Racial and ethnic disparities in perceptions of physician style and trust.
While pervasive racial and ethnic inequalities in access to care and health status have been documented, potential underlying causes, such as patients' perceptions of their physicians, have not been explored as thoroughly. To assess whether a person's race or ethnicity is associated with low trust in the physician. Data were obtained from the 1996 through 1997 Community Tracking Survey, a nationally representative sample. Adults who identified a physician as their regular provider and had at least 1 physician visit in the preceding 12 months were included (N = 32,929). Patients' ratings of their satisfaction with the style of their physician and their trust in physicians. The Satisfaction With Physician Style Scale measured respondents' perceptions of their physicians' listening skills, explanations, and thoroughness. The Trust in Physician Scale measured respondents' perceptions that their physicians placed the patients' needs above other considerations, referred the patient when needed, performed unnecessary tests or procedures, and were influenced by insurance rules. After adjustment for socioeconomic and other factors, minority group members reported less positive perceptions of physicians than whites on these 2 conceptually distinct scales. Minority group members who lacked physician continuity on repeat clinic visits reported even less positive perceptions of their physicians on these 2 scales than whites. Patients from racial and ethnic minority groups have less positive perceptions of their physicians on at least 2 important dimensions. The reasons for these differences should be explored and addressed. Arch Fam Med. 2000;9:1156-1163


The soft-confined method for creating molecular models of amorphous polymer surfaces.
The goal of this work was to use molecular dynamics (MD) simulations to build amorphous surface layers of polypropylene (PP) and cellulose and to inspect their physical and interfacial properties. A new method to produce molecular models for these surfaces was developed, which involved the use of a "soft" confining layer comprised of a xenon crystal. This method compacts the polymers into a density distribution and a degree of molecular surface roughness that corresponds well to experimental values. In addition, calculated properties such as density, cohesive energy density, coefficient of thermal expansion, and the surface energy agree with experimental values and thus validate the use of soft confining layers. The method can be applied to polymers with a linear backbone such as PP as well as those whose backbones contain rings, such as cellulose. The developed PP and cellulose surfaces were characterized by their interactions with water. It was found that a water nanodroplet spreads on the amorphous cellulose surfaces, but there was no significant change in the dimension of the droplet on the PP surface; the resulting MD water contact angles on PP and amorphous cellulose surfaces were determined to be 106 and 33°, respectively.


Measuring management practices in primary health care facilities - development and validation of management practices scorecard in Nigeria.
In low- and middle-income countries, there is scarcity of validated and reliable measurement tools for health facility management, and many interventions to improve primary health care (PHC) facilities are designed without adequate evidence base on what management practices are critical. This article developed and validated a scorecard to measure management practices at primary health care facilities under the performance-based financing (PBF) scheme in Nigeria. Relevant management practice domains and indicators for PHC facilities were determined based on literature review and a prior qualitative study conducted in Nigeria. The domains and indicators were tested for face validity via experts review and organized into an interviewer-administered scorecard. A stratified random sampling of PHC facilities in three States in Nigeria was conducted to assess the reliability and construct validity of the scorecard. Inter-rater reliability using inter-class correlation (ICC) (1, k) was assessed with one-way ANOVA. Exploratory factor analysis (EFA) was conducted to assess the construct validity, and an updated factor structure were developed. 32 indicators and 6 management practice domains were initially described. Ordinal responses were derived for each indicator. Data on the scorecard were obtained from 111 PHC facilities. The ICC of mean ratings for each team of judges was 0.94. The EFA identified 6 domains (Stakeholder engagement and communication; Community-level activities; Update of plan and target; Performance management; Staff attention to planning, target, and performance; and Drugs and financial management) and reduced the number of indicators to 17. The average communality of selected items was 0.45, and item per factor ratio was 17:6. Despite a few areas for further refinement, this paper presents a reliable and valid scorecard for measuring management practices in PHC facilities. The scorecard can be applied for routine supervisory visits to PHC facilities, and can help accumulate knowledge on facility management, how it affects performance, and how it may be strengthened.


[Altered gravity affects subnucleolus localization of fibrillarin and NopA64, the most important proteins of rRNA processing].
Fibrillarin and plant nucleolin homologue NopA64 are two important nucleolar proteins involved in pre-rRNA processing. To understand better the effects of the altered gravity environment on the nucleolus functioning we have investigated the location of fibrillarin and NopA64 in nucleolar subcomponents of cress (Lepidium sativum L.) root meristematic cells grown under simulated microgravity that was compared to the control cells grown in normal conditions at I g. Cress fibrillarin was first shown to have the molecular weight 41 kDa. Both fibrillarin and NopA64 in the cress cell nucleolus are located in the zones known to contain processing pre-rRNA molecules as it has been previously reported in other species. The data confirm participation of these proteins in processomes--RNP complex particles involved in pre-rRNA processing. Under altered gravity a decrease in the quantity of both fibrillarin and NopA64 in the transition zone between fibrillar centres and the dense fibrillar component was observed, compared to control, which could point out to a lowering of the level of early pre-rRNA processing in these experimental conditions. This decrease was also detected in the bulk of the dense fibrillar component. These data support the idea that altered (reduced) gravity results in lowering the level of functional activity of the nucleolus.


Astrocytes regulate adult hippocampal neurogenesis through ephrin-B signaling.
Neurogenesis in the adult hippocampus involves activation of quiescent neural stem cells (NSCs) to yield transiently amplifying NSCs, progenitors, and, ultimately, neurons that affect learning and memory. This process is tightly controlled by microenvironmental cues, although a few endogenous factors are known to regulate neuronal differentiation. Astrocytes have been implicated, but their role in juxtacrine (that is, cell-cell contact dependent) signaling in NSC niches has not been investigated. We found that ephrin-B2 presented from rodent hippocampal astrocytes regulated neurogenesis in vivo. Furthermore, clonal analysis in NSC fate-mapping studies revealed a previously unknown role for ephrin-B2 in instructing neuronal differentiation. In addition, ephrin-B2 signaling, transduced by EphB4 receptors on NSCs, activated β-catenin in vitro and in vivo independently of Wnt signaling and upregulated proneural transcription factors. Ephrin-B2(+) astrocytes therefore promote neuronal differentiation of adult NSCs through juxtacrine signaling, findings that advance our understanding of adult neurogenesis and may have future regenerative medicine implications.


Health Care Delivery Practices in Huntington's Disease Specialty Clinics: An International Survey.
Little is known about the organization of clinical services for Huntington's disease (HD). To describe how health care services are organized and delivered in HD-clinics taking part in or eligible for the Enroll-HD study. In 2014, a 69-item survey was administered to sites taking part in or eligible for the Enroll-HD study. Of 231 sites surveyed, 121 (52.2%) sites in Europe, North America, Latin America, and Oceania responded. Most sites in the sample serve large populations, with 61.1% serving more than 1.5 million people, and a further 33% serving >500,000. Almost all (86.0%) centers see patients from outside their region. The majority of centers (59.7%) follow 50-199 patients, 21.9% care for more than 200. Most centers provide care in all stages of HD, and nearly all review pre-symptomatic cases. Multidisciplinary case reviews are offered in 54.5% of sites, with outreach clinics offered by 48.1%. Videoconferencing and telemedicine are used by 23.6%. Separate consultations for caregivers are offered in more than half of the centers. Most centers (70.4%) report following published guidelines or local care pathways for HD. Most centers serve a large population and use a multidisciplinary approach. The survey gives insight into factors underpinning HD service delivery globally. There is a need for more in-depth studies of clinical practice to understand how services are organized and how such features may be associated with quality of care.


Hypoxia and resistance exercise: a comparison of localized and systemic methods.
It is generally believed that optimal hypertrophic and strength gains are induced through moderate- or high-intensity resistance training, equivalent to at least 60% of an individual's 1-repetition maximum (1RM). However, recent evidence suggests that similar adaptations are facilitated when low-intensity resistance exercise (~20-50% 1RM) is combined with blood flow restriction (BFR) to the working muscles. Although the mechanisms underpinning these responses are not yet firmly established, it appears that localized hypoxia created by BFR may provide an anabolic stimulus by enhancing the metabolic and endocrine response, and increase cellular swelling and signalling function following resistance exercise. Moreover, BFR has also been demonstrated to increase type II muscle fibre recruitment during exercise. However, inappropriate implementation of BFR can result in detrimental effects, including petechial haemorrhage and dizziness. Furthermore, as BFR is limited to the limbs, the muscles of the trunk are unable to be trained under localized hypoxia. More recently, the use of systemic hypoxia via hypoxic chambers and devices has been investigated as a novel way to stimulate similar physiological responses to resistance training as BFR techniques. While little evidence is available, reports indicate that beneficial adaptations, similar to those induced by BFR, are possible using these methods. The use of systemic hypoxia allows large groups to train concurrently within a hypoxic chamber using multi-joint exercises. However, further scientific research is required to fully understand the mechanisms that cause augmented muscular changes during resistance exercise with a localized or systemic hypoxic stimulus.


Lipid and Some Other Cardiovascular Risk Factors Assessment in a Rural Community in Eastern Nigeria.
Continuous re-evaluation of modifiable cardiovascular risk factors (cardiovascular diseases [CVDs]) in developing nations is imperative as it lays foundation for early preventive/intervention measures at grass root level to improve/prevent CVD morbidity and mortality in those nations where health indices still score below the standard. The aim was to assess CVD risk factors as a continuous re-evaluation of these may underscore the need for early intervention measures at grass root level. A total of 257 apparently healthy inhabitants aged 18-85 years were recruited in a rural community in South Eastern Nigeria by convenient sampling. Blood pressure, waist circumference and blood lipid analysis were done procedurally and data analyzed using SPSS 16.0 statistical software. The males were older (59.41 [5.22]) than the females (53.31 [16.90]). 69.2% (133/192) were low level farmers, retirees and dependents. Total cholesterol (TC), low density lipoprotein (LDL), and risk predictive index were higher in females while triglyceride (TG), high density lipoprotein and very LDL (VLDL) were higher in males. The middle aged and elderly respectively had higher TG and VLDL compared to the young. Aside hypertriglyceridemia, all lipid abnormalities were higher in females than males both singly (high TC: 28.9% [35/121] vs. 16.9% [12/71]; high LDL cholesterol: 52.0% [63/121] vs. 31.0% [22/71]) and in combination hypercholesterolemia with hypertriglyceridemia (42.9% [52/121] vs. 36.6% [26/71]). "Multiple risk factors" also occurred more in females with seeming further increase in older age. The chances of a female having CVD after menopause seemed to outweigh that of the male. CVD preventive measures should be focused at the primary/community level as a means to curtailing the increasing morbidity and eventual mortality from CVDs.


Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer.
Both abundant epidermal growth factor receptor (EGFR or ErbB1) and high activity of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway are common and therapeutically targeted in triple-negative breast cancer (TNBC). However, activation of another EGFR family member [human epidermal growth factor receptor 3 (HER3) (or ErbB3)] may limit the antitumor effects of these drugs. We found that TNBC cell lines cultured with the EGFR or HER3 ligand EGF or heregulin, respectively, and treated with either an Akt inhibitor (GDC-0068) or a PI3K inhibitor (GDC-0941) had increased abundance and phosphorylation of HER3. The phosphorylation of HER3 and EGFR in response to these treatments was reduced by the addition of a dual EGFR and HER3 inhibitor (MEHD7945A). MEHD7945A also decreased the phosphorylation (and activation) of EGFR and HER3 and the phosphorylation of downstream targets that occurred in response to the combination of EGFR ligands and PI3K-Akt pathway inhibitors. In culture, inhibition of the PI3K-Akt pathway combined with either MEHD7945A or knockdown of HER3 decreased cell proliferation compared with inhibition of the PI3K-Akt pathway alone. Combining either GDC-0068 or GDC-0941 with MEHD7945A inhibited the growth of xenografts derived from TNBC cell lines or from TNBC patient tumors, and this combination treatment was also more effective than combining either GDC-0068 or GDC-0941 with cetuximab, an EGFR-targeted antibody. After therapy with EGFR-targeted antibodies, some patients had residual tumors with increased HER3 abundance and EGFR/HER3 dimerization (an activating interaction). Thus, we propose that concomitant blockade of EGFR, HER3, and the PI3K-Akt pathway in TNBC should be investigated in the clinical setting.


Sonication versus Tissue Sampling for Diagnosis of Prosthetic Joint and Other Orthopedic Device-Related Infections.
Current guidelines recommend collection of multiple tissue samples for diagnosis of prosthetic joint infections (PJI). Sonication of explanted devices has been proposed as a potentially simpler alternative; however, reported microbiological yield varies. We evaluated sonication for diagnosis of PJI and other orthopedic device-related infections (DRI) at the Oxford Bone Infection Unit between October 2012 and August 2016. We compared the performance of paired tissue and sonication cultures against a "gold standard" of published clinical and composite clinical and microbiological definitions of infection. We analyzed explanted devices and a median of five tissue specimens from 505 procedures. Among clinically infected cases the sensitivity of tissue and sonication culture was 69% (95% confidence interval, 63 to 75) and 57% (50 to 63), respectively (P < 0.0001). Tissue culture was more sensitive than sonication for both PJI and other DRI, irrespective of the infection definition used. Tissue culture yield was higher for all subgroups except less virulent infections, among which tissue and sonication culture yield were similar. The combined sensitivity of tissue and sonication culture was 76% (70 to 81) and increased with the number of tissue specimens obtained. Tissue culture specificity was 97% (94 to 99), compared with 94% (90 to 97) for sonication (P = 0.052) and 93% (89 to 96) for the two methods combined. Tissue culture is more sensitive and may be more specific than sonication for diagnosis of orthopedic DRI in our setting. Variable methodology and case mix may explain reported differences between centers in the relative yield of tissue and sonication culture. Culture yield was highest for both methods combined.


A model for Chagas disease with oral and congenital transmission.
This work presents a new mathematical model for the domestic transmission of Chagas disease, a parasitic disease affecting humans and other mammals throughout Central and South America. The model takes into account congenital transmission in both humans and domestic mammals as well as oral transmission in domestic mammals. The model has time-dependent coefficients to account for seasonality and consists of four nonlinear differential equations, one of which has a delay, for the populations of vectors, infected vectors, infected humans, and infected mammals in the domestic setting. Computer simulations show that congenital transmission has a modest effect on infection while oral transmission in domestic mammals substantially contributes to the spread of the disease. In particular, oral transmission provides an alternative to vector biting as an infection route for the domestic mammals, who are key to the infection cycle. This may lead to high infection rates in domestic mammals even when the vectors have a low preference for biting them, and ultimately results in high infection levels in humans.


Rationality in medical decision making: a review of the literature on doctors' decision-making biases.
The objectives of this study were to describe ways in which doctors make suboptimal diagnostic and treatment decisions, and to discuss possible means of alleviating those biases, using a review of past studies from the psychological and medical decision-making literatures. A number of biases can affect the ways in which doctors gather and use evidence in making diagnoses. Biases also exist in how doctors make treatment decisions once a definitive diagnosis has been made. These biases are not peculiar to the medical domain but, rather, are manifestations of suboptimal reasoning to which people are susceptible in general. None the less, they can have potentially grave consequences in medical settings, such as erroneous diagnosis or patient mismanagement. No surefire methods exist for eliminating biases in medical decision making, but there is some evidence that the adoption of an evidence-based medicine approach or the incorporation of formal decision analytic tools can improve the quality of doctors' reasoning. Doctors' reasoning is vulnerable to a number of biases that can lead to errors in diagnosis and treatment, but there are positive signs that means for alleviating some of these biases are available.


Learning to be inflexible: Enhanced attentional biases in Parkinson's disease.
Impaired attentional flexibility is considered to be one of the core cognitive deficits in Parkinson's disease (PD). However, the mechanisms that underlie this impairment are contested. Progress in resolving this dispute has also been hindered by the fact that cognitive deficits in PD are heterogeneous; therefore, it is unclear whether attentional impairments are only present in a subgroup of patients. Here, we demonstrate that what differentiates PD patients from age-matched controls is an inability to shift attention away from previously relevant information (perseveration) and an inability to shift attention towards previously irrelevant information (learned irrelevance). In contrast, there was no evidence that PD patients, compared to controls, were impaired in being able to appropriately attend to, or ignore, novel information. Furthermore, when patients were stratified according to their level of executive impairment, the executively impaired group showed a selective deficit in set formation compared to the unimpaired group, a behavioural pattern reminiscent of cortical dopamine depletion. Cumulatively, these results suggest that cognitive inflexibility in PD relates to a specific form of attentional dysfunction, in which learned attentional biases cannot be overcome.


Immunization response varies with intensity of acute lymphoblastic leukemia therapy.
Twenty-four children receiving maintenance chemotherapy for acute lymphoblastic leukemia were given booster doses of tetanus-diphtheria combined toxoids. One month later, 19 of the 24 children were given Haemophilus influenzae B oligosaccharide-cross-reacting material conjugate vaccine. Following immunization, all patients had protective antibody titers against tetanus, 92% had protective antidiphtheria titers, and 84% had protective titers against H influenzae. Preimmunization titers, postimmunization titers, and response to immunization varied according to the intensity of therapy. There was no correlation with duration of therapy or quantitative hematologic values in the peripheral blood. These observations support the recommendation that children treated for acute lymphoblastic leukemia should be immunized against H influenzae B.


Referral patterns and proximity to palliative care inpatient services by level of socio-economic disadvantage. A national study using spatial analysis.
A range of health outcomes at a population level are related to differences in levels of social disadvantage. Understanding the impact of any such differences in palliative care is important. The aim of this study was to assess, by level of socio-economic disadvantage, referral patterns to specialist palliative care and proximity to inpatient services. All inpatient and community palliative care services nationally were geocoded (using postcode) to one nationally standardised measure of socio-economic deprivation - Socio-Economic Index for Areas (SEIFA; 2006 census data). Referral to palliative care services and characteristics of referrals were described through data collected routinely at clinical encounters. Inpatient location was measured from each person's home postcode, and stratified by socio-economic disadvantage. This study covered July - December 2009 with data from 10,064 patients. People from the highest SEIFA group (least disadvantaged) were significantly less likely to be referred to a specialist palliative care service, likely to be referred closer to death and to have more episodes of inpatient care for longer time. Physical proximity of a person's home to inpatient care showed a gradient with increasing distance by decreasing levels of socio-economic advantage. These data suggest that a simple relationship of low socioeconomic status and poor access to a referral-based specialty such as palliative care does not exist. Different patterns of referral and hence different patterns of care emerge.


Prognostic Role of Preoperative Serum Lipid Levels in Patients Undergoing Radical Prostatectomy for Clinically Localized Prostate Cancer.
The prognostic role of preoperative serum lipid levels in patients undergoing radical prostatectomy (RP) for clinically localized prostate cancer (PCa) is unclear. The aim of the present study was to investigate preoperative serum lipid levels in patients with clinically localized PCa undergoing RP and their association with clinicopathological features and oncological outcome. Preoperative lipid levels (total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides) and statin use from consecutive patients with clinically localized PCa undergoing RP in a tertiary referral center between 2008 and 2015 were recorded and patients were followed prospectively. Logistic regression analysis was used to test the association between lipid levels and clinicopathological parameters. Lipid values were analyzed both as continuous and dichotomized variables. Univariable and multivariable Cox regression analyses were performed to identify predictors for recurrence-free survival (RFS). Recurrence was defined as rising and verified PSA levels >0.1 ng/ml. Our cohort consisted of 371 men with a median age of 63 years (range 41-78 years) and a median preoperative PSA value of 6.79 ng/ml (0.43-81.4 ng/ml). Median follow-up was 28 months (1-64). No association was found between lipid levels and adverse pathological characteristics such as ≥pT3, Gleason score ≥8, positive nodal status and positive surgical margins. Recurrence occurred in 49 patients (15.4%) at a median time of 18 months (2-51 month). Compared to low LDL cholesterol, high LDL cholesterol was associated with longer RFS in univariable analysis (continuous: Hazard Ratio (HR): 0.67, 95%-Confidence Interval (CI): 0.47-0.96, P = 0.03; 3 mM cut-point: HR: 0.44, 95%-CI: 0.24-0.79, P = 0.006). Neither levels of other lipids, nor statin use were associated with RFS. Preoperative LDL cholesterol remained an independent predictor for PCa recurrence in a multivariable model adjusted for age, preoperative PSA, statin use, tumor stage, Gleason score, nodal status and surgical margin status (continuous: HR: 0.66, 95%-CI: 0.44-0.99, P = 0.04; 3 mM cut-point: HR: 0.41, 95%-CI: 0.21-0.78, P = 0.007). This is the first prospective study showing the potential adverse and independent prognostic role of low preoperative LDL cholesterol levels in patients with localized PCa undergoing RP. Prostate 77:549-556, 2017. © 2017 Wiley Periodicals, Inc.


Population Management: A Tool to Improve Timely Care in Pediatric and Young Adult Patients with Inflammatory Bowel Disease.
Maintenance of health leads to better outcomes in patients with chronic illness. ImproveCareNow, an international inflammatory bowel disease (IBD) quality improvement (QI) network, recommends maintenance-of-health visits twice a year. We identified a gap in care, with only 64% of IBD patients having documented visits within 200 days. Therefore, we sought to improve our follow-up rate to a goal of 80%. Using population management (PM) reports, we identified patient-, data-, and treatment-related reasons for no documented visit within 200 days. We used the Pareto chart, key drivers, and process flow mapping and implemented changes using Plan-Do-Study-Act (PDSA) cycles to improve follow-up visit rates. Outcomes were presented using a control run chart with pre- and post- intervention data. The most common reasons for no visits were patient nonadherence with appointments (50%) and relocation/transition to an adult provider (25%). The median percentage of documented visits within 200 days increased from 64% to 83% (p < 0.0001), and this increase has been sustained for one year. Using the PM tool and focused QI interventions improved data quality and the percentage of patients with a documented visit within 200 days. The process is simple and can be applied to patients with other chronic illnesses.


Melatonin, the Hormone of Darkness: From Sleep Promotion to Ebola Treatment.
Melatonin is a hormone secreted by the enigmatic pineal gland in response to darkness, hence the name hormone of darkness. It has generated a great deal of interest as a therapeutic modality for various diseases particularly sleep disorders. This pleiotropic molecule has anti-inflammatory, antioxidant and anticoagulopathic properties in addition to its endothelial protective effects. In this article we discuss melatonin secretion and mechanisms of action as well as therapeutic rationale. We also highlight the potential utility of melatonin in the deadly modern-day Ebola epidemic.


Vitamin D intake and season modify the effects of the GC and CYP2R1 genes on 25-hydroxyvitamin D concentrations.
Vitamin D deficiency {defined by the blood concentration of 25-hydroxyvitamin D [25(OH)D]} has been associated with many adverse health outcomes. Genetic and nongenetic factors account for variation in 25(OH)D, but the role of interactions between these factors is unknown. To assess this, we examined 1204 women of European descent from the Carotenoids in Age-Related Eye Disease Study, an ancillary study of the Women's Health Initiative Observational Study. Twenty-nine single nucleotide polymorphisms (SNPs) in 4 genes, GC, CYP2R1, DHCR7, and CYP24A1, from recent meta-analyses of 25(OH)D genome-wide association studies were genotyped. Associations between these SNPs and 25(OH)D were tested using generalized linear regression under an additive genetic model adjusted for age, blood draw month, and ancestry. Results were stratified by season of blood draw and, separately, vitamin D intake for the 6 SNPs showing a significant association with 25(OH)D at the P < 0.01 level. Two nonsynonymous SNPs in GC and 4 SNPs in CYP2R1 were strongly associated with 25(OH)D in individuals whose blood was drawn in summer (P ≤ 0.002) but not winter months and, independently, in individuals with vitamin D intakes ≥400 (P ≤ 0.004) but not <400 IU/d (10 μg/d). This effect modification, if confirmed, has important implications for the design of genetic studies for all health outcomes and for public health recommendations and clinical practice guidelines regarding the achievement of adequate vitamin D status.


The lipid peroxidation by-product 4-hydroxy-2-nonenal (4-HNE) induces insulin resistance in skeletal muscle through both carbonyl and oxidative stress.
Numerous oxidants are produced as by-products of aerobic cell metabolism, and there is growing evidence that they play key roles in the pathogenesis of insulin resistance. Under conditions of oxidative stress, lipid peroxidation of ω6-polyunsaturated fatty acids leads to the production of 4-hydroxy-2-nonenal (4-HNE). Several lines of evidence suggest that 4-HNE could be involved in the pathophysiology of metabolic diseases; therefore, in this study we assessed the direct effects of 4-HNE on skeletal muscle insulin sensitivity. Gastrocnemius muscle and L6 muscle cells were treated with 4-HNE. Insulin signaling was measured by Western blotting and glucose uptake using 2-deoxy-d-[3H]glucose. Carbonyl stress, glutathione content, and oxidative stress were assessed as potential mechanisms leading to insulin resistance. Protection of cells was induced by pretreatment with 3H-1,2-dithiole-3-thione, N-acetyl-cysteine, aminoguanidine, or S-adenosyl-methionine. 4-HNE induced a time- and dose-dependent decrease in insulin signaling and insulin-induced glucose uptake in muscle. It induced a state of carbonyl stress through adduction of proteins as well as a depletion in reduced glutathione and production of radical oxygen species. A pharmacological increase in glutathione pools was achieved by 3H-1,2-dithiole-3-thione and protected the cells against all deleterious effects of 4-HNE; furthermore, N-acetylcysteine, aminoguanidine, and S-adenosylmethionine prevented 4-HNE noxious effects. 4-HNE can impair insulin action in muscle cells through oxidative stress and oxidative damage to proteins, eventually leading to insulin resistance. These deleterious effects can be prevented by pretreatment with antioxidants, scavengers, or an increase in intracellular glutathione pools. Use of such molecules could represent a novel strategy to combat insulin resistance and other oxidative stress-associated pathologies.


Treatment Outcomes of Multidrug-Resistant Tuberculosis in Taiwan: Tackling Loss to Follow-up.
The proportion of treatment success among patients with multidrug-resistant tuberculosis (MDR-TB) enrolled between 1992 and 1996 was 51.2%, and that among patients enrolled between 2000 and April 2007 was 61%. To address the challenge of MDR-TB, the Taiwan MDR-TB Consortium (TMTC) was established in May 2007. To assess the performance of the TMTC, we analyzed the data of patients enrolled in its first 5 years. Comprehensive care was provided at no cost to patients, who were usually hospitalized for 1 month initially. Treatment regimens consisted of 4-5 drugs and the duration of treatment was 18-24 months. A case manager and a directly observed therapy provider were assigned to each patient. Psychosocial support was provided to address emotional stress and stigma. Financial support was offered to avoid the financial hardship faced by patients and their families. We assessed treatment outcomes at 30 months using internationally recommended outcome definitions. Of the 692 MDR-TB patients, 570 (82.4%) were successfully treated, 84 (12.1%) died, 18 (2.6%) had treatment failure, and 20 (2.9%) were lost to follow-up. Age ≥65 years (adjusted odds ratio [aOR], 6.78 [95% confidence interval {CI}, 3.14-14.63]), cancer (aOR, 11.82 [95% CI, 5.55-25.18]), and chronic kidney disease (aOR, 3.62 [95% CI, 1.70-7.71]) were significantly associated with death. Resistance to fluoroquinolone (aOR, 10.89 [95% CI, 3.97-29.88]) was significantly associated with treatment failure. The TMTC, which operates under a strong collaboration between the public health authority and clinical teams, has been a highly effective model of care in the management of MDR-TB.


Amplitude and phase modulation by free-carrier injection in III-V semiconducting waveguides for the 10.6-microm wavelength.
We give experimental results for amplitude and phase modulation by free-carrier injection in planar and rib waveguides at a wavelength of 10.6 microm. These waveguides have been formed by metal-organic chemical-vapor deposition of InP and GalnAs layers on InP substrates. Absorptions of 95% associated with phase shifts greater than 3pi have been measured for injection-current densities below 1 A/cm(2) with a planar guiding structure and drive currents of approximately 10 mA for typical channel waveguides.


Accuracy of intraocular lens power estimation in eyes having phacovitrectomy for rhegmatogenous retinal detachment.
To evaluate the accuracy of intraocular lens power estimation in eyes having phacovitrectomy for rhegmatogenous retinal detachment. Retrospective case review of 100 consecutive eyes that underwent phacovitrectomy for rhegmatogenous retinal detachment. Axial lengths were measured using optical biometry and/or ultrasound A-scan. Achieved and predicted refraction were compared to calculate the mean postoperative refractive prediction error and the mean absolute prediction error. Factorial analysis of variance models were developed to assess outcome on the whole and that between the subgroups. Ninety-five eyes had postoperative refraction: 41 macula-on (43%) and 54 macula-off (57%). The mean postoperative prediction error was -0.34 ± 0.89 diopters. There was no statistical significant difference in the refractive outcomes between macula-on and macula-off groups (P > 0.05). Overall, using mean absolute prediction error as the outcome measure, optical biometry was more accurate than ultrasound (P = 0.040). However, significantly more ultrasound-measured axial lengths were selected for intraocular lens power estimation in macula-off group compared with the macula-on group (P = 0.016). Combined phacovitrectomy in rhegmatogenous retinal detachment included a small biometric error that was within the tolerable range in most cases. Both optical biometry and ultrasound should be used to estimate axial lengths, for macula-off rhegmatogenous retinal detachment cases, to improve the accuracy of intraocular lens power calculation.


Delivery of gender-sensitive comprehensive primary care to women veterans: implications for VA Patient Aligned Care Teams.
The Veterans Health Administration (VA) has undertaken a major initiative to transform primary care delivery through implementation of Patient Aligned Care Teams (PACTs). Based on the patient-centered medical home concept, PACTs aim to improve access, continuity, coordination, and comprehensiveness using team-based care that is patient driven and patient centered. However, how PACT principles should be applied to meet the needs of special populations, including women veterans, is not entirely clear. While historical differences in military participation meant women veterans were rarely seen in VA healthcare settings, they now represent the fastest growing segment of new VA users. They also have complex healthcare needs, adding gender-specific services and other needs to the spectrum of services that the VA must deliver. These trends are changing the VA landscape, introducing challenges to how VA care is organized, how VA providers need to be trained, and how VA considers implementation of new initiatives, such as PACT. We briefly describe the evolution of VA primary care delivery for women veterans, review VA policy for delivering gender-sensitive comprehensive primary care for women, and discuss the challenges that women veterans' needs pose in the context of PACT implementation. We conclude with recommendations for addressing some of these challenges moving forward.


Visceral leishmaniasis: Spatiotemporal heterogeneity and drivers underlying the hotspots in Muzaffarpur, Bihar, India.
Despite the overall decrease in visceral leishmaniasis (VL) incidence on the Indian subcontinent, there remain spatiotemporal clusters or 'hotspots' of new cases. The characteristics of these hotspots, underlying transmission dynamics, and their importance for shaping control strategies are not yet fully understood and are investigated in this study for a VL endemic area of ~100,000 inhabitants in Bihar, India between 2007-2015. VL incidence (cases/10,000/year) dropped from 12.3 in 2007 to 0.9 in 2015, which is just below the World Health Organizations' threshold for elimination as a public health problem. Clustering of VL was assessed between subvillages (hamlets), using multiple geospatial and (spatio)temporal autocorrelation and hotspot analyses. One to three hotspots were identified each year, often persisting for 1-5 successive years with a modal radius of ~500m. The relative risk of having VL was 5-86 times higher for inhabitants of hotspots, compared to those living outside hotspots. Hotspots harbour significantly more households from the two lowest asset quintiles (as proxy for socio-economic status). Overall, children and young adelescents (5-14 years) have the highest risk for VL, but within hotspots and at the start of outbreaks, older age groups (35+ years) show a comparable high risk. This study demonstrates significant spatiotemporal heterogeneity in VL incidence at subdistrict level. The association between poverty and hotspots confirms that VL is a disease of 'the poorest of the poor' and age patterns suggest a potential role of waning immunity as underlying driver of hotspots. The recommended insecticide spraying radius of 500m around detected VL cases corresponds to the modal hotspot radius found in this study. Additional data on immunity and asymptomatic infection, and the development of spatiotemporally explicit transmission models that simulate hotspot dynamics and predict the impact of interventions at the smaller geographical scale will be crucial tools in sustaining elimination.


Yoga for Trauma and Related Mental Health Problems: A Meta-Review With Clinical and Service Recommendations.
Health and human service providers have expressed growing interest in the benefits of yoga to help individuals cope with the effects of trauma, including anxiety, depression, and posttraumatic stress disorder (PTSD). Despite the growing popularity and strong appeal of yoga, providers must be mindful of the evidence regarding the efficacy of yoga in treating trauma effects as well as trauma-related mental health symptoms and illnesses. Therefore, our research team sought to answer two questions: (a) What is the evidence regarding yoga as a treatment for trauma effects, including anxiety, depression, and PTSD and (b) what are the clinical and service recommendations for using yoga with trauma-exposed individuals? Our initial scans identified a substantial body of research, including reviews. Rather than replicate earlier efforts, we undertook a systematic meta-review of 13 literature reviews, one of which included a meta-analysis. We determined the 13 reviews examined 185 distinct studies. Findings show that the evidence regarding yoga as an intervention for the effects of trauma as well as the mental health symptoms and illnesses often associated with trauma is encouraging but preliminary. Overall, the body of research is lacking in rigor as well as specificity regarding trauma. Review results also only allow for the recommendation of yoga as an ancillary treatment. Further, the reviews had considerable differences in their methods and limitations. Nonetheless, the results yielded findings concerning how clinicians and service providers can use yoga in their own practices, which is an important step for building an evidence base in this area.


Repurposing of statins via inhalation to treat lung inflammatory conditions.
Despite many therapeutic advancements over the past decade, the continued rise in chronic inflammatory lung diseases incidence has driven the need to identify and develop new therapeutic strategies, with superior efficacy to treat these diseases. Statins are one class of drug that could potentially be repurposed as an alternative treatment for chronic lung diseases. They are currently used to treat hypercholesterolemia by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, that catalyses the rate limiting step in the mevalonate biosynthesis pathway, a key intermediate in cholesterol metabolism. Recent research has identified statins to have other protective pleiotropic properties including anti-inflammatory, anti-oxidant, muco-inhibitory effects that may be beneficial for the treatment of chronic inflammatory lung diseases. However, clinical studies have yielded conflicting results. This review will summarise some of the current evidences for statins pleiotropic effects that could be applied for the treatment of chronic inflammatory lung diseases, their mechanisms of actions, and the potential to repurpose statins as an inhaled therapy, including a detailed discussion on their different physical-chemical properties and how these characteristics could ultimately affect treatment efficacies. The repurposing of statins from conventional anti-cholesterol oral therapy to inhaled anti-inflammatory formulation is promising, as it provides direct delivery to the airways, reduced risk of side effects, increased bioavailability and tailored physical-chemical properties for enhanced efficacy.


Nanobacteria and psammoma bodies: ultrastructural observations in a case of pathological placental calcification.
Nanobacteria are controversial infectious agents with nanometric size, the capacity to nucleate hydroxyapatite and grow in culture, and present in human diseases associated with calcification and psammoma bodies. The authors report a case of pathological placental calcifications associated with nanobacteria. Electron microscopy and electron energy loss spectroscopy imaging were used to recognize 160-nm-sized calcium-free bodies mainly presenting as extracellular fibrillary tangles and 500-nm-sized calcified bodies; they encrusted the syncito-trophoblast basal membrane and aggregated into miniaturized psammoma bodies. Nanobacteria may be composed of a prionoid protein with self-assembling and self-propagating abilities whose growth is associated with the formation of psammoma bodies.


Integrated functional, gene expression and genomic analysis for the identification of cancer targets.
The majority of new drug approvals for cancer are based on existing therapeutic targets. One approach to the identification of novel targets is to perform high-throughput RNA interference (RNAi) cellular viability screens. We describe a novel approach combining RNAi screening in multiple cell lines with gene expression and genomic profiling to identify novel cancer targets. We performed parallel RNAi screens in multiple cancer cell lines to identify genes that are essential for viability in some cell lines but not others, suggesting that these genes constitute key drivers of cellular survival in specific cancer cells. This approach was verified by the identification of PIK3CA, silencing of which was selectively lethal to the MCF7 cell line, which harbours an activating oncogenic PIK3CA mutation. We combined our functional RNAi approach with gene expression and genomic analysis, allowing the identification of several novel kinases, including WEE1, that are essential for viability only in cell lines that have an elevated level of expression of this kinase. Furthermore, we identified a subset of breast tumours that highly express WEE1 suggesting that WEE1 could be a novel therapeutic target in breast cancer. In conclusion, this strategy represents a novel and effective strategy for the identification of functionally important therapeutic targets in cancer.


A novel method for identifying potential disease-related miRNAs via a disease-miRNA-target heterogeneous network.
MicroRNAs (miRNAs), as a kind of important small endogenous single-stranded non-coding RNA, play critical roles in a large number of human diseases. However, the currently known experimental verifications of the disease-miRNA associations are still rare and experimental identification is time-consuming and labor-intensive. Accordingly, identifying potential disease-related miRNAs to help people understand the pathogenesis of complex diseases has become a hot topic. In this study, we take advantage of known disease-miRNA associations combined with a large number of experimentally validated miRNA-target associations, and further develop a novel disease-miRNA-target heterogeneous network for identifying disease-related miRNAs. The leave-one-out cross validation experiment and several statistical measures demonstrate that our method can effectively identify potential disease-related miRNAs. Furthermore, the good predictive performance of 15 common diseases and the manually confirmed analyses of the top 30 candidates of hepatocellular carcinoma, ovarian neoplasms and breast neoplasms further provide convincing evidence of the practical ability of our method. The source code implemented by our method is freely available at: .


Arthroscopic Complete Posterior Capsulotomy for Knee Flexion Contracture.
Knee flexion contracture is a clinically important complication that can be observed after trauma, after knee surgery, or as a result of osteoarthritis. When it is left untreated, knee shearing forces increase not only in the affected joint but also in the contralateral knee, leading to mechanical overload in both limbs. Conservative management is a first-line treatment option for extension deficits, but when it fails, surgical treatment is necessary. Open as well as arthroscopic techniques focus mainly on an anterior arthrolysis and a posterior capsular release. Until now, posterior capsulotomy involved either a medial posterior capsular release or medial and lateral posterior capsular releases. Our aim is to present the technique of arthroscopic complete posterior capsulotomy for knee flexion contractures.


Self-perception of symptoms of anemia and fatigue before and after blood transfusions in patients with myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal bone marrow disorders characterized by chronic refractory anemia. Many patients with MDS are dependent on regular blood transfusions. The study aimed to investigate symptoms of anemia and fatigue in patients with MDS immediately before and after blood transfusion and to capture patients' descriptions of their symptoms. Sixteen transfusion-dependent MDS patients with a median age of 74 years (range 67-91) were included. Data were collected longitudinally using the Functional Assessment of Cancer Therapy Anemia (FACT-An) questionnaire, which measured anemia and fatigue symptoms before and after one blood transfusion (day 0-4 and 7). In addition, each patient was interviewed about his or her symptoms. The median total score on FACT-An increased after blood transfusion from 50 to 58 (day 0-7, p = 0.016), indicating decreased symptom burden. A positive correlation was found between increments in the FACT-An score and hemoglobin value (rs 0.66, p = 0.02). One of seven items measuring symptoms of anemia (shortness of breath) and two of 13 symptoms of fatigue (feeling fatigue and weakness) changed significantly for the better from day 0 to day 7. The interviews confirmed the FACT-An results and revealed that patients experienced severe fatigue that negatively affected the maintenance of interpersonal relationships. After blood transfusion, symptoms of anemia and fatigue decreased in patients with MDS. The patients felt their symptoms had a negative impact on social life. Providing psychosocial support may contribute to improve the care of patients with transfusion-dependent MDS.


Increased NEFA levels reduce blood Mg2+ in hypertriacylglycerolaemic states via direct binding of NEFA to Mg2.
The blood triacylglycerol level is one of the main determinants of blood Mg2+ concentration in individuals with type 2 diabetes. Hypomagnesaemia (blood Mg2+ concentration <0.7 mmol/l) has serious consequences as it increases the risk of developing type 2 diabetes and accelerates progression of the disease. This study aimed to determine the mechanism by which triacylglycerol levels affect blood Mg2+ concentrations. Using samples from 285 overweight individuals (BMI >27 kg/m2) who participated in the 300-Obesity study (an observational cross-sectional cohort study, as part of the Human Functional Genetics Projects), we investigated the association between serum Mg2+ with laboratory variables, including an extensive lipid profile. In a separate set of studies, hyperlipidaemia was induced in mice and in healthy humans via an oral lipid load, and blood Mg2+, triacylglycerol and NEFA concentrations were measured using colourimetric assays. In vitro, NEFAs harvested from albumin were added in increasing concentrations to several Mg2+-containing solutions to study the direct interaction between Mg2+ and NEFAs. In the cohort of overweight individuals, serum Mg2+ levels were inversely correlated with triacylglycerols incorporated in large VLDL particles (r = -0.159, p ≤ 0.01). After lipid loading, we observed a postprandial increase in plasma triacylglycerol and NEFA levels and a reciprocal reduction in blood Mg2+ concentration both in mice (Δ plasma Mg2+ -0.31 mmol/l at 4 h post oral gavage) and in healthy humans (Δ plasma Mg2+ -0.07 mmol/l at 6 h post lipid intake). Further, in vitro experiments revealed that the decrease in plasma Mg2+ may be explained by direct binding of Mg2+ to NEFAs. Moreover, Mg2+ was found to bind to albumin in a NEFA-dependent manner, evidenced by the fact that Mg2+ did not bind to fatty-acid-free albumin. The NEFA-dependent reduction in the free Mg2+ concentration was not affected by the presence of physiological concentrations of other cations. This study shows that elevated NEFA and triacylglycerol levels directly reduce blood Mg2+ levels, in part explaining the high prevalence of hypomagnesaemia in metabolic disorders. We show that blood NEFA level affects the free Mg2+ concentration, and therefore, our data challenge how the fractional excretion of Mg2+ is calculated and interpreted in the clinic.


Reaction to a Visual Stimulus: Anticipation with Steady and Dynamic Contractions.
Reacting fast to visual stimuli is important for many activities of daily living and sports. It remains unknown whether the strategy used during the anticipatory period influences the speed of the reaction. The purpose of this study was to determine if reaction time (RT) differs following a steady and a dynamic anticipatory strategy. Twenty-two young adults (21.0 ± 2.2 yrs, 13 women) participated in this study. Participants performed 15 trials of a reaction time task with ankle dorsiflexion using a steady (steady force at 15% MVC) and a dynamic (oscillating force from 10-20% MVC) anticipatory strategy. We recorded primary agonist muscle (tibialis anterior; TA) electromyographic (EMG) activity. We quantified RT as the time interval from the onset of the stimulus to the onset of force. We found that a dynamic anticipatory strategy, compared to the steady anticipatory strategy, resulted in a longer RT (p = 0.04). We classified trials of the dynamic condition based on the level and direction of anticipatory force at the moment of the response. We found that RT was longer during the middle descending relative to the middle ascending and the steady conditions (p < 0.01). All together, these results suggest that RT is longer when preceded by a dynamic anticipatory strategy. Specifically, the longer RT is a consequence of the variable direction of force at which the response can occur, which challenges the motor planning process.


JaponicusDB: rapid deployment of a model organism database for an emerging model species.
The fission yeast Schizosaccharomyces japonicus has recently emerged as a powerful system for studying the evolution of essential cellular processes, drawing on similarities as well as key differences between S. japonicus and the related, well-established model Schizosaccharomyces pombe. We have deployed the open-source, modular code and tools originally developed for PomBase, the S. pombe model organism database (MOD), to create JaponicusDB (www.japonicusdb.org), a new MOD dedicated to S. japonicus. By providing a central resource with ready access to a growing body of experimental data, ontology-based curation, seamless browsing and querying, and the ability to integrate new data with existing knowledge, JaponicusDB supports fission yeast biologists to a far greater extent than any other source of S. japonicus data. JaponicusDB thus enables S. japonicus researchers to realize the full potential of studying a newly emerging model species and illustrates the widely applicable power and utility of harnessing reusable PomBase code to build a comprehensive, community-maintainable repository of species-relevant knowledge.


In vitro sensitivity to ultraviolet B light and skin cancer risk: a case-control analysis.
Mutagen sensitivity, measured as mutagen-induced chromatid breaks per cell in primary lymphocytes in vitro, has been used to study susceptibility to various epithelial cancers. Patients with xeroderma pigmentosum are highly sensitive to ultraviolet (UV) light due to inherited defects in DNA repair and have a 1000-fold higher risk of UV-induced skin cancer than the general population. However, an association between UV-induced chromosomal aberrations and risk of skin cancer in the general population has not been established. We assessed in vitro UVB-induced chromatid breaks in a hospital-based case-control study. The study included 469 patients with skin cancer (231 with nonmelanoma skin cancer [NMSC] and 238 with cutaneous malignant melanoma [CMM]) and 329 cancer-free control subjects. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Compared with the frequency of UVB-induced chromatid breaks per cell in control subjects (mean = 0.28 breaks per cell, 95% CI = 0.27 to 0.30), that in NMSC patients (basal cell carcinoma [BCC], n = 143, mean = 0.36 breaks per cell, 95% CI = 0.33 to 0.39 and squamous cell carcinoma [SCC], n = 88, mean = 0.35 breaks per cell, 95% CI = 0.32 to 0.38) was higher (P = .001 and P < .001, respectively), but that in CMM case patients (mean = 0.30 breaks per cell, 95% CI = 0.28 to 0.33) was not (P = .22). A frequency of chromatid breaks per cell above the median of control subjects was associated with nearly threefold increased risks for BCC (OR = 2.78, 95% CI = 1.79 to 4.30) and SCC (OR = 2.62, 95% CI = 1.50 to 4.60), but not with an increased risk of CMM. A dose-response relationship was evident between mutagen sensitivity and risk for both BCC (Ptrend < .001) and SCC (Ptrend < .001). Multiplicative interactions between mutagen sensitivity and sun exposure variables on risk, particularly for sunburn in BCC and hair color, tanning ability, and family history of skin cancer in SCC, were seen for NMSC but not CMM. UVB-induced mutagen sensitivity may play a role in susceptibility to NMSC but not to CMM.


Distinct cognitive mechanisms involved in the processing of single objects and object ensembles.
Behavioral research has demonstrated that the shape and texture of single objects can be processed independently. Similarly, neuroimaging results have shown that an object's shape and texture are processed in distinct brain regions with shape in the lateral occipital area and texture in parahippocampal cortex. Meanwhile, objects are not always seen in isolation and are often grouped together as an ensemble. We recently showed that the processing of ensembles also involves parahippocampal cortex and that the shape and texture of ensemble elements are processed together within this region. These neural data suggest that the independence seen between shape and texture in single-object perception would not be observed in object-ensemble perception. Here we tested this prediction by examining whether observers could attend to the shape of ensemble elements while ignoring changes in an unattended texture feature and vice versa. Across six behavioral experiments, we replicated previous findings of independence between shape and texture in single-object perception. In contrast, we observed that changes in an unattended ensemble feature negatively impacted the processing of an attended ensemble feature only when ensemble features were attended globally. When they were attended locally, thereby making ensemble processing similar to single-object processing, interference was abolished. Overall, these findings confirm previous neuroimaging results and suggest that distinct cognitive mechanisms may be involved in single-object and object-ensemble perception. Additionally, they show that the scope of visual attention plays a critical role in determining which type of object processing (ensemble or single object) is engaged by the visual system.


Dimethyl sulfoxide therapy in subjective tinnitus of unknown origin.
In fifteen patients affected by essential nonvibratory tinnitus, local applications in the external auditive canal of 2 ml medicated DMSO spray were made. The spray solution contained DMSO integrated with anti-inflammatory and vasodilatory substances. This application was repeated every four days for a month. At the same time each patient was administered a daily intramuscular injection of a preparation that contained DMSO and a vasodilatory component. The therapeutic effect was evaluated through the subjective modification of the symptom and functional tests of the auditory system. Of the fifteen patients treated, the tinnitus symptom completely disappeared in nine, and did not return during a one-year observation period. The patient's symptoms diminished in two cases, and in four cases the permanent tinnitus became occasional, triggered principally by environmental cold. It is important to note that among the concomitant signs, the five patients with vertigo noted improvement. Hypacusis diminished in three of the six patients affected. Insomnia disappeared in eight and diminished in seven cases. The rise in the average tympanic membrane temperature from 36.8 degrees C before to 37.9 degrees C after treatment was noteworthy. This could indicate an improvement of the blood flow in the inner ear.


The effects and safety of telerehabilitation in patients with lower-limb joint replacement: A systematic review and narrative synthesis.
As the number of patients undergoing primary lower-limb joint replacement has risen continuously, hospital-based healthcare resources have become limited. Delivery of any ongoing rehabilitation needs to adapt to this trend. This systematic literature aimed to examine the effects and safety of telerehabilitation in patients with lower-limb joint replacement. A systematic review of randomized controlled trials was conducted according to procedures by the Joanna Briggs Institute. Studies published prior to February 2020 were identified from Medline Ovid, Scopus, Ebsco Databases and Web of Science. Reference lists of relevant studies were also manually checked to find additional studies. Two researchers conducted study selection separately. The Joanna Briggs Institute Critical Appraisal Checklist for Randomized Controlled Trials was used to evaluate the quality of the relevant studies published. A narrative synthesis was used to report the results whereas effect sizes were estimated for different outcomes. Nine studies with 1266 patients were included. Study quality was predominantly affected by the lack of blinding. The patients who completed telerehabilitation showed an improvement in physical functioning that was similar to that of patients completing conventional in-person outpatient physical therapy without an increase in adverse events or resource utilization. The effect of telerehabilitation on physical functioning, however, was assessed as heterogeneous and moderate- to low-quality evidence. Telerehabilitation is a practical alternative to conventional in-person outpatient physical therapy in patients with lower-limb joint replacement. However, more robust studies are needed to build evidence about telerehabilitation.


Monitoring Photochemical Reaction Pathways of Tungsten Hexacarbonyl in Solution from Femtoseconds to Minutes.
Metal-organic complexes are widely used across disciplines for energy and biological applications, however, their photophysical and photochemical reaction coordinates remain unclear in solution due to pertaining molecular motions on ultrafast time scales. In this study, we apply transient absorption and tunable femtosecond stimulated Raman spectroscopy (FSRS) to investigate the UV photolysis of tungsten hexacarbonyl and subsequent solvent binding events. On the macroscopic time scale with UV lamp irradiation, no equilibrated intermediate is observed from W(CO)6 to W(CO)5(solvent), corroborated by vibrational normal mode calculations. Upon 267 nm femtosecond laser irradiation, the excited-state absorption band within ∼400-500 nm exhibits distinct dynamics in methanol, tetrahydrofuran, and acetonitrile on molecular time scales. In methanol, solvation of the nascent pentacarbonyl-solvent complex occurs in ∼8 ps and in tetrahydrofuran, 13 ps which potentially involves the associative oxygen-donating ligand rearrangement reaction. In contrast, a stimulated emission feature above 480 nm emerges after ∼1 ps in acetonitrile with a nitrogen-donating ligand. These structural dynamics insights demonstrate the combined resolving power of ultrafast electronic and stimulated Raman spectroscopy to elucidate photochemistry of functional organometallic complexes in solution. The delineated reaction pathways in relation to ligand nucleophilicity and solvent reorientation time provide the rational design principles for solution precursors in nanowrite applications.


Exploring workplace actors experiences of the social organization of return-to-work.
There is a limited body of research on how the actual social exchange among workplace actors influences the practice of return-to-work. The objective of this study was to explore how workplace actors experience social relations at the workplace and how organizational dynamics in workplace-based return-to-work extends before and beyond the initial return of the sick listed worker to the workplace. An exploratory qualitative method approach was used, consisting of individual open-ended interviews with 33 workplace actors at seven worksites that had re-entering workers. The workplace actors represented in these interviews include: re-entering workers, supervisors, co-workers, and human resource managers. The analysis identified three distinct phases in the return to work process: while the worker is off work, when the worker returns back to work, and once back at work during the phase of sustainability of work ability. The two prominent themes that emerged across these phases include the theme of invisibility in relation to return-to-work effort and uncertainty, particularly, about how and when to enact return-to-work. The findings strengthen the notion that workplace-based return-to-work interventions need to take social relations amongst workplace actors into account. They also highlight the importance and relevance of the varied roles of different workplace actors during two relatively unseen or grey areas, of return-to-work: the pre-return and the post-return sustainability phase. Attention to the invisibility of return-to-work efforts of some actors and uncertainty about how and when to enact return-to-work between workplace actors can promote successful and sustainable work ability for the re-entering worker.


Medullary Reticular Neurons Mediate Neuropeptide Y-Induced Metabolic Inhibition and Mastication.
Hypothalamic neuropeptide Y (NPY) elicits hunger responses to increase the chances of surviving starvation: an inhibition of metabolism and an increase in feeding. Here we elucidate a key central circuit mechanism through which hypothalamic NPY signals drive these hunger responses. GABAergic neurons in the intermediate and parvicellular reticular nuclei (IRt/PCRt) of the medulla oblongata, which are activated by NPY-triggered neural signaling from the hypothalamus, potentially through the nucleus tractus solitarius, mediate the NPY-induced inhibition of metabolic thermogenesis in brown adipose tissue (BAT) via their innervation of BAT sympathetic premotor neurons. Intriguingly, the GABAergic IRt/PCRt neurons innervating the BAT sympathetic premotor region also innervate the masticatory motor region, and stimulation of the IRt/PCRt elicits mastication and increases feeding as well as inhibits BAT thermogenesis. These results indicate that GABAergic IRt/PCRt neurons mediate hypothalamus-derived hunger signaling by coordinating both autonomic and feeding motor systems to reduce energy expenditure and to promote feeding.


Bioactivity of phytochemicals in some lesser-known plants and their effects and potential applications in livestock and aquaculture production systems.
Livestock and aquaculture production is under political and social pressure, especially in the European Union (EU), to decrease pollution and environmental damage arising due to animal agriculture. The EU has banned the use of antibiotics and other chemicals, which have been shown to be effective in promoting growth and reducing environment pollutants because of the risk caused to humans by chemical residues in food and by antibiotic resistance being passed on to human pathogens. As a result of this, scientists have intensified efforts in exploiting plants, plant extracts or natural plant compounds as potential natural alternatives for enhancing the livestock productivity. This paper discusses work on the effects of various phytochemicals and plant secondary metabolites in ruminant and fish species. The focus is on (i) plants such as Ananas comosus (pine apple), Momordica charantia (bitter gourd) and Azadirachta indica (neem) containing anthelmintic compounds and for their use for controlling internal parasites; (ii) plants containing polyphenols and their applications for protecting proteins from degradation in the rumen, increasing efficiency of microbial protein synthesis in rumen and decreasing methane emission; for using as antioxidants, antibacterial and antihelmintic agents; and for changing meat colour and for increasing n-3 fatty acids and conjugated linoleic acid in meat; (iii) saponin-rich plants such as quillaja, yucca and Sapindus saponaria for increasing the efficiency of rumen fermentation, decreasing methane emission and enhancing growth; for producing desired nutritional attributes such as lowering of cholesterol in monogastric animals; for increasing growth of fish (common carp and Nile tilapia) and for changing male to female ratio in tilapia; and for use as molluscicidal agents; (iv) Moringa oleifera leaves as a source of plant growth factor(s), antioxidants, beta-carotene, vitamin C, and various glucosinolates and their degraded products for possible use as antibacterial, antioxidant, anticarcinogenic and antipest agents; (v) Jatropha curcas toxic variety with high levels of various phytochemicals such as trypsin inhibitor, lectin, phytate and phorbol esters in seeds limiting the use of seed meal in fish and livestock diets; and the use of phorbol esters as bio-pesticidal agent; and (vi) lesser-known legumes such as Entada phaseoloides seeds containing high levels of trypsin inhibitor and saponins, Sesbania aculeate seeds rich in non-starch polysaccharides and Mucuna pruriens var. utilis seeds rich in l-3,4-dihydroxyphenylalanine and their potential as fish feed; Cassia fistula seeds as a source of antioxidants; and the use of Canavalia ensiformis, C. gladiata and C. virosa seeds containing high levels of trypsin inhinitor, lectins and canavanine. The paper also presents some challenges and future areas of work in this field.


Linear Accelerators for Protons: New Developments: Some recent developments have made feasible proton accelerators of much higher power than earlier models.
The performance of existing linear accelerators has improved dramatically in the last few years as a result of redesign of the injector. The peak beams available surpass in intensity and quality those from other accelerators. Usually the operation has been pulsed, with a low duty factor. However, the recently developed accelerating structures now make it attractive to raise the average beam power by several orders of magnitude. New possibilities are apparent for the use of such beams for research in nuclear physics and other sciences.


Effect of volatile compounds in grass silage on voluntary intake by growing cattle.
Twenty-four low dry matter (DM) silages differing in fermentation quality were harvested at the same time from a crop that consisted mainly of timothy (Phleum pratense), and meadow fescue (Festuca pratensis). The silage samples were analysed by gas chromatography (GC) - mass spectrometry and gas chromatography - flame ionisation detection in order to determine and quantify volatiles present in silage. The voluntary intake of the 24 silages had been measured in a previous feeding trial with growing steers of Norwegian Red. Thirteen esters, five aldehydes, three alcohols, and one sulphide were identified and quantified. A total of 51 variables describing the chemical composition of the silages were included in a partial least-squares regression, and the relationship of silage fermentation quality to voluntary intake was elucidated. The importance of variables describing silage fermentation quality in relation to intake was judged from a best combination procedure, jack-knifing, and empirical correlations of the variables to intake. The GC-analysed compounds were mainly present in poorly fermented silages. However, compared with other explanatory chemical variables none of these compounds was of importance for the voluntary intake as evaluated by partial least-squares regression. A validated variance of 71% in silage DM intake was explained with the selected variables: total acids (TA), total volatile fatty acids (TVFA), lactic acid/total acid ratio and propionic acid. In this study extent (by the variable TA) and type of silage fermentation (by TVFA) influenced intake. Further, it is suggested that by restricting the fermentation in low DM grass silages the potential intake of silage DM is maximised.


[Continuous-use medication and associated factors in the elderly living in Quixadá, Ceará, Brazil].
To analyze polypharmacy (daily use of two or more) of continuous use medication and its associated factors in the elderly. A cross sectional study conducted with elderly individuals living in an urban area of the municipality of Quixadá, Ceara, Brazil from May to December, 2009. The sample consisted of 384 individuals who were 60 years old or older and users of continuous medication. The variables studied were sociodemographic, economical, and health characteristics related to use of medications. For the analysis of the association between the dependent variable polypharmacy of continuous-use medication and the independent variables a logistic regression model was developed. Results showed a predominance of females, between 60 and 69 years old, married, with incomplete elementary school education, non-paid job, family income of one minimum salary, living in their own home and together with up to three individuals. A prevalence of 70.6% of polypharmacy in the elderly was found, and it was higher in women (66.4%). Factors positively associated with the use of two or more continuous-use medication were: family income over one minimum salary (OR 2.83; CI95% = 1.54-5.32); two or more self-reported chronic conditions (OR 17.71; CI95% = 9.80-31.990) and self-perception of regular to poor quality of life (OR 2.85; CI95% = 1.60-5.07). The study observed a practice of polypharmacy of continuous-use medications in the elderly with family income over one minimum wage, two or more chronic conditions and self-perception of regular to poor quality of life. Such status leads to questions on social, cultural, economic and health aspects.


Two contrasting classes of nucleolus-associated domains in mouse fibroblast heterochromatin.
In interphase eukaryotic cells, almost all heterochromatin is located adjacent to the nucleolus or to the nuclear lamina, thus defining nucleolus-associated domains (NADs) and lamina-associated domains (LADs), respectively. Here, we determined the first genome-scale map of murine NADs in mouse embryonic fibroblasts (MEFs) via deep sequencing of chromatin associated with purified nucleoli. We developed a Bioconductor package called NADfinder and demonstrated that it identifies NADs more accurately than other peak-calling tools, owing to its critical feature of chromosome-level local baseline correction. We detected two distinct classes of NADs. Type I NADs associate frequently with both the nucleolar periphery and the nuclear lamina, and generally display characteristics of constitutive heterochromatin, including late DNA replication, enrichment of H3K9me3, and little gene expression. In contrast, Type II NADs associate with nucleoli but do not overlap with LADs. Type II NADs tend to replicate earlier, display greater gene expression, and are more often enriched in H3K27me3 than Type I NADs. The nucleolar associations of both classes of NADs were confirmed via DNA-FISH, which also detected Type I but not Type II probes enriched at the nuclear lamina. Type II NADs are enriched in distinct gene classes, including factors important for differentiation and development. In keeping with this, we observed that a Type II NAD is developmentally regulated, and present in MEFs but not in undifferentiated embryonic stem (ES) cells.


National Guidelines for Colorectal Cancer Screening in Saudi Arabia with strength of recommendations and quality of evidence.
Colorectal cancer is the most common cancer among Saudi men and the third commonest among Saudi women. Given the predominance of colorectal cancer compared with other cancers in Saudi Arabia, context-specific guidelines are needed for screening. Experts from the Saudi Society of Colon and Rectal Surgery, Saudi Gastroenterology Association, Saudi Oncology Society, Saudi Chapter of Enterostomal Therapy, Family Medicine and Department of Public Health at the Saudi Arabian Ministry of Health and a patient advocate was assembled by the Saudi Centre for Evidence-Based Healthcare, a subsidiary of the Saudi Arabian Ministry of Health. The panel collaborated with a methodological team from McMaster University, Canada to develop national guidelines for colorectal cancer screening. After identifying key questions, the panel conducted a systematic review of all reports on the utility of screening, the cost of screening for colorectal cancer in Saudi Arabia and on the values and preferences of Saudi patients. Meta- analyses, when appropriate, were performed to generate pooled estimates of effect. Using the GRADE approach, the panel used the evidence-to-decision (EtD) framework to assess all domains important in determining the strength and direction of the recommendations (benefits and harms, values and preferences, resource implications, equity, acceptability, and feasibility). Judgments related to the EtD domains were resolved through consensus or voting, if consensus was not reached. The final recommendations were developed during a two-day meeting held in Riyadh, Saudi Arabia in March 2015. Conflicts of interests among the panel members were handled according to the World Health Organization rules. There is lack of national data on the incidence of adenomatous polyps or the age groups in which the incidence surges. There were no national clinical trials assessing the effectiveness of the different modalities of screening for colorectal cancer and their impact on mortality. The panel recommends screening for colorectal cancer in Saudi Arabia in asymptomatic Saudi patients at average risk of colorectal cancer. An infrastructure should be built to achieve that goal.


Role of vandetanib in the management of medullary thyroid cancer.
Traditionally available treatments, like cytotoxic chemotherapy and external-beam radiation therapy, are limited and essentially ineffective for metastatic medullary thyroid carcinoma (MTC). In the last decade, small-molecule tyrosine kinase inhibitors (TKI) have been introduced in the field of thyroid cancer, after having been shown effective in a wide variety of other tumors. This review focuses on vandetanib (ZD6474, Zactima™; AstraZeneca) and its role in the treatment of MTC. Vandetanib is an oral TKI that targets VEGF receptors 2 and 3, RET, and at higher concentrations, the epidermal growth factor (EGF) receptor. This drug has been tested in two important phase II studies which demonstrated that both the 100 and 300 mg/day dosage of vandetanib have antitumor activity on advanced MTC. A phase III trial (ZETA trial) evaluating vandetanib in 331 patients with locally advanced or metastatic MTC showed a significant prolongation of PFS for patients receiving vandetanib compared with placebo. Toxicity surveillance in all studies reported high rates of adverse effects with diarrhea, rash, fatigue and nausea being the most commonly experienced by patients. Vandetanib is currently approved in the United States for unresectable locally advanced or metastatic MTC and has become a new standard of care in this rare and indolent pathology.


Adenoviral vectors: systemic delivery and tumor targeting.
The development of a targeted adenoviral vector, which can be delivered systemically, is one of the major challenges facing cancer gene therapy. The virus is readily cleared from the bloodstream, can be neutralised by pre-existing antibodies, and has a permissive cellular tropism. Clinical studies using the ONYX virus have shown limited efficacy, but there are several hurdles to overcome to achieve an effective tumor-specific systemic therapy. In this review, we have summarized the various strategies used to overcome the limitations of adenoviral-mediated gene delivery.


Nuclear dynamics of influenza A virus ribonucleoproteins revealed by live-cell imaging studies.
The negative sense RNA genome of influenza A virus is transcribed and replicated in the nuclei of infected cells by the viral RNA polymerase. Only four viral polypeptides are required but multiple cellular components are potentially involved. We used fluorescence recovery after photobleaching (FRAP) to characterise the dynamics of GFP-tagged viral ribonucleoprotein (RNP) components in living cells. The nucleoprotein (NP) displayed very slow mobility that significantly increased on formation of transcriptionally active RNPs. Conversely, single or dimeric polymerase subunits showed fast nuclear dynamics that decreased upon formation of heterotrimers, suggesting increased interaction of the full polymerase complex with a relatively immobile cellular component(s). Treatment with inhibitors of cellular transcription indicated that in part, this reflected an interaction with cellular RNA polymerase II. Analysis of mutated influenza virus polymerase complexes further suggested that this was through an interaction between PB2 and RNA Pol II separate from PB2 cap-binding activity.


The effects of a distracting N-back task on recognition memory are reduced by negative emotional intensity.
Memory performance is usually impaired when participants have to encode information while performing a concurrent task. Recent studies using recall tasks have found that emotional items are more resistant to such cognitive depletion effects than non-emotional items. However, when recognition tasks are used, the same effect is more elusive as recent recognition studies have obtained contradictory results. In two experiments, we provide evidence that negative emotional content can reliably reduce the effects of cognitive depletion on recognition memory only if stimuli with high levels of emotional intensity are used. In particular, we found that recognition performance for realistic pictures was impaired by a secondary 3-back working memory task during encoding if stimuli were emotionally neutral or had moderate levels of negative emotionality. In contrast, when negative pictures with high levels of emotional intensity were used, the detrimental effects of the secondary task were significantly attenuated.


Derivation of a Provisional, Age-dependent, AIS2+ Thoracic Risk Curve for the THOR50 Test Dummy via Integration of NASS Cases, PMHS Tests, and Simulation Data.
A provisional, age-dependent thoracic risk equation (or, "risk curve") was derived to estimate moderate-to-fatal injury potential (AIS2+), pertaining to men with responses gaged by the advanced mid-sized male test dummy (THOR50). The derivation involved two distinct data sources: cases from real-world crashes (e.g., the National Automotive Sampling System, NASS) and cases involving post-mortem human subjects (PMHS). The derivation was therefore more comprehensive, as NASS datasets generally skew towards younger occupants, and PMHS datasets generally skew towards older occupants. However, known deficiencies had to be addressed (e.g., the NASS cases had unknown stimuli, and the PMHS tests required transformation of known stimuli into THOR50 stimuli). For the NASS portion of the analysis, chest-injury outcomes for adult male drivers about the size of the THOR50 were collected from real-world, 11-1 o'clock, full-engagement frontal crashes (NASS, 1995-2012 calendar years, 1985-2012 model-year light passenger vehicles). The screening for THOR50-sized men involved application of a set of newly-derived "correction" equations for self-reported height and weight data in NASS. Finally, THOR50 stimuli were estimated via field simulations involving attendant representative restraint systems, and those stimuli were then assigned to corresponding NASS cases (n=508). For the PMHS portion of the analysis, simulation-based closure equations were developed to convert PMHS stimuli into THOR50 stimuli. Specifically, closure equations were derived for the four measurement locations on the THOR50 chest by cross-correlating the results of matched-loading simulations between the test dummy and the age-dependent, Ford Human Body Model. The resulting closure equations demonstrated acceptable fidelity (n=75 matched simulations, R2≥0.99). These equations were applied to the THOR50-sized men in the PMHS dataset (n=20). The NASS and PMHS datasets were combined and subjected to survival analysis with event-frequency weighting and arbitrary censoring. The resulting risk curve--a function of peak THOR50 chest compression and age--demonstrated acceptable fidelity for recovering the AIS2+ chest injury rate of the combined dataset (i.e., IR_dataset=1.97% vs. curve-based IR_dataset=1.98%). Additional sensitivity analyses showed that (a) binary logistic regression yielded a risk curve with nearly-identical fidelity, (b) there was only a slight advantage of combining the small-sample PMHS dataset with the large-sample NASS dataset,


Pattern of cerebral atherosclerosis in Hong Kong Chinese. Severity in intracranial and extracranial vessels.
The clinical pattern of stroke and the angiographic distribution of cerebral atherosclerosis in Chinese are different from those in Caucasians. Pathological data from autopsy studies are lacking. The intracranial and extracranial arteries supplying the brains of 114 consecutive Chinese patients undergoing autopsy in a regional general hospital were examined by computer-assisted morphometric analysis under a microscope as well as by macroscopic grading for atherosclerotic narrowing. The severity was correlated with various atherosclerosis-related factors. Atherosclerosis of the intracranial cerebral vessels was more severe than that of the extracranial vessels. The distal branches of the intracranial vessels were also commonly involved. Hypertension and diabetes mellitus were identified as factors associated only with intracranial atherosclerosis (p < 0.001), whereas ischemic heart disease was associated with atherosclerosis in both the intracranial (p < 0.001) and extracranial (p = 0.012) vessels. Smoking was associated with narrowing of the extracranial vessels only (p = 0.0054). Compared with figures from Caucasian and Japanese populations, the extent of intracranial atherosclerosis is much more severe in Hong Kong Chinese, whereas atherosclerotic narrowing of the extracranial carotid artery is less severe in Hong Kong Chinese than in Caucasians.


Giant Cell Tumor of the Patella Tendon Sheath Presenting as a Painful Locked Knee.
The giant cell tumor of the tendon sheath (GCT-TS) is a benign proliferative synovial tumor manifesting as an intra-articular solitary nodule. When it involves the infrapatellar fat pad it can present acutely as a painful locked knee. A 26-year-old white male presented with a 2-week history of painful locking in his right knee. Clinical examination revealed lack of extension by approximately 20°. To help establish the diagnosis, an MRI scan of the right knee was performed, showing a large (5×4×2 cm), oval, well-circumscribed mass with a low-intensity homogenous signal. The size of the mass prohibited the removal by arthroscopy and we therefore proceeded with an open arthrotomy. Histological examination showed a tendosynovial giant cell tumor of the patella tendon sheath. At the latest follow-up, 2 years postoperatively, there was no local tumor recurrence. These rare tumorous lesions should be included in the differential diagnosis of painful locking knee, especially in the absence of definite traumatic history.


An interview with Nipam Patel.
Nipam Patel is a developmental biologist based at the University of California, Berkeley, USA, where he uses a variety of organisms to study the evolution of developmental systems, from arthropod body plans to butterfly colouration. We asked him about his career and scientific interests, his role as an editor at Development, and his growing butterfly collection.


Outlier-based identification of copy number variations using targeted resequencing in a small cohort of patients with Tetralogy of Fallot.
Copy number variations (CNVs) are one of the main sources of variability in the human genome. Many CNVs are associated with various diseases including cardiovascular disease. In addition to hybridization-based methods, next-generation sequencing (NGS) technologies are increasingly used for CNV discovery. However, respective computational methods applicable to NGS data are still limited. We developed a novel CNV calling method based on outlier detection applicable to small cohorts, which is of particular interest for the discovery of individual CNVs within families, de novo CNVs in trios and/or small cohorts of specific phenotypes like rare diseases. Approximately 7,000 rare diseases are currently known, which collectively affect ∼6% of the population. For our method, we applied the Dixon's Q test to detect outliers and used a Hidden Markov Model for their assessment. The method can be used for data obtained by exome and targeted resequencing. We evaluated our outlier-based method in comparison to the CNV calling tool CoNIFER using eight HapMap exome samples and subsequently applied both methods to targeted resequencing data of patients with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease. In both the HapMap samples and the TOF cases, our method is superior to CoNIFER, such that it identifies more true positive CNVs. Called CNVs in TOF cases were validated by qPCR and HapMap CNVs were confirmed with available array-CGH data. In the TOF patients, we found four copy number gains affecting three genes, of which two are important regulators of heart development (NOTCH1, ISL1) and one is located in a region associated with cardiac malformations (PRODH at 22q11). In summary, we present a novel CNV calling method based on outlier detection, which will be of particular interest for the analysis of de novo or individual CNVs in trios or cohorts up to 30 individuals, respectively.


A Systematic Review and Meta-analysis of Associations between Clinical Prostatitis and Prostate Cancer: New Estimates Accounting for Detection Bias.
Previous meta-analyses have estimated summary positive associations between clinical prostatitis and prostate cancer. However, none have accounted for detection bias, the possibility for increased prostate cancer screening and detection in men with clinical prostatitis, in their pooled estimates. We searched for studies that investigated the relation between clinical prostatitis and prostate cancer through November 2018. Random effects meta-analysis was used to calculate summary odds ratios (OR) among all studies and in strata defined by methods used to reduce detection bias.Results: Although an increased odds of prostate cancer was seen among men with a history of clinical prostatitis in all 38 eligible studies combined [OR, 2.05; 95% confidence interval (CI), 1.64-2.57], this estimate attenuated to null among studies that performed the most rigorous analyses to limit detection bias (OR, 1.16; 95% CI, 0.77-1.74). Our findings indicate that previously reported positive associations between clinical prostatitis and prostate cancer are likely due to detection bias. Studies using rigorous detection bias methods are warranted to replicate these findings, as well as to examine the possible relation between prostate inflammation and prostate cancer directly, rather than indirectly through the diagnosis of "prostatitis," which includes a large proportion of men without evidence of prostate inflammation.


Clinical survey: patterns of utilization of lumbar epidural steroid injections by a cohort of spinal surgeons.
There are few data on responses to conservative therapy in the management of lumbar degenerative diseases. To understand the use of epidural steroid injections (ESIs) by spine surgeons in the treatment of 2 distinct lumbar spinal conditions-herniated nucleus pulposus (HNP) and degenerative disk disease (DDD)-a survey of orthopedic and neurosurgical spine surgeons was conducted. Participants were surveyed via posting of a survey on a commercially maintained Web site. Respondents were queried on individual preferences regarding epidural steroid injections for HNP and DDD. N/A. The survey was completed by 61 surgeons; not all surgeons completed the entire survey. There was equal representation between orthopedic and neurosurgical spine surgeons; most surgeons reported being in practice for greater than 10 years (41%) and most surgeons reported completing between either 50 and 100 or 100 and 200 spine surgeries each year (26% and 31%). Results were tabulated and assessed for variance. Both individual responses to the different ESI treatment protocols offered and difference in use of lumbar epidural steroids between diagnoses were analyzed. In treatment of lumbar HNP, the majority of respondents considered ESIs after 6 weeks of noninterventional care (69%). In lumbar DDD, there was no consensus as to overall use, timing, number of ESIs constituting a treatment regimen, number of treatment cycles recommended, and length of treatment before considering other intervention. In comparing treatment of lumbar HNP or DDD, there was no agreement with regard to timing of ESIs, with regard to duration of treatment, nor with regard to number of injections comprising a treatment regimen (kappa = -0.01, 0.03, and -0.02, respectively). No consensus was found as to timing, frequency, and duration of ESI treatment in lumbar HNP and DDD patients in a survey of practicing spine surgeons. These results illustrate one example of lack of consensus in conservative treatment protocols.


The salience of social referents: a field experiment on collective norms and harassment behavior in a school social network.
Persistent, widespread harassment in schools can be understood as a product of collective school norms that deem harassment, and behavior allowing harassment to escalate, as typical and even desirable. Thus, one approach to reducing harassment is to change students' perceptions of these collective norms. Theory suggests that the public behavior of highly connected and chronically salient actors in a group, called social referents, may provide influential cues for individuals' perception of collective norms. Using repeated, complete social network surveys of a public high school, we demonstrate that changing the public behavior of a randomly assigned subset of student social referents changes their peers' perceptions of school collective norms and their harassment behavior. Social referents exert their influence over peers' perceptions of collective norms through the mechanism of everyday social interaction, particularly interaction that is frequent and personally motivated, in contrast to interaction shaped by institutional channels like shared classes. These findings clarify the development of collective social norms: They depend on certain patterns of and motivations for social interactions within groups across time, and are not static but constantly reshaped and reproduced through these interactions. Understanding this process creates opportunities for changing collective norms and behavior.


Identification of a phosphothionate analogue of lysophosphatidic acid (LPA) as a selective agonist of the LPA3 receptor.
Lysophosphatidic acid (LPA) is a bioactive lysophospholipid mediator that acts through G protein-coupled receptors. Most cell lines in culture express one or more LPA receptors, making it difficult to assign a response to specific LPA receptors. Dissection of the signaling properties of LPA has been hampered by lack of LPA receptor subtype-specific agonists and antagonists. The present study characterizes an ester-linked thiophosphate derivative (1-oleoyl-2-O-methyl-rac-glycerophosphothionate, OMPT) of LPA. OMPT is a functional LPA analogue with potent mitogenic activity in fibroblasts. In contrast to LPA, OMPT does not couple to the pheromone response through the LPA(1) receptor in yeast cells. OMPT induces intracellular calcium increases efficiently in LPA(3) receptor-expressing Sf9 cells but poorly in LPA(2) receptor-expressing cells. Guanosine 5'-O-(3-[(35)S]thio)triphosphate binding assays in mammalian cells showed that LPA exhibits agonistic activity on all three LPA receptor subtypes, whereas OMPT has a potent agonistic effect only on the LPA(3) receptor. In transiently transfected HEK293 cells, OMPT stimulates mitogen-activated protein kinases through the LPA(3) but not the LPA(1) or LPA(2) receptors. Furthermore, OMPT-induced intracellular calcium mobilization in mammalian cells is efficiently inhibited by the LPA(1)/LPA(3) receptor-selective antagonist VPC12249. These results establish that OMPT is an LPA(3)-selective agonist. OMPT binding to the LPA(3) receptor in mammalian cells is sufficient to elicit multiple responses, including activation of G proteins, calcium mobilization, and activation of mitogen-activated protein kinases. Thus OMPT offers a powerful probe for the dissection of LPA signaling events in complex mammalian systems.


Glycolysis preferentially inhibits ATP-sensitive K+ channels in isolated guinea pig cardiac myocytes.
In heart, glycolysis may be a preferential source of adenosine triphosphate (ATP) for membrane functions. In this study the patch-clamp technique was used to study potassium channels sensitive to intracellular ATP levels in permeabilized ventricular myocytes. Activation of these K+ channels has been implicated in marked cellular K+ loss leading to electrophysiological abnormalities and arrhythmias during myocardial ischemia. The results showed that glycolysis was more effective than oxidative phosphorylation in preventing ATP-sensitive K+ channels from opening. Experiments in excised inside-out patches suggested that key glycolytic enzymes located in the membrane or adjacent cytoskeleton near the channels may account for their preference for glycolytic ATP.


A fully automated approach to segmentation of irregularly shaped cellular structures in EM images.
While there has been substantial progress in segmenting natural images, state-of-the-art methods that perform well in such tasks unfortunately tend to underperform when confronted with the different challenges posed by electron microscope (EM) data. For example, in EM imagery of neural tissue, numerous cells and subcellular structures appear within a single image, they exhibit irregular shapes that cannot be easily modeled by standard techniques, and confusing textures clutter the background. We propose a fully automated approach that handles these challenges by using sophisticated cues that capture global shape and texture information, and by learning the specific appearance of object boundaries. We demonstrate that our approach significantly outperforms state-of-the-art techniques and closely matches the performance of human annotators.