alp14 homologue) only weakly promotes nucleation, but acts synergistically with TPX2. Hence, a combination of distinct and complementary activities is sufficient for efficient microtubule formation in vitro. Importins control the efficiency of the microtubule nucleation by selectively blocking the interaction of TPX2 with microtubule nucleation intermediates. This in vitro reconstitution reveals the molecular mechanism of regulated microtubule formation by a minimal nucleation module essential for chromatin-dependent microtubule nucleation in cells.


Patients with acute coronary syndromes without persistent ST elevation undergoing percutaneous coronary intervention benefit most from early intervention with protection by a glycoprotein IIb/IIIa receptor blocker.
Many patients with acute coronary syndromes are offered percutaneous coronary intervention. However, the appropriate indications for, and optimal timing of, such procedures are uncertain. We analysed timing of intervention and associated events (death and myocardial infarction) in the PURSUIT trial in which 9461 patients received a platelet glycoprotein IIb/IIIa inhibitor, eptifibatide, or placebo for 72 h. Other treatment was left to the investigators. 2430 patients underwent percutaneous coronary intervention within 30 days. Four groups were distinguished, who underwent percutaneous coronary intervention on day 1; on days 2 or 3; at 4 to 7 days; or between 8 until 30 days, for eptifibatide- and placebo-treated patients. The four groups treated with placebo demonstrated total 30-day events of 15.9% for day 1 percutaneous coronary intervention, 17.7%, 15.0% and 18.2%, respectively, for successive intervals of later intervention. Later intervention was associated with more pre-procedural events (2.2% to 13.7%, P=0.001) which was balanced by a decrease in procedure-related events (12.1 to 3.1%, P=0.001), while the overall 30-day event rates were similar. Eptifibatide-treated patients with percutaneous coronary intervention on day 1 had the lowest rate of 30-day events (9.2%, P<0.05 vs other groups). In this group, pre-procedural risk was only 0.3%, while percutaneous coronary intervention on eptifibatide treatment was associated with low procedural risk (7.2%). The total 30-day event rate for later percutaneous coronary intervention in patients receiving eptifibatide was 14.0 on days 2 and 3, 15.0% for days 4 to 7 and 17.4% for days 7 to 30, respectively. Patients treated with a platelet glycoprotein IIb/IIIa receptor blocker, and early percutaneous coronary intervention (within 24 h) had the lowest event rate in this post hoc analysis. Thus 'watchful waiting' may not be the optimal strategy. Rather an early invasive strategy with percutaneous coronary intervention under protection of a platelet glycoprotein IIb/IIIa receptor blocker should be considered in selected patients. Randomized trials are warranted to verify this issue.


Intramolecular loop/tail interactions are essential for connexin 43-hemichannel activity.
Connexin-assembled gap junctions (GJs) and hemichannels coordinate intercellular signaling processes. Although the regulation of connexins in GJs has been well characterized, the molecular determinants controlling connexin-hemichannel activity are unresolved. Here we investigated the regulation of Cx43-hemichannel activity by actomyosin contractility and intracellular [Ca(2+)] ([Ca(2+)](i)) using plasma membrane-permeable TAT peptides (100 μM) designed to interfere with interactions between the cytoplasmic loop (CL) and carboxy-terminal (CT) in primary bovine corneal endothelial cells and HeLa, C6 glioma, and Xenopus oocytes ectopically expressing Cx43. Peptides corresponding to the last 10 CT aa (TAT-Cx43CT) prevented the inhibition of Cx43-hemichannel activity by contractility/high [Ca(2+)](i), whereas a reverse peptide (TAT-Cx43CTrev) did not. These effects were independent of zonula occludens-1, a cytoskeletal-associated Cx43-binding protein. In contrast, peptides corresponding to CL (TAT-L2) inhibited Cx43-hemichannel responses, whereas a mutant peptide (TAT-L2(H126K/I130N)) did not inhibit. In these assays, TAT-Cx43CT acted as a scaffold for TAT-L2 and vice versa, a finding supported by surface plasmon resonance measurements. Loop/tail interactions appeared essential for Cx43-hemichannel activity, because TAT-Cx43CT restored the activity of nonfunctional hemichannels, consisting of either Cx43 lacking the C-terminal tail (Cx43(M239)) or intact Cx43 ectopically expressed in Xenopus oocytes. We conclude that intramolecular loop/tail interactions control Cx43-hemichannel activity, laying the basis for developing hemichannel-specific blockers.


Induction and selection of Sox17-expressing endoderm cells generated from murine embryonic stem cells.
Embryonic stem (ES) cells offer a valuable source for generating insulin-producing cells. However, current differentiation protocols often result in heterogeneous cell populations of various developmental stages. Here we show the activin A-induced differentiation of mouse ES cells carrying a homologous dsRed-IRES-puromycin knock-in within the Sox17 locus into the endoderm lineage. Sox17-expressing cells were selected by fluorescence-assisted cell sorting (FACS) and characterized at the transcript and protein level. Treatment of ES cells with high concentrations of activin A for 10 days resulted in up to 19% Sox17-positive cells selected by FACS. Isolated Sox17-positive cells were characterized by defini- tive endoderm-specific Sox17/Cxcr4/Foxa2 transcripts, but lacked pluripotency-associated Oct4 mRNA and protein. The Sox17-expressing cells showed downregulation of extraembryonic endoderm (Sox7, Afp, Sdf1)-, mesoderm (Foxf1, Meox1)- and ectoderm (Pax6, NeuroD6)-specific transcripts. The presence of Hnf4α, Hes1 and Pdx1 mRNA demonstrated the expression of primitive gut/foregut cell-specific markers. Ngn3, Nkx6.1 and Nkx2.2 transcripts in Sox17-positive cells were determined as properties of pancreatic endocrine progenitors. Immunocytochemistry of activin A-induced Sox17-positive embryoid bodies revealed coexpression of Cxcr4 and Foxa2. Moreover, the histochemical demonstration of E-cadherin-, Cxcr4-, Sox9-, Hnf1β- and Ngn3-positive epithelial-like structures underlined the potential of Sox17-positive cells to further differentiate into the pancreatic lineage. By reducing the heterogeneity of the ES cell progeny, Sox17-expressing cells are a suitable model to evaluate the effects of growth and differentiation factors and of culture conditions to delineate the differentiation process for the generation of pancreatic cells in vitro.


Structure-function studies of the RNA polymerase II elongation complex.
RNA polymerase II (Pol II) is the eukaryotic enzyme that is responsible for transcribing all protein-coding genes into messenger RNA (mRNA). The mRNA-transcription cycle can be divided into three stages: initiation, elongation and termination. During elongation, Pol II moves along a DNA template and synthesizes a complementary RNA chain in a processive manner. X-ray structural analysis has proved to be a potent tool for elucidating the mechanism of Pol II elongation. Crystallographic snapshots of different functional states of the Pol II elongation complex (EC) have elucidated mechanistic details of nucleotide addition and Pol II translocation. Further structural studies in combination with in vitro transcription experiments led to a mechanistic understanding of various additional features of the EC, including its inhibition by the fungal toxin alpha-amanitin, the tunability of the active site by the elongation factor TFIIS, the recognition of DNA lesions and the use of RNA as a template.


The effect of flexor tenotomy on healing and prevention of neuropathic diabetic foot ulcers on the distal end of the toe.
Flexor tenotomy is a minimally invasive surgical alternative for the treatment of neuropathic diabetic foot ulcers on the distal end of the toe. The influence of infection on healing and time to heal after flexor tenotomy is unknown. Flexor tenotomy can also be used as a prophylactic treatment. The effectiveness as a prophylactic treatment has not been described before. A retrospective study was performed with the inclusion of all consecutive flexor tenotomies from one hospital between January 2005 and December 2011. From 38 ulcers, 35 healed (92%), with a mean time to heal of 22 ± 26 days. The longest duration for healing was found for infected ulcers that were penetrating to bone (35 days; p = .042). Cases of prophylactic flexor tenotomies (n=9) did not result in any ulcer or other complications during follow-up. The results of this study suggest that flexor tenotomy may be beneficial for neuropathic diabetic foot ulcers on the distal end of the toe, with a high healing percentage and a short mean time to heal. Infected ulcers that penetrated to bone took a significantly longer time to heal. Prospective research, to confirm the results of this retrospective study, should be performed.


Combined ergonomic exposures and development of musculoskeletal pain in the general working population: A prospective cohort study.
This study aimed to investigate the importance of combined ergonomic exposures at work for the development of musculoskeletal pain. Through four rounds (2012-2018) of the Work Environment and Health in Denmark Study, 18 905 employees of the general working population replied to a baseline and 2-year follow-up questionnaire. First, a k-means cluster analysis of seven ergonomic factors (back bending, arm above shoulders, lifting etc., from 'never' to 'almost all the time') identified nine naturally occurring clusters. Second, using a weighted survey regression model controlling for age, gender, survey year, education, lifestyle, influence at work, and pain intensity at baseline, we estimated development of pain intensity (0-10) in the neck-shoulder and low-back in these clusters. The largest cluster served as reference to the other clusters and was characterized by low ergonomic exposures. Clusters characterized by multiple combined ergonomic exposures for a relatively high percentage of the working time showed the largest increase in neck-shoulder as well as low-back pain intensity from baseline to follow-up. However, clusters characterized by high exposure to a few specific ergonomic factors also increased pain significantly, eg, standing/walking combined with lifting/carrying or twisted/bent back for the majority of the working time increased low-back pain, whereas repetitive arm movements for the majority of the working time with or without standing/walking increased neck-shoulder pain. Combined occupational ergonomic exposures play an important role in the development of musculoskeletal pain. Workplace preventive approaches should consider this in risk assessments and organization of the work.


Is spreading depolarization characterized by an abrupt, massive release of gibbs free energy from the human brain cortex?
In the evolution of the cerebral cortex, the sophisticated organization in a steady state far away from thermodynamic equilibrium has produced the side effect of two fundamental pathological network events: ictal epileptic activity and spreading depolarization. Ictal epileptic activity describes the partial disruption, and spreading depolarization describes the near-complete disruption of the physiological double Gibbs-Donnan steady state. The occurrence of ictal epileptic activity in patients has been known for decades. Recently, unequivocal electrophysiological evidence has been found in patients that spreading depolarizations occur abundantly in stroke and brain trauma. The authors propose that the ion changes can be taken to estimate relative changes in Gibbs free energy from state to state. The calculations suggest that in transitions from the physiological state to ictal epileptic activity to spreading depolarization to death, the cortex releases Gibbs free energy in a stepwise fashion. Spreading depolarization thus appears as a twilight state close to death. Consistently, electrocorticographic recordings in the core of focal ischemia or after cardiac arrest display a smooth transition from the initial spreading depolarization component to the later ultraslow negative potential, which is assumed to reflect processes in cellular death.


Relationship between Dysphagia and Exacerbations in Chronic Obstructive Pulmonary Disease: A Literature Review.
Introduction The literature presents studies correlating chronic obstructive pulmonary disease to dysphagia and suggesting that the aspiration laryngeal phenomenon related to changes in the pharyngeal phase contributes significantly to the exacerbation of symptoms of lung disease. Objectives This study aimed to conduct a literature review to identify the relation between dysphagia and exacerbations of chronic obstructive pulmonary disease. Data Synthesis We found 21 studies and included 19 in this review. The few studies that related to the subject agreed that the presence of dysphagia, due to lack of coordination between swallowing and breathing, may be one of the triggering factors of chronic obstructive pulmonary disease exacerbation. Conclusions The review noted that there is a relationship between dysphagia and exacerbations of chronic obstructive pulmonary disease, identified by studies demonstrating that the difficulties associated with swallowing may lead to exacerbation of the disease. There was difficulty in comparing studies by their methodological differences. More research is needed to clarify the relationship between dysphagia and exacerbations of chronic obstructive pulmonary disease, making it possible to develop multiprofessional treatment strategies for these patients, catered to specific needs due to the systemic manifestations of the disease.


Identification of a second Asian soybean rust resistance gene in Hyuuga soybean.
ABSTRACT Asian soybean rust (ASR) is an economically significant disease caused by the fungus Phakopsora pachyrhizi. The soybean genes Rpp3 and Rpp?(Hyuuga) confer resistance to specific isolates of the pathogen. Both genes map to chromosome 6 (Gm06) (linkage group [LG] C2). We recently identified 12 additional soybean accessions that harbor ASR resistance mapping to Gm06, within 5 centimorgans of Rpp3 and Rpp?(Hyuuga). To further characterize genotypes with resistance on Gm06, we used a set of eight P. pachyrhizi isolates collected from geographically diverse areas to inoculate plants and evaluate them for differential phenotypic responses. Three isolates elicited different responses from soybean accessions PI 462312 (Ankur) (Rpp3) and PI 506764 (Hyuuga) (Rpp?[Hyuuga]). In all, 11 of the new accessions yielded responses identical to either PI 462312 or Hyuuga and 1 of the new accessions, PI 417089B (Kuro daizu), differed from all others. Additional screening of Hyuuga-derived recombinant inbred lines indicated that Hyuuga carries two resistance genes, one at the Rpp3 locus on Gm06 and a second, unlinked ASR resistance gene mapping to Gm03 (LG-N) near Rpp5. These findings reveal a natural case of gene pyramiding for ASR resistance in Hyuuga and underscore the importance of utilizing multiple isolates of P. pachyrhizi when screening for ASR resistance.


Changes in Serum Calcitonin Concentrations, Incidence of Medullary Thyroid Carcinoma, and Impact of Routine Calcitonin Concentration Monitoring in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL).
Increases in serum calcitonin, a tumor marker for medullary thyroid carcinoma (MTC), have been associated with glucagon-like peptide 1 receptor agonist use in some preclinical studies. We report calcitonin changes in exenatide-treated and placebo-administered participants and MTC incidence in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) and consider the impact of within-trial calcitonin monitoring. EXSCEL participants were randomized 1:1 to once-weekly exenatide 2 mg or placebo. Serum calcitonin was measured at baseline (with trial medication discontinued if >40 ng/L) and annually thereafter (with trial medication discontinued if ≥50 ng/L). Median calcitonin concentrations were calculated at each time point, and thyroid malignancies were collected prospectively. Data regarding follow-up after an elevated calcitonin were collected retrospectively. At baseline, 52 (30 exenatide and 22 placebo) participants had calcitonin >40 ng/L, and during follow-up an additional 23 participants (15 exenatide and 8 placebo) had calcitonin ≥50 ng/L in the intention-to-treat population. Median calcitonin concentrations were similar between treatment groups at baseline with no increase over time. Confirmed MTC occurred in three participants (2 exenatide and 1 placebo), all of whom had significantly elevated baseline calcitonin values (413, 422, and 655 ng/L). During a median 3.2 years' follow-up, no change in serum calcitonin was seen with exenatide therapy. The three confirmed cases of MTC all occurred in participants with markedly elevated baseline calcitonin levels, measured prior to trial medication administration. Regular calcitonin monitoring identified no additional cases of MTC, suggesting no benefit of routine calcitonin monitoring during exenatide treatment.


Differences in the haematological profile of healthy 70 year old men and women: normal ranges with confirmatory factor analysis.
Reference ranges are available for different blood cell counts. These ranges treat each cell type independently and do not consider possible correlations between cell types. Participants were identified from the Community Health Index as survivors of the 1947 Scottish Mental Survey, all born in 1936, who were resident in Lothian (potential n = 3,810) and invited to participate in the study. Those who consented were invited to attend a Clinical Research Facility where, amongst other assessments, blood was taken for full blood count. First we described cell count data and bivariate correlations. Next we performed principal components analysis to identify common factors. Finally we performed confirmatory factor analysis to evaluate suitable models explaining relationships between cell counts in men and women. We examined blood cell counts in 1027 community-resident people with mean age 69.5 (range 67.6-71.3) years. We determined normal ranges for each cell type using Q-Q plots which showed that these ranges were significantly different between men and women for all cell types except basophils. We identified three principal components explaining around 60% of total variance of cell counts. Varimax rotation indicated that these could be considered as erythropoietic, leukopoietic and thrombopoietic factors. We showed that these factors were distinct for men and women by confirmatory factor analysis: in men neutrophil count was part of a 'thrombopoietic' trait whereas for women it was part of a 'leukopoietic' trait. First, normal ranges for haematological indices should be sex-specific; at present this only pertains to those associated with erythrocytes. Second, differences between individuals across a range of blood cell counts can be explained to a considerable extent by three major components, but these components are not the same in men and women.


It's Complicated: Patient and Informal Caregiver Performance of Outpatient Parenteral Antimicrobial Therapy-Related Tasks.
Outpatient parenteral antimicrobial therapy (OPAT) requires patients and caregivers to infuse antimicrobials through venous catheters (VCs) in the home. The objective of this study was to perform a patient-centered goal-directed task analysis to identify what is required for successful completion of OPAT. The authors performed 40 semi-structured patient interviews and 20 observations of patients and caregivers performing OPAT-related tasks. Six overall goals were identified: (1) understanding and developing skills in OPAT, (2) receiving supplies, (3) medication administration and VC maintenance, (4) preventing VC harm while performing activities of daily living, (5) managing when hazards lead to failures, and (6) monitoring status. The authors suggest that patients and caregivers use teach-back, take formal OPAT classes, receive visual and verbal instructions, use cognitive aids, learn how to troubleshoot, and receive clear instructions to address areas of uncertainty. Addressing these goals is essential to ensuring the safety of and positive experiences for our patients.


Decorin-binding adhesins from Borrelia burgdorferi.
Lyme disease is a tick-transmitted infection caused by the spirochete Borrelia burgdorferi. Ticks deposit B. burgdorferi into the dermis of the host, where they eventually become associated with collagen fibres. We demonstrated previously that B. burgdorferi is unable to bind collagen, but can bind the collagen-associated proteoglycan decorin and expresses decorin-binding proteins (Dbps). We have now cloned and sequenced two genes encoding the proteins, DbpA and DbpB, which have a similar structure, as revealed by circular dichroism (CD) spectroscopy of recombinant proteins. Competition experiments revealed a difference in binding specificity between DbpA and DbpB. Western blot analysis of proteinase K-treated intact B. burgdorferi and transmission electron microscopy studies using antibodies raised against recombinant Dbps demonstrated that these proteins are surface exposed. DbpA effectively inhibits the attachment of B. burgdorferi to a decorin substrate, whereas DbpB had a marginal effect, suggesting a difference in substrate specificity between the two Dbps. Polystyrene beads coated with DbpA adhered to a decorin-containing extracellular matrix produced by cultured skin fibroblasts, whereas beads coated with OspC did not. Taken together, these data suggest that Dbps are adhesins of the MSCRAMM (microbial surface component-recognizing adhesive matrix molecule) family, which mediate B. burgdorferi attachment to the extracellular matrix of the host.


Perceived quality of life and preferences for life-sustaining treatment in older adults.
We investigated whether perceived quality of life is associated with preferences for life-sustaining treatment for older adults. Participants included chronically ill, elderly outpatients (N = 258) and their primary physicians (N = 105). Patients and physicians were independently administered a questionnaire regarding patient quality of life and preferences for cardiopulmonary resuscitation and mechanical ventilation for the patient. Physicians rated patients' global quality of life, physical comfort, mobility, depression, anxiety, and family relationships significantly worse than did patients. Nearly all perceptions of patients' quality of life were significantly associated with physicians' perceptions, but not patients' treatment preferences. Patient-physician agreement on patient global quality of life was not significantly associated with agreement regarding treatment preferences. We conclude that primary physicians generally consider their older outpatients' quality of life to be worse than do the patients. Furthermore, physicians' estimations of patient quality of life are significantly associated with physicians' attitudes toward life-sustaining treatment for the patients. For the patients, however, perceived quality of life does not appear to be associated with their preferences for life-sustaining treatment.


Tumor Dormancy and Relapse: From a Natural Byproduct of Evolution to a Disease State.
Species evolve by mutations and epigenetic changes acting on individuals in a population; tumors evolve by similar mechanisms at a cellular level in a tissue. This article reviews growing evidence about tumor dormancy and suggests that (i) cellular malignancy is a natural byproduct of evolutionary mechanisms, such as gene mutations and epigenetic modifications, which is manifested in the form of tumor dormancy in healthy individuals as well as in cancer survivors; (ii) cancer metastasis could be an early dissemination event that could occur during malignant dormancy even before primary cancer is clinically detectable; and (iii) chronic inflammation is a key factor in awakening dormant malignant cells at the primary site, leading to primary cancer development, and at distant sites, leading to advanced stage diseases. On the basis of this evidence, it is reasonable to propose that we are all cancer survivors rather than cancer-free individuals because of harboring dormant malignant cells in our organs. A better understanding of local and metastatic tumor dormancy could lead to novel cancer therapeutics for the prevention of cancer. Cancer Res; 77(10); 2564-9. ©2017 AACR.


Three-year analysis of zirconia implants used for single-tooth replacement and three-unit fixed dental prostheses: A prospective multicenter study.
The aim of the present investigation was to evaluate clinically and radiographically the outcome of zirconia oral implants after 3 years in function. In 60 patients in need of either a single-tooth replacement or a three-unit fixed dental prosthesis (FDP), a total of 71 one-piece zirconia implants were placed and immediately restored with temporary fixed prostheses. After a period of at least 2 months in the mandible and at least 4 months in the maxilla, zirconia-based reconstructions were cemented. The implants were clinically and radiologically examined at implant insertion, prosthetic delivery, at 6 months and then yearly up to 3 years. A linear mixed model was used to analyze statistically the influence of prognostic factors on changes in the marginal bone level. Seventy-one implants (48 in the mandible, 23 in the maxilla) inserted in 60 patients were restored with 49 crowns and 11 FDP. One patient lost his implant after 5 weeks. Five patients with one implant each could not be evaluated after 3 years. Based on 55 patients with a total of 66 implants, the mean survival rate was 98.5% after 3 years in function. A statistically significant mean marginal bone loss (0.70 mm ± 0.72 mm) has been detected from implant insertion to the 3-year follow-up. The largest marginal bone loss occurred between implantation and prosthetic delivery (0.67 mm ± 0.56 mm). After delivery, no statistically significant bone level change was observed (0.02 mm ± 0.59 mm). None of the investigated prognostic factors had a significant influence on changes in the marginal bone level. After 3 years in function, the investigated one-piece zirconia implant showed a high survival rate and a low marginal bone loss. The implant system was successful for single-tooth replacement and three-unit FDPs. Further investigations with long-term data are needed to confirm these findings.