Predicting the Landscape of Recombination Using Deep Learning.
Accurately inferring the genome-wide landscape of recombination rates in natural populations is a central aim in genomics, as patterns of linkage influence everything from genetic mapping to understanding evolutionary history. Here, we describe recombination landscape estimation using recurrent neural networks (ReLERNN), a deep learning method for estimating a genome-wide recombination map that is accurate even with small numbers of pooled or individually sequenced genomes. Rather than use summaries of linkage disequilibrium as its input, ReLERNN takes columns from a genotype alignment, which are then modeled as a sequence across the genome using a recurrent neural network. We demonstrate that ReLERNN improves accuracy and reduces bias relative to existing methods and maintains high accuracy in the face of demographic model misspecification, missing genotype calls, and genome inaccessibility. We apply ReLERNN to natural populations of African Drosophila melanogaster and show that genome-wide recombination landscapes, although largely correlated among populations, exhibit important population-specific differences. Lastly, we connect the inferred patterns of recombination with the frequencies of major inversions segregating in natural Drosophila populations.


The Relationship Between β-Endorphin and Experimental Pain Sensitivity in Older Adults With Knee Osteoarthritis.
Osteoarthritis (OA) is the most common cause of pain in people aged >45 years, and the knee is the most commonly affected joint. There is a growing interest in understanding the biological factors that influence pain among older adults, but few studies have examined the relationship between β-endorphin and experimental pain sensitivity in older adults with knee OA pain. The purpose of this study was to investigate the relationship between resting plasma levels of β-endorphin and experimental pain sensitivity. This study was a secondary analysis of data for 40 adults with knee OA pain in whom quantitative sensory testing was used to measure experimental sensitivity to heat- and mechanically induced pain. The mean age of the sample was 60 years (SD = 9 years), and approximately half were female (53%). Regression analyses indicated that β-endorphin level was negatively related to pressure pain threshold (β = -17.18, p = .02) and positively related to punctate mechanical pain (β = 17.13, p = .04), after controlling for age, gender, and OA severity. We did not find a significant relationship between β-endorphin and heat pain tolerance. The results suggest that higher circulating levels of β-endorphin at rest are associated with increased sensitivity to mechanical pain in older adults with knee OA. These findings add to the literature regarding biological factors associated with pain sensitivity in older adults with chronic pain. Additional studies are needed to identify mediators of the relationship between β-endorphin and pain sensitivity in OA and other musculoskeletal pain conditions.


Twelve weeks of moderate aerobic exercise without dietary intervention or weight loss does not affect 24-h energy expenditure in lean and obese adolescents.
Exercise might have a persistent effect on energy expenditure and fat oxidation, resulting in increased fat loss. However, even without weight loss, exercise results in positive metabolic effects. The effect of an aerobic exercise program on 24-h total energy expenditure (TEE) and its components-basal (BEE), sleep (SEE), and awake sedentary (SEDEE) energy expenditure and substrate oxidation-has not been studied in lean and obese adolescents. The objective was to test the hypothesis that 24-h energy expenditure and fat oxidation increase in lean and obese adolescents after 12 wk of moderate aerobic exercise without dietary intervention and weight loss. Twenty-eight postpubertal Hispanic adolescents (13 lean [mean +/- SE: age, 15.3 +/- 0.3 y; body mass index (BMI; in kg/m(2)), 20.2 +/- 0.7; body fat, 18.7 +/- 1.6%] and 15 obese [age, 15.6 +/- 0.3 y; BMI, 33.1 +/- 0.9; body fat, 38.1 +/- 1.4%]) completed a 12-wk aerobic exercise program (4 x 30 min/wk at > or =70% of VO(2 peak)) without weight loss. Energy expenditure and substrate oxidation were quantified by 24-h room calorimetry at baseline and postexercise. This aerobic exercise program did not affect 24-h TEE, BEE, SEE, or SEDEE in lean or obese participants. In obese adolescents, respiratory quotient (RQ) and substrate oxidation also did not change. In lean adolescents, 24-h RQ and RQ during SEE decreased (both P < 0.01) and fat oxidation increased (P < 0.01). A 12-wk aerobic exercise program did not increase TEE, BEE, SEE, or SEDEE in either lean or obese sedentary adolescents. Furthermore, 24-h fat oxidation did not change in the obese adolescents, whereas it increased in the lean adolescents.


Epinephrine causes a reduction in lymph node cell output in sheep.
The lymphatic system has a critical role in the return of fluids, proteins, and cells to the circulatory system. However, the effects of stress, including exercise, on this system have not been adequately studied. We investigated the effect of a physiological dose (1 mg) of epinephrine (Epi) on lymph flow, cell concentration, and lymphocyte subsets in efferent subcutaneous lymph in sheep. Blood leukocyte numbers, differential, lymphocyte subsets, and blood and lymph pools of lymphocytes were determined simultaneously. A significant acute increase in lymph flow was followed by a post-injection decrease in flow and cellular output. No changes in lymphocyte subsets or pools of lymphocytes were seen in either blood or lymph. The timing of elevated plasma and lymph concentrations of Epi and norepinephrine (NE) corresponded with the increased lymph flow. In conclusion, Epi injection caused no change in lymphocyte subset distribution, leukocyte concentration, or pools of lymphocytes. A decrease in lymph flow and cellularity was documented post-injection, indicating that lymphatic tissue has no role in the leukocytosis seen after Epi injection. Lymphocyte retention by lymph nodes, however, may contribute to post-injection lymphopenia.


Challenges in image-guided therapy system design.
System development for image-guided therapy (IGT), or image-guided interventions (IGI), continues to be an area of active interest across academic and industry groups. This is an emerging field that is growing rapidly: major academic institutions and medical device manufacturers have produced IGT technologies that are in routine clinical use, dozens of high-impact publications are published in well regarded journals each year, and several small companies have successfully commercialized sophisticated IGT systems. In meetings between IGT investigators over the last two years, a consensus has emerged that several key areas must be addressed collaboratively by the community to reach the next level of impact and efficiency in IGT research and development to improve patient care. These meetings culminated in a two-day workshop that brought together several academic and industrial leaders in the field today. The goals of the workshop were to identify gaps in the engineering infrastructure available to IGT researchers, develop the role of research funding agencies and the recently established US-based National Center for Image Guided Therapy (NCIGT), and ultimately to facilitate the transfer of technology among research centers that are sponsored by the National Institutes of Health (NIH). Workshop discussions spanned many of the current challenges in the development and deployment of new IGT systems. Key challenges were identified in a number of areas, including: validation standards; workflows, use-cases, and application requirements; component reusability; and device interface standards. This report elaborates on these key points and proposes research challenges that are to be addressed by a joint effort between academic, industry, and NIH participants.


Quantitative assessment of acetabular bone defects: A study of 50 computed tomography data sets.
Acetabular bone defect quantification and classification is still challenging. The objectives of this study were to suggest and define parameters for the quantification of acetabular bone defects, to analyze 50 bone defects and to present the results and correlations between the defined parameters. The analysis was based on CT-data of pelvises with acetabular bone defects and their reconstruction via a statistical shape model. Based on this data, bone volume loss and new bone formation were analyzed in four sectors (cranial roof, anterior column, posterior column, and medial wall). In addition, ovality of the acetabulum, lateral center-edge angle, implant migration, and presence of wall defects were analyzed and correlations between the different parameters were assessed. Bone volume loss was found in all sectors and was multidirectional in most cases. Highest relative bone volume loss was found in the medial wall with median and [25, 75]-percentile values of 72.8 [50.6, 95.0] %. Ovality, given as the length to width ratio of the acetabulum, was 1.3 [1.1, 1.4] with a maximum of 2.0, which indicated an oval shape of the defect acetabulum. Lateral center-edge angle was 30.4° [21.5°, 40.4°], which indicated a wide range of roof coverage in the defect acetabulum. Total implant migration was 25.3 [14.8, 32.7] mm, whereby cranial was the most common direction. 49/50 cases showed a wall defect in at least one sector. It was observed that implant migration in cranial direction was associated with relative bone volume loss in cranial roof (R = 0.74) and ovality (R = 0.67). Within this study, 50 pelvises with acetabular bone defects were successfully analyzed using six parameters. This could provide the basis for a novel classification concept which would represent a quantitative, objective, unambiguous, and reproducible classification approach for acetabular bone defects.


Gene-specific DNA methylation profiles and LINE-1 hypomethylation are associated with myocardial infarction risk.
DNA methylation profiles are responsive to environmental stimuli and metabolic shifts. This makes DNA methylation a potential biomarker of environmental-related and lifestyle-driven diseases of adulthood. Therefore, we investigated if white blood cells' (WBCs) DNA methylation profiles are associated with myocardial infarction (MI) occurrence. Whole-genome DNA methylation was investigated by microarray analysis in 292 MI cases and 292 matched controls from the large prospective Italian European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (EPICOR study). Significant signals (false discovery rate (FDR) adjusted P < 0.05) were replicated by mass spectrometry in 317 MI cases and 262 controls from the Dutch EPIC cohort (EPIC-NL). Long interspersed nuclear element-1 (LINE-1) methylation profiles were also evaluated in both groups. A differentially methylated region (DMR) within the zinc finger and BTB domain-containing protein 12 (ZBTB12) gene body and LINE-1 hypomethylation were identified in EPICOR MI cases and replicated in the EPIC-NL sample (ZBTB12-DMR meta-analysis: effect size ± se = -0.016 ± 0.003, 95 % CI = -0.021;-0.011, P = 7.54 × 10(-10); LINE-1 methylation meta-analysis: effect size ± se = -0.161 ± 0.040, 95 % CI = -0.239;-0.082, P = 6.01 × 10(-5)). Moreover, cases with shorter time to disease had more pronounced ZBTB12-DMR hypomethylation (meta-analysis, men: effect size ± se = -0.0059 ± 0.0017, P TREND = 5.0 × 10(-4); women: effect size ± se = -0.0053 ± 0.0019, P TREND = 6.5 × 10(-3)) and LINE-1 hypomethylation (meta-analysis, men: effect size ± se = -0.0010 ± 0.0003, P TREND = 1.6 × 10(-3); women: effect size ± se = -0.0008 ± 0.0004, P TREND = 0.026) than MI cases with longer time to disease. In the EPIC-NL replication panel, DNA methylation profiles improved case-control discrimination and reclassification when compared with traditional MI risk factors only (net reclassification improvement (95 % CI) between 0.23 (0.02-0.43), P = 0.034, and 0.89 (0.64-1.14), P < 1 × 10(-5)). Our data suggest that specific methylation profiles can be detected in WBCs, in a preclinical condition, several years before the occurrence of MI, providing an independent signature of cardiovascular risk. We showed that prediction accuracy can be improved when DNA methylation is taken into account together with traditional MI risk factors, although further confirmation on a larger sample is warranted. Our findings support the potential use of DNA methylation patterns in peripheral blood white cells as promising early biomarkers of MI.


A global sensitivity analysis of performance of a medical diagnostic test when verification bias is present.
Current advances in technology provide less invasive or less expensive diagnostic tests for identifying disease status. When a diagnostic test is evaluated against an invasive or expensive gold standard test, one often finds that not all patients undergo the gold standard test. The sensitivity and specificity estimates based only on the patients with verified disease are often biased. This bias is called verification bias. Many authors have examined the consequences of verification bias and have proposed bias correction methods based on the assumption of independence between disease status and election for verification conditionally on the test result, or equivalently on the assumption that the disease status is missing at random using missing data terminology. This assumption may not be valid and one may need to consider adjustment for a possible non-ignorable verification bias resulting from the non-ignorable missing data mechanism. Such an adjustment involves ultimately uncheckable assumptions and requires sensitivity analysis. The sensitivity analysis is most often accomplished by perturbing parameters in the chosen model for the missing data mechanism, and it has a local flavour because perturbations are around the fitted model. In this paper we propose a global sensitivity analysis for assessing performance of a diagnostic test in the presence of verification bias. We derive a region of all sensitivity and specificity values consistent with the observed data and call this region a test ignorance region (TIR). The term 'ignorance' refers to the lack of knowledge due to the missing disease status for the not verified patients. The methodology is illustrated with two clinical examples.


Influenza Research in the Eastern Mediterranean Region: A Review.
Given the importance of influenza infections in the Eastern Mediterranean Region (EMR), we conducted a comprehensive literature review to analyze the status of influenza research in the region from 2012. Influenza research has gained more momentum recently with the emergence of H5N1 and new virus strains. Research covering epidemiological, veterinary, and basic science aspects is growing. More sequences were being generated per year, not only for diagnostic purposes but also for research. We included gray literature publications in our search and found several graduate student dissertations from Egypt, which were published on an online portal. However, the search revealed some weaknesses, mostly in the areas of study design and the lack of surveillance studies. Another weakness was the fact that the publications originated from very few countries, mainly Egypt and Iran. Although improving, influenza research in the EMR remains weak. We recommend encouraging countries in the EMR to conduct more influenza research using stronger methodologies.


Sex as a response to oxidative stress: a twofold increase in cellular reactive oxygen species activates sex genes.
Organisms are constantly subjected to factors that can alter the cellular redox balance and result in the formation of a series of highly reactive molecules known as reactive oxygen species (ROS). As ROS can be damaging to biological structures, cells evolved a series of mechanisms (e.g. cell-cycle arrest, programmed cell death) to respond to high levels of ROS (i.e. oxidative stress). Recently, we presented evidence that in a facultatively sexual lineage--the multicellular green alga Volvox carteri--sex is an additional response to increased levels of stress, and probably ROS and DNA damage. Here we show that, in V. carteri, (i) sex is triggered by an approximately twofold increase in the level of cellular ROS (induced either by the natural sex-inducing stress, namely heat, or by blocking the mitochondrial electron transport chain with antimycin A), and (ii) ROS are responsible for the activation of sex genes. As most types of stress result in the overproduction of ROS, we believe that our findings will prove to extend to other facultatively sexual lineages, which could be indicative of the ancestral role of sex as an adaptive response to stress and ROS-induced DNA damage.


Population neuroscience: why and how.
Population neuroscience endeavours to identify environmental and genetic factors that shape the function and structure of the human brain; it uses tools and knowledge of genetics, epidemiology, and cognitive neuroscience. Here, I focus on the application of population neuroscience in studies of brain development. By describing in some detail four existing large-scale magnetic resonance (MR) imaging studies of typically developing children and adolescents, I provide an overview of their design, including population sampling and recruitment, assessments of environmental and genetic "exposures," and measurements of brain and behavior "outcomes." I then discuss challenges faced by investigators carrying out such MR-based studies, including quality assurance, quality control and intersite coordination, and provide a brief overview of the achievements made so far. I conclude by outlining future directions vis-à-vis population neuroscience, such as design strategies that can be used to evaluate the presence of absence of causality in associations discovered by observational studies.


The findings of standardized echography for choroidal folds.
Twenty-four patients (31 eyes) with choroidal folds unassociated with orbital tumors were evaluated with standardized echography. Hypermetropia was the most commonly associated finding (eight eyes); in ten eyes, no consistent abnormal findings could be established. Among the less common causes were swelling of the optic nerve proper or the perineural sheaths and thickened extraocular muscles. Standardized echography demonstrated ocular changes, orbital changes, or both, in all but two patients (two eyes) with idiopathic folds. The most frequent findings were flattening of the posterior ocular wall (18 eyes), thickening of the retinochoroid layer (12 eyes), and distention of the optic nerve sheaths (eight eyes). While fluorescein angiography is well established as the preferred method of demonstrating choroidal folds, standardized echography may now be used to delineate the often subtle associated ocular and orbital findings.


Effects of physical exercise in older adults with reduced physical capacity: meta-analysis of resistance exercise and multimodal exercise.
Older adults with reduced physical capacity are at greater risk of progression to care dependency. Progressive resistance strength exercise and multimodal exercise have been studied to restore reduced physical capacity. To summarize the best evidence of the two exercise regimes, this meta-analysis study appraised randomized-controlled trials from published systematic reviews. Medline, Embase, and the Cochrane Database of Systematic Review and Cochrane Central Register of Controlled Clinical Trials were searched for relevant systematic reviews. Two reviewers independently screened the relevant systematic reviews to identify eligible trials, assessed trial methodological quality, and extracted data. RevMan 5.3 software was used to analyze data on muscle strength, physical functioning, activities of daily living, and falls. Twenty-three eligible trials were identified from 22 systematic reviews. The mean age of the trial participants was 75 years or older. Almost all multimodal exercise trials included muscle strengthening exercise and balance exercise. Progressive resistance exercise is effective in improving muscle strength of the lower extremity and static standing balance. Multimodal exercise is effective in improving muscle strength of the lower extremity, dynamic standing balance, gait speed, and chair stand. In addition, multimodal exercise is effective in reducing falls. Neither type of exercise was effective in improving activities of daily living. For older adults with reduced physical capacity, multimodal exercise appears to have a broad effect on improving muscle strength, balance, and physical functioning of the lower extremity, and reducing falls relative to progressive resistance exercise alone.


Inhibitory Potential of Constituents from Osmanthus fragrans and Structural Analogues Against Advanced Glycation End Products, α-Amylase, α-Glucosidase, and Oxidative Stress.
Inhibition of α-amylase and α-glucosidase, advanced glycation end products (AGEs) formation, and oxidative stress by isolated active constituents of Osmanthus fragrans flowers (9,12-octadecadienoic acid and 4-(2,6,6-trimethyl-1-cyclohexenyl)-3-buten-2-one) and their structural analogues were evaluated. 9,12-Octadecadienoic acid was 10.02 and 22.21 times more active against α-amylase and α-glucosidase, respectively, than acarbose and ascorbic acid, followed by 9,12,15-octadecatrienoic acid, 9-octadecenoic acid, 4-(2,6,6-trimethyl-1-cyclohexenyl)-3-buten-2-one, 4-(2,6,6-trimethyl-2-cyclohexenyl)-3-buten-2-one, 1-heptadecanecarboxylic acid, and 1-pentadecanecarboxylic acid. Concerning the inhibition of AGEs formation, similar with data for 2,2'-diphenyl-1-picrylhydrazl radical scavenging activities, 9,12-octadecadienoic acid was 3.54 times more active than aminoguanidine, followed by 9,12,15-octadecatrienoic acid, and 9-octadecenoic acid. These results indicate that 4-(2,6,6-trimethyl-1-cyclohexenyl)-3-buten-2-one, 9,12-octadecadienoic acid and their analogues inhibit α-amylase and α-glucosidase, AGEs formation, and oxidative stress have potential value in alleviating diabetic pathological conditions.


Hassles with medication management perceived by caregivers of adults who have intellectual or developmental disabilities.
Background Medication management is undertaken by caregivers of people who have intellectual or developmental disabilities. Objective The objectives were to measure the medication management hassles reported by caregivers of adults who have intellectual or developmental disabilities and to describe associations between characteristics of caregivers, medication regimens, and the person with intellectual or developmental disability and the scale score. Setting Web-based survey conducted in the United States. Method A newsletter announcement with a link to the survey was sent to members of a disability advocacy organization. Caregivers were age 18 years and older who manage medications for adults with intellectual or developmental disabilities. The survey questions were used to obtain characteristics of the caregiver, the medication regimen they managed, and the care-recipient. The study was approved by the Institutional Review Board of Michigan Medicine (HUM00091002). Main outcome measure The Family Caregiver Medication Administration Hassles Scale (caregiver scale). Results Forty-two caregivers responded, with 41 being female with a mean age of 56.7 years. The mean caregiver scale score was 28.9 (possible range 0-120). Highest scores (greatest hassles) were significantly associated with a greater level of support required by the care-recipient, stronger caregiver beliefs of the necessity of medication and concern about using medications, lack of previous caregiver health-care training, and being an employed caregiver rather than family member. Conclusion Medication management can contribute to caregiver stress. Pharmacists should ensure that caregivers are counseled about medication that they manage, be accessible for questions, and examine medication regimens to reduce polypharmacy and complexity of regimens.


Cosegregation of novel mitochondrial 16S rRNA gene mutations with the age-associated T414G variant in human cybrids.
Ever increasing evidence has been provided on the accumulation of mutations in the mitochondrial DNA (mtDNA) during the aging process. However, the lack of direct functional consequences of the mutant mtDNA load on the mitochondria-dependent cell metabolism has raised many questions on the physiological importance of the age-related mtDNA variations. In the present work, we have analyzed the bioenergetic properties associated with the age-related T414G mutation of the mtDNA control region in transmitochondrial cybrids. The results show that the T414G mutation does not cause per se any detectable bioenergetic change. Moreover, three mtDNA mutations clustered in the 16S ribosomal RNA gene cosegregated together with the T414G in the same cybrid cell line. Two of them, namely T1843C and A1940G, are novel and associate with a negative bioenergetic phenotype. The results are discussed in the more general context of the complex heterogeneity and the dramatic instability of the mitochondrial genome during cell culture of transmitochondrial cybrids.


Deletion of oligodendrocyte Cx32 and astrocyte Cx43 causes white matter vacuolation, astrocyte loss and early mortality.
CNS glia exhibit a variety of gap junctional interactions: between neighboring astrocytes, between neighboring oligodendrocytes, between astrocytes and oligodendrocytes, and as 'reflexive' structures between layers of myelin in oligodendrocytes. Together, these junctions are thought to form a network facilitating absorption and removal of extracellular K(+) released during neuronal activity. In mice, loss of the two major oligodendrocyte connexins causes severe demyelination and early mortality, while loss of the two major astrocyte connexins causes mild dysmyelination and sensorimotor impairment, suggesting that reflexive and/or oligo-oligo coupling may be more important for the maintenance of myelin than other forms. To further explore the functional relationships between glial connexins, we generated double knockout mice lacking one oligodendrocyte and one astrocyte connexin. Cx32-Cx43 dKO animals develop white matter vacuolation without obvious ultrastructural abnormalities in myelin. Progressive loss of astrocytes but not oligodendrocytes or microglia accompanies sensorimotor impairment, seizure activity and early mortality at around 16 weeks of age. Our data reveal an unexpected role for connexins in the survival of white matter astrocytes, requiring the expression of particular isoforms in both oligodendrocytes and astrocytes.


Turnover of mRNAs is one of the essential functions of RNase E.
RNase E is an essential bacterial endoribonuclease with a central role in processing tRNAs and rRNA, and turning over mRNAs. Previous studies in strains carrying mutations in the rne structural gene have shown that tRNA processing is likely to be an essential function of RNase E but have not determined whether mRNA turnover is also an essential function. To address this we selected extragenic suppressors of temperature-sensitive mutations in rne that cause a large increase in mRNA half-life at the non-permissive temperature. Fifteen suppressors were mapped to three different loci: relBE (toxin-antitoxin system); vacB (RNase R); and rpsA (ribosomal protein S1). Each suppressor class has the potential to interact with mRNA and each restores wild-type levels of mRNA turnover but does not reverse the minor defects in tRNA and rRNA processing. RelE toxin is especially interesting because its only known activity is to cleave mRNAs in the ribosomal A-site. The relBE suppressor mutations increase transcription of relE, and controlled overexpression of RelE alone was sufficient to suppress the rne ts phenotype. Suppression increased turnover of some major mRNAs (tufA, ompA) but not all mRNAs. We propose that turnover of some mRNAs is one of the essential functions of RNase E.


[Transmissible and natural infections in Siberia and the Far East].
The common and specific features in the time course and structure of morbidity as regards tick-borne rickettsiasis, tick-borne encephalitis, and Lyme disease in Siberia and Far East are discussed. The differentiation of nosological areas of tick-borne rickettsiasis and encephalitis is demonstrated and 9 variants of ratios of epidemiological zones of different hazard of infection established. The subject of comparative epidemiology of focal infections is formulated. General conceptual approaches to epidemiologic survey as the basis for optimizing preventive measures are outlined.


Diagnostic value of serum erythropoietin level in patients with absolute erythrocytosis.
The diagnosis of polycythemia vera (PV) is based on clinical and biological criteria defined by either the Polycythemia Vera Study Group (PVSG) or the World Health Organization (WHO). Both the PVSG and WHO PV criteria have proved helpful and are extensively used, yet diagnostic strategies and scheduling of biological investigations vary. We assessed the value of measuring serum erythropoietin (Epo) as a first intention diagnostic test in patients with absolute erythrocytosis (AE). Serum and bone marrow (BM) samples of 241 patients with a suspicion of erythrocytosis were collected in 8 hospital centers. One hundred and ninety had an absolute erythrocytosis (116 had PV, 66 had secondary erythrocytosis and 4 had idiopathic erythrocytosis). Serum Epo was assayed (ELISA) in 186. Statistical analysis (ROC curves) was used to define serum Epo thresholds that were specific for PV and secondary erythrocytosis and to analyze the diagnostic value of a low or high serum Epo level. A large majority of PV patients (87% or 101/116) had a serum Epo level below the normal range in healthy patients (3.3 IU/L), giving this value a specificity of 97% with a 97.8% positive predictive value for the diagnosis of PV. Statistical analysis (ROC curves) defined two thresholds allowing a specific and direct diagnosis of 65.6% (65/99) of untreated PV (Epo < 1.4 IU/L) and 19.7% (13/66) of those with secondary erythrocytosis (Epo > 13.7 IU/L). Based on these data, we propose that measurement of serum Epo level, a simple, reliable and inexpensive test, should be considered as a first intention diagnostic test for patients with absolute erythrocytosis.


Peritonsillar Abscess.
Peritonsillar abscess is the most common deep infection of the head and neck, occurring primarily in young adults. Diagnosis is usually made on the basis of clinical presentation and examination. Symptoms and findings generally include fever, sore throat, dysphagia, trismus, and a "hot potato" voice. Drainage of the abscess, antibiotic therapy, and supportive therapy for maintaining hydration and pain control are the cornerstones of treatment. Most patients can be managed in the outpatient setting. Peritonsillar abscesses are polymicrobial infections, and antibiotics effective against group A streptococcus and oral anaerobes should be first-line therapy. Corticosteroids may be helpful in reducing symptoms and speeding recovery. Promptly recognizing the infection and initiating therapy are important to avoid potentially serious complications, such as airway obstruction, aspiration, or extension of infection into deep neck tissues. Patients with peritonsillar abscess are usually first encountered in the primary care outpatient setting or in the emergency department. Family physicians with appropriate training and experience can diagnose and treat most patients with peritonsillar abscess.


Hypophosphatemic encephalopathy in a CAPD patient.
Severe refeeding hypophosphatemia has been reported in infants and adults on continuous ambulatory peritoneal dialysis. We report an episode of transient encephalopathy and cardiac suppression in a diabetic, malnourished end-stage renal disease patient undergoing peritoneal dialysis with a glucose-based solution, which was associated with severe hypophosphatemia. Further investigation revealed an adynamic bone disease. The potential factors precipitating this episode of hypophosphatemia are discussed.


Combining control measures for more effective management of fisheries under uncertainty: quotas, effort limitation and protected areas.
We consider combinations of three types of control measures for the management of fisheries when the input information for policy decisions is uncertain. The methods considered include effort controls, catch quotas and area closures. We simulated a hypothetical fishery loosely based on the Icelandic cod fishery, using a simple spatially explicit dynamic model. We compared the performance with respect to conserving the resource and economic return for each type of control measure alone and in combination. In general, combining more than one type of primary direct control on fishing provides a greater buffer to uncertainty than any single form of fishery control alone. Combining catch quota control with a large closed area is a most effective system for reducing the risk of stock collapse and maintaining both short and long-term economic performance. Effort controls can also be improved by adding closed areas to the management scheme. We recommend that multiple control methods be used wherever possible and that closed areas should be used to buffer uncertainty. To be effective, these closed areas must be large and exclude all principal gears to provide real protection from fishing mortality.


Outcome after traumatic brain injury in the U.S. military medical system.
Personality and behavioral change after traumatic brain injury (TBI) are often the most significant concerns for the families of TBI patients. This report examines discharge from military service after TBI for medical and behavioral criteria. When compared with the total discharge population (n = 1,879,724), the relative risk for behavioral discharge was 1.8 times greater for those with mild TBI (n = 1,778), and no difference for those with moderate (n = 174) or severe TBI (n = 274). Discharge for alcoholism or drug use was 2.6 times for mild TBI, 5.4 times for moderate TBI, and no difference for severe TBI compared with the total discharge population. Discharge for criminal conviction was 2.7 times for those with mild head injury, and no difference for those with moderate or severe TBI when compared with the total discharge population. Discharge for medical disability ranged from 7.5 times to 40.4 times, and mortality ranged from 11.6 to 142.4 times the total discharge population. Total sick days defined as the time from admission to return to duty or separation from service increased with head injury severity. Mean Injury Severity Score for mild TBI was 5.5, and 20.9 for severe TBI. Patients who sustain TBI should be monitored after injury for development of behavioral problems. The most effective way to reduce the cost of TBI is primary prevention of these injuries and examining military practices to reduce exposure to risk of TBI. Secondary and tertiary prevention measures such as evaluation and rehabilitation, where indicated, should be undertaken on a routine basis after TBI.


Genotype-phenotype correlations in Chinese von Hippel-Lindau disease patients.
von Hippel-Lindau (VHL) disease is caused by mutations in the VHL gene and demonstrates marked phenotypic variability. Genotype-phenotype correlations in Chinese VHL patients have been unclear. To establish genotype-phenotype correlations in Chinese VHL patients, we collected VHL mutations and phenotypes of 291 patients with VHL disease from 115 unrelated families. Genotype-phenotype correlations at mutation type level, mutation region level, and mutation codon level were analyzed by Kaplan-Meier curves and Cox regression models. We found missense mutations conferred an increased risk of pheochromocytoma developments, but a decreased risk of central nervous system hemangioblastomas (CHBs) and pancreatic lesions. Patients with VHL deletions were more prone to developing retinal angiomas. Renal cell carcinomas were more frequent in nonsense, frameshift or splice-site mutations. Mutations in Exon 2 conferred a higher risk and earlier diagnostic age of CHBs than mutations in other exons (HR = 1.684, 95% CI 1.082-2.620, p = 0.021; 27.0 ± 9.7 years versus 32.8 ± 11.7 years, p = 0.024), while patients with mutations in Exon 3 were more prone to developing pheochromocytomas (HR = 2.760, 95% CI 1.419-5.370, p = 0.003). Mutations at codon 80 or codon167 conferred significantly higher risks of pheochromocytomas than other mutations (HR = 4.678, 95% CI 1.392-15.724, p = 0.013; HR = 4.683, 95% CI 2.515-8.719, p < 0.001 respectively). In conclusion, VHL mutation types, mutation regions and mutation codons can act as phenotypic predictors of VHL disease. Mutation regions and mutation codons may aid in directed surveillance and monitoring of VHL patients.


Sphingobacterium tabacisoli sp. nov., isolated from a tobacco field soil sample.
A Gram-staining-negative, non-motile and rod-shaped bacterium, designated strain h337T, was isolated from an arable soil sample of a tobacco field in Kunming, south-west China. The cells showed oxidase-positive and catalase-positive reactions. Growth was observed at 10-35 °C, at pH 6.0-9.0 and in the presence of up to 3 % (w/v) NaCl, with optimal growth at 30 °C, pH 7.0 and with 1-2 % (w/v) NaCl. The predominant isoprenoid quinone was MK-7. The major fatty acids were identified as iso-C15 : 0, iso-C17 : 0 3-OH, summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c) and summed feature 4 (iso-C17 : 1 I and/or anteiso-C17 : 1 B). The cellular polar lipids contained phosphatidylethanolamine, sphingophospholipid, four unidentified phospholipids, five unidentified lipids and three unidentified aminophospholipids. The genomic DNA G+C content was 41.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain h337T should be assigned to the genus Sphingobacterium. 16S rRNA gene sequence similarity analysis showed that strain h337T was most closely related to 'Sphingobacteriumyamdrokense' 3-0-1 (98.8 %) and Sphingobacteriumyanglingense CCNWSP36-1T (98.5 %) and shared less than 97 % similarity with other species of the genus Sphingobacterium. DNA-DNA hybridization data indicated that the isolate represented a novel genomic species belonging to the genus Sphingobacterium. The characteristics determined in this polyphasic taxonomic study indicated that strain h337T represents a novel species of the genus Sphingobacterium, for which the name Sphingobacterium tabacisoli sp. nov. (type strain h337T=KCTC 52298T=CCTCC AB 2017155T) is proposed.


Lightweight Multi-Class Support Vector Machine-Based Medical Diagnosis System with Privacy Preservation.
Machine learning, powered by cloud servers, has found application in medical diagnosis, enhancing the capabilities of smart healthcare services. Research literature demonstrates that the support vector machine (SVM) consistently demonstrates remarkable accuracy in medical diagnosis. Nonetheless, safeguarding patients' health data privacy and preserving the intellectual property of diagnosis models is of paramount importance. This concern arises from the common practice of outsourcing these models to third-party cloud servers that may not be entirely trustworthy. Few studies in the literature have delved into addressing these issues within SVM-based diagnosis systems. These studies, however, typically demand substantial communication and computational resources and may fail to conceal classification results and protect model intellectual property. This paper aims to tackle these limitations within a multi-class SVM medical diagnosis system. To achieve this, we have introduced modifications to an inner product encryption cryptosystem and incorporated it into our medical diagnosis framework. Notably, our cryptosystem proves to be more efficient than the Paillier and multi-party computation cryptography methods employed in previous research. Although we focus on a medical application in this paper, our approach can also be used for other applications that need the evaluation of machine learning models in a privacy-preserving way such as electricity theft detection in the smart grid, electric vehicle charging coordination, and vehicular social networks. To assess the performance and security of our approach, we conducted comprehensive analyses and experiments. Our findings demonstrate that our proposed method successfully fulfills our security and privacy objectives while maintaining high classification accuracy and minimizing communication and computational overhead.


Evaluation of polyethylene terephthalate glycol (PETG), Simubone™, and photopolymer resin as 3D printed temporal bone models for surgical simulation.
Among types of 3D printing, fused deposition modeling (FDM) and digital light processing (DLP) are the most accessible, making them attractive, low-cost options for simulating surgical procedures. This study characterized and compared inexpensive, synthetic temporal bone models printed using Resin, PETG, and Simubone™. This study compared models made of polyethylene terephthalate glycol (PETG), Simubone™ produced from a FDM printer, and photopolymer resin from a DLP printer. These temporal bone models were processed by: (1) DICOM files from a patient's CT scan were segmented to define critical parts expected in a temporal bone surgery. (2) The model was appended with a base that articulates with a 3D-printed temporal bone holder. (3) The refined, patient-specific model was manufactured using FDM and DLP printing technologies. (4) The models were sent to evaluators, who assessed the models based on anatomic accuracy, dissection experience, and its applicability as a surgical simulation tool for temporal bone dissection. The photopolymer resin outperformed PETG and Simubone™ in terms of anatomical accuracy and dissection experience. Additionally, resin and PETG were evaluated to be appropriate for simple mastoidectomy and canal wall down mastoidectomy while Simubone™ was only suitable for simple mastoidectomy. All models were unsuitable for posterior tympanotomy and labyrinthectomy. Photopolymer resin and PETG have shown to be suitable materials for dissection models with 3D-printed resin models showing more accuracy in replicating anatomical structures and dissection experience. Hence, the use of 3D-printed temporal bones may be a suitable low-cost alternative to cadaveric dissection.


Role of estrogen receptor-alpha in the anterior pituitary gland.
Targeted insertional disruption of the mouse estrogen receptor-alpha (ER alpha) gene has provided a genetic model in which to test hypotheses that estrogens exert important effects in development and homeostatic functions of the anterior pituitary gland, particularly in the lactotroph and gonadotroph cell types. Analysis of ER alpha gene-disrupted mice reveals a marked reduction in PRL mRNA and a decrease in lactotroph cell number, but normal specification of lactotroph cell phenotype. Gonadotropin mRNA levels in ER alpha gene-disrupted female mice are elevated, consistent with previously described transcriptional suppression of gonadotropin subunit gene expression in response to sustained administration of estrogen in wild type mice. These results provide genetic evidence that ER alpha plays a critical role in PRL and gonadotropin gene transcription and is involved in lactotroph cell growth, but is not required for specification of lactotroph cell phenotype.


Intense noise-induced apoptosis in hair cells of guinea pig cochleae.
Cells can die by two distinct pathways: apoptosis and necrosis. To explore whether intense noise can induce hair cell (HC) death via the apoptotic pathway, we systematically examined morphological changes in guinea pig cochlear HC nuclei stained with Hoechst 33342, a fluorescent dye specifically labelling the nuclear DNA. A narrow band noise centred at 4 kHz with levels at 110 dB, 115 dB or 120 dB (SPL) was applied for 4 h and the exposed cochleae were collected at various intervals (3 h, 3 or 14 days) after the noise exposure. Auditory function was monitored by measuring thresholds of auditory brain stem responses. In the noise-damaged cochleae, there were two major types of nuclear changes, nuclear condensation appeared as karyorrhexis or karyopyknosis and nuclear swelling. Karyorrhexis and karyopyknosis predominately appeared in the severely damaged cochlear region in the animals exposed to 120 dB noise and examined 3 h after the noise exposure. In contrast, swelling of nuclei occurred in all of the noise-exposed cochleae, and was the feature change in the animals exposed to 110 and 115 dB noise. This pathological change persisted at least for 14 days after the noise exposure. The typical changes of karyorrhexis and karyopyknosis noted in the animals exposed to 120 dB noise were morphologically similar to those nuclear changes described in previous studies for apoptosis, suggesting that the apoptotic process may be involved in intense noise-induced HC death.


Imaging of hip and groin injuries in athletes.
Proper function of the hip joint is imperative for athletes who participate in sporting activities that rely on utilization of the lower extremity; these primarily include kicking, running, and jumping activities. Sports-related injuries of the hip and groin are not frequent sources of disability in athletes; however, they may present a significant diagnostic dilemma, both from a clinical and radiological standpoint. Delay in diagnosis and treatment may result in undesired complications, such as premature degenerative disease, as well as time lost from athletic activities. Magnetic resonance (MR) imaging of the hip, particularly following the intra-articular administration of gadolinium, has proven to be extremely valuable in the diagnosis of radiographically occult osseous abnormalities as well as soft-tissue injuries, such as pubalgia, musculotendinous abnormalities, and bursitis. This article will review several pathological conditions of the hip and groin in both recreational and professional athletes, with an emphasis on MR imaging as the modality of choice in the diagnosis of these injuries.


Antibodies against Proinsulin and Homologous MAP Epitopes Are Detectable in Hashimoto's Thyroiditis Sardinian Patients, an Additional Link of Association.
Hashimoto's thyroiditis (HT) is the prevailing organ-specific autoimmune disease in Sardinia, often complicated with other autoimmune disorders, most commonly type 1 diabetes (T1D). While numerous studies describe levels of anty-thyroid antibodies (Abs) in T1D patients, few papers evaluate the status of anti-islet autoimmunity in subjects affected by HT. Previously, we portrayed Mycobacterium avium subspecies paratuberculosis (MAP) as an environmental factor strongly associated with both diseases. In this study, we analyzed plasma of Sardinian HT patients (n=177) and healthy controls (HCs; n=175) for the presence of Abs against proinsulin and MAP-derived homologous epitopes: MAP1,4αgbp157-173/PI64-80 were recognized by 5,08% and 18,64% of HT vs 0,57% and 7,43% of HCs (AUC=0,6 for both; p<0,0003 and 0,002, respectively), whereas the prevalence of Abs against MAP2404c70-85/PI46-61 peptides was higher but not significant in patients when compared to HCs. In women (n=152), Abs against MAP1,4αgbp157-173 were detected in 12,50% of HT vs 2,75% of HCs (AUC=0,63; p<0,0002), while positivity to its human homolog PI64-80 was observed in 16,42% of HT vs 6,42% of HCs (AUC=0,61; p<0,001). In men (n=25), a significant anti-PI46-61 Abs levels were detected in 4% of HT vs none of the HCs (AUC=0,7; p<0,003). Age-related analyses revealed the highest prevalence between 31-40 years old (45,83%) in the total study population and among males (33,33%); in contrast, women had a higher seroreactivity between 51-60 years (42,11%). A further follow-up and determination of anti-islet Abs levels is needed to evaluate the association of immune responses directed against the MAP/PI homologous peptides with progression to overt diabetes in HT subjects.


Reactivity of tetrahydrobiopterin bound to nitric-oxide synthase.
Levels of tetrahydrobiopterin (BH(4)) bound to nitric-oxide synthase (NOS) were examined during multiple turnovers of the enzyme in the presence of an NADPH-regenerating system. Our findings show that NOS-bound BH(4) does not remain in a static state but undergoes redox reactions. Under these experimental conditions, the redox state of BH(4) was determined by the balance between calcium/calmodulin (Ca(2+)/CaM)-dependent oxidation of BH(4) mediated by the uncoupled formation of superoxide/hydrogen peroxide on the one hand and by reductive regeneration of BH(4) on the other hand. BH(4) oxidation was appreciably increased in the presence of arginine. Levels of NOS-bound BH(4) were also examined under single turnover conditions in the absence of an NADPH-regenerating system and in the presence of added superoxide dismutase and catalase to suppress the accumulation of superoxide and hydrogen peroxide. BH(4) oxidation was again dependent on Ca(2+)/CaM. The insensitivity to superoxide dismutase and catalase suggested that the single turnover oxidation of BH(4) did not proceed through superoxide/peroxide, although the involvement of these oxidants could not be definitively excluded. The amount of BH(4) oxidized was highest in the presence of arginine, and this oxidation significantly exceeded that in the presence of N(G)-hydroxy-L-arginine. The findings that single turnover oxidation of BH(4) is stimulated by arginine in the presence of Ca(2+)/CaM and that BH(4) is regenerated are consistent with a role for the pterin as an electron donor in product formation; this role remains to be defined.


Comparison of orally administered bisphosphonate drugs in reducing the risk of hip fracture in older adults: a population-based cohort study.
Orally administered bisphosphonate drugs (i.e., alendronate, etidronate, risedronate) can reduce the risk of vertebral fracture. However, only alendronate and risedronate have proven efficacy in reducing the risk of hip fracture. We sought to examine the comparative effectiveness of orally administered bisphosphonate drugs in reducing hip fractures among older adults. We identified new users of orally administered bisphosphonate drugs in British Columbia and Ontario between 2001 and 2008. We used province- and sex-specific propensity score-matching strategies to maximize comparability between exposure groups. We used Cox proportional hazards models to compare time-to-hip fracture within 1 year of treatment between exposures by sex in each province. Our secondary analyses considered hip fracture rates within 2 and 3 years' follow-up. We used alendronate as the reference for all comparisons and pooled provincial estimates using random effects variance-weighted meta-analysis. We identified 321 755 patients who were eligible for inclusion in the study. We found little difference in fracture rates between men (pooled hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74-1.14) or women (pooled HR 1.15, 95% CI 0.73-1.56) taking risedronate and those taking alendronate. We similarly identified little difference in fracture rates between women taking etidronate and those taking alendronate (pooled HR 1.00, 95% CI 0.82-1.18). However, we identified lower rates of hip fracture among men taking etidronate relative to alendronate (pooled HR 0.77, 95% CI 0.60-0.94). Results extended to 2 and 3 years' follow-up were similar. However, with 3 years' follow-up, rates of hip fracture were lower among women in British Columbia who had taken alendronate. We identified little overall difference between alendronate and risedronate in reducing the risk of hip fracture in men or women. Our finding that etidronate is associated with lower fracture risk among men is likely due to selection bias. The long-term comparative effects of orally administered bisphosphonate drugs warrant further study.


Activism, Coping, and Hopefulness Among Parents of Children With Cancer.
Background: Coping styles employed by parents of children with cancer have significant implications for parents' and children's well-being. To supplement the minimal literature in this area, activism (participation in activities that serve to benefit children with cancer as a group) was investigated as a potential coping strategy. Method: Parents (N = 67) of children with cancer completed an online survey that included measures of COPE inventory (COPE), hopefulness (Adult Hope Scale), and depression (Patient Health Questionnaire-9-item). Participants retrospectively reported their engagement in activism to benefit children with cancer and to benefit other causes, including actions that were taken before and after their child's cancer diagnosis. Relations between activism, overall styles of coping, hopefulness, and depression were assessed. Results: Activism was positively correlated with hope and active coping, but not associated with depression. Participants reported a significant increase in childhood-cancer-related activism following their own child's diagnosis, with 100% of parents endorsing engagement in such activism. Postdiagnosis childhood-cancer-related activism uniquely explained 17% of the variance in hopefulness after other forms of activism had been accounted for. Discussion: Childhood-cancer-related activism is a common activity among parents of children with cancer that has significant implications for parental hopefulness. Parents who endorse an active, solution-focused approach to coping with the childhood cancer experience may be more likely than others to engage in activism. Further research is needed to clarify the role of activism in the lives of families of children with cancer.


The importance of manganese in the cytoplasmic maturation of cattle oocytes: blastocyst production improvement regardless of cumulus cells presence during in vitro maturation.
Adequate dietary intake of manganese (Mn) is required for normal reproductive performance in cattle. This study was carried out to investigate the effect of Mn during in vitro maturation of bovine cumulus-oocyte complexes (COC) on apoptosis of cumulus cells, cumulus expansion, and superoxide dismutase (SOD) activity in the COC. The role of cumulus cells on Mn transport and subsequent embryo development was also evaluated. Early apoptosis decreased in cumulus cells matured with Mn compared with medium alone. Cumulus expansion did not show differences in COC matured with or without Mn supplementation. SOD activity was higher in COC matured with 6 ng/ml Mn than with 0 ng/ml Mn. Cleavage rates were higher in COC and denuded oocytes co-cultured with cumulus cells, either with or without Mn added to in vitro maturation (IVM) medium. Regardless of the presence of cumulus cells during IVM, the blastocyst rates were higher when 6 ng/ml Mn was supplemented into IVM medium compared with growth in medium alone. Blastocyst quality was enhanced when COC were matured in medium with Mn supplementation. The results of the present study indicated that Mn supplementation to IVM medium enhanced the 'health' of COC, and improved subsequent embryo development and embryo quality.


Seasonal behavior and forecasting trends of tuberculosis incidence in Holy Kerbala, Iraq.
Pulmonary tuberculosis (PTB) remains major public health problem over the world. Cities witnessing religious event throughout of the year like Kerbala/Iraq require great efforts to minimize the incidence of deadly communicable diseases like TB. The aim of this study is to model the monthly incidence rates of PTB cases in Kerbala/Iraq. This is a retrospective study in which records of confirmed PTB patients whom they referred to the chest and respiratory illnesses center of Holy Kerbala governorate were obtained. Monthly registered new smear-positive PTB cases from January 2010 to December 2016 were analyzed. Seasonal autoregressive integrated moving average (SARIMA), SARIMA-exponential smoothing method (ETS), SARIMA-neural network autoregressive, and SARIMA-adaptive neuro-fuzzy inference system (SARIMA-ANFIS) were used for forecasting monthly incidence rate of TB in Kerbala, Iraq. Mean absolute percentage error, root mean square error, and mean absolute square error were used to compare the models, and Akaike information criterion (AIC) and Bayesian information criterion (BIC) were used to selected best model. The trend of PTB incidence showed a seasonal characteristic, with peaks in spring and winter. Predicted estimates using all models proposed to forecast the number of PTB cases from 2016 to 2018 showed that the PTB cases indicated marginal decrease trends and best forecasted in SARIMA-ANFIS model (the lower AIC and BIC values, 712.69 and 731.05, respectively). Seasonal characteristic of PTB incidence was observed with peaks during spring and winter. Forecasting of PTB incidence between the period 2016 and 2018 showed marginal decrease trends, and the best forecasting model was SARIMA-ANFIS model.


Inter-ethics: towards an interactive and interdependent bioethics.
Since its origin bioethics has been a specialized, academic discipline, focussing on moral issues, using a vast set of globalized principles and rational techniques to evaluate and guide healthcare practices. With the emergence of a plural society, the loss of faith in experts and authorities and the decline of overarching grand narratives and shared moralities, a new approach to bioethics is needed. This approach implies a shift from an external critique of practices towards embedded ethics and interactive practice improvement, and from a legal defence of rights towards fostering interdependent practices of responsibility. This article describes these transitions within bioethics in relation to the broader societal and cultural dynamics within Western societies, and traces the implications for the methodologies and changing roles of the bioethicist. The bioethicist we foresee is not just a clever expert but also a relationally sensitive person who engages stakeholders in reciprocal dialogues about their practice of responsibility and helps to integrate various sorts of knowledge (embodied, experiential, visual, and cognitive-scientific). In order to illustrate this new approach, we present a case study. It concerns a project focusing on an innovation in elderly care, based on the participation of various stakeholders, especially older people themselves.


[Analogs and models of systemic arterial circulation].
This review article is primarily aimed at those researches using the experimental physiological approach and gives a survey of analogs and models of the systemic arterial blood flow. They are presented in increasing order of complexity in two sections: the "lumped" and the "distributed" parameter models. In the first section a brief description is given of the purely resistive, Windkessel and multi-element analogs with emphasis on their use in physiology for estimating several hemodynamic variables. The distributed parameter models, whose central idea is pulse wave propagation along the arterial tree, are then presented in five categories, using a new classification scheme. These categories are based on four criteria derived from the assumptions used in the formulation of the fluid and wall equations. The most recent non-linear models are treated in more detail with their common properteis as well as their particular contribution emphasized. In conclusion it is noted that the distributed parameter models also begin to be used to evaluate physiological variables in the experimental and clinical context and that this trend can only become more important in view of the advances made in the field of biomedical instrumentation.


Surgical management of a locally advanced jejunal stromal tumor: A case report of a challenging condition.
Locally advanced jejunal stromal tumors stand as a captivating and relatively rare entity, garnering attention for several reasons. Their inaccessible location by conventional endoscopy poses a diagnostic challenge. Further, treatment decisions necessitate a multidisciplinary approach, compounded by the absence of high-level evidence studies. A 54-year-old patient was admitted to our surgical department with abdominal pain and chronic anemia. Abdominal CT imaging confirmed the presence of a non-metastatic sizable jejunal tumor. The patient underwent laparotomy, revealing a locally advanced jejunal tumor contracting the ileum and the ascending colon. A monobloc oncological resection was performed, followed by the restoration of digestive continuity. Anatomopathological analysis delineated a locally advanced Stromal Tumor with a high risk of recurrence. The patient underwent a course of tyrosine kinase inhibitors for 3 years, with no reported recurrence during the subsequent 3-year follow-up. Locally advanced jejunal stromal tumors are rare. Most patients present with unspecific symptoms. Diagnosis remains challenging due to their intricate anatomical location. Decisions regarding management must be deliberated within a multidisciplinary framework, tailored to each patient's unique characteristics. While combined therapeutic modalities have demonstrated efficacy in recent studies, prudence is advised given the heightened incidence of both short and long-term complications. In the absence of randomized controlled trials, the management of locally advanced jejunal stromal tumors underscores the imperative of multidisciplinary collaboration in treatment deliberations. A wide, sometimes mutilating excision is only permissible if it is complete.


Adjuvant chemotherapy in patients with clinically node-negative but pathologically node-positive rectal cancer in the Netherlands: A retrospective analysis.
Accurate clinical staging of rectal cancer is hampered by suboptimal sensitivity of MRI in the detection of regional lymph node metastases. Consequently, some patients may be understaged and have been withheld neoadjuvant (chemo)radiotherapy in retrospect. Although Dutch guidelines do not advocate adjuvant chemotherapy (ACT) in rectal cancer, some of these clinically understaged patients receive ACT according to local policy. We aim to assess the benefit of ACT in these patients. Population-based data from patients with clinically node-negative (cN0) but pathologically node-positive (pN+) rectal cancer that underwent total mesorectal excision (TME) without neoadjuvant treatment between 2008 and 2018 were obtained from the Netherlands Cancer Registry. Missing data were handled by multiple imputation. Stabilised inverse probability treatment weighting (sIPTW) was used to balance clinical characteristics. Overall survival (OS) was compared in ACT and non-ACT patients. Of 34,724 patients, 13,861 had cN0 disease of whom 3016 were pN+ (21.8%). 1466 (48.6%) of these patients underwent upfront TME and were included. Median follow-up was 84 months (95% confidence interval [CI] 76-97) versus 79 months (95% CI 77-81) in patients that did (n = 290, 19.8%) and did not (n = 1176, 80.2%) receive ACT, respectively. After sIPTW adjustment, ACT was associated with improved OS (hazard ratio 0.70; 95% CI 0.49-0.99; p = 0.04). The estimated 5-year OS rate was 74.2% versus 65.3%, respectively. In this population-based cohort of patients with cN0 but pN+ rectal cancer who underwent upfront TME, ACT was associated with a significant OS benefit. These data support to discuss ACT in this population.


Characterization of phosphoproteins and protein kinase activity of virions, noninfectious enveloped particles, and dense bodies of human cytomegalovirus.
Phosphorylation of the proteins of human cytomegalovirus (CMV) virions, noninfectious enveloped particles (NIEPs), and dense bodies was investigated. Analyses of particles phosphorylated in vivo showed the following. Virions contain three predominant phosphoproteins (i.e., basic phosphoprotein and upper and lower matrix proteins) and at least nine minor phosphorylated species. NIEPs contain all of these and one additional major species, the assembly protein. Dense bodies contain only one (i.e., lower matrix) of the predominant and four of the minor virion phosphoproteins. Two-dimensional (charge-size) separations in denaturing polyacrylamide gels showed that the relative net charges of the predominant phosphorylated species ranged from the basic phosphoprotein to the more neutral upper matrix protein. In vitro assays showed that purified virions of human CMV have an associated protein kinase activity. The activity was detected only after disrupting the envelope; it had a pH optimum of approximately 9 to 9.5 and required a divalent cation, preferring magnesium to manganese. In vitro, this activity catalyzed phosphorylation of the virion proteins observed to be phosphorylated in vivo. Peptide comparisons indicated that the sites phosphorylated in vitro are a subset of those phosphorylated in vivo, underscoring the probable biological relevance of the kinase activity. Casein, phosvitin, and to a minor extent lysine-rich histones served as exogenous phosphate acceptors. Arginine-rich and lysine-rich histones and protamine sulfate, as well as the polyamines spermine and spermidine, stimulated incorporation of phosphate into the endogenous viral proteins. Virions of all human and simian CMV strains tested showed this activity. Analyses of other virus particles, including three intracellular capsid forms (i.e., A, B, and C capsids), NIEPs, and dense bodies, indicated that the active enzyme was not present in the capsid. Rate-velocity sedimentation of disrupted virions separated the protein kinase activity into two fractions: one that phosphorylated exogenous casein and another that phosphorylated primarily the endogenous virion proteins.


Role of pelvic lymph node dissection in prostate cancer treatment.
Pelvic lymph node dissection (PLND) is the most accurate and reliable staging procedure for detecting lymph node invasion (LNI) in prostate cancer. Recently, [(11)C]-choline positron emission tomography imaging and magnetic resonance imaging with lymphotropic superpara-magnetic nanoparticles have shown potential for detecting LNI but are still under investigation. The risk of LNI in low-risk groups could be underestimated by use of the current nomograms, which rely on data collected from patients who underwent only limited PLND. Extended PLND (ePLND) shows higher lymph node yield, which leads to the removal of more positive nodes and fewer missed positive nodes. It may be possible to refrain from performing PLND on low-risk patients with a prostate-specific antigen value <10 ng/ml and a biopsy Gleason score ≤6, but the risk of biopsy-related understaging should be kept in mind. Theoretically, meticulous ePLND may also impact prostate cancer survival by clearing low-volume diseases and occult micrometastasis even in pN0. The therapeutic role of PLND in prostate cancer patients is still an open question, especially in individuals with low-risk disease. Patients with intermediate- to high-risk disease are more likely to benefit from ePLND.


Transport of folinate and related compounds in Pediococcus cerevisiae.
The properties of folinate and 5-methyltetrahydrofolate (5-CH(3)-H(4)PteGlu) transport mechanism of Pediococcus cerevisiae were studied. The uptake was dependent on temperature, pH (optimum for both compounds at pH 6.0), and glucose. Iodoacetate, potassium fluoride, and sodium azide inhibited the uptake. 5-CH(3)-H(4)-PteGlu was apparently not metabolized but folinate was metabolized. Metabolism of folinate was reduced by preincubation of cells with fluorodeoxyuridine. The transport system for folinate and 5-CH(3)-H(4)PteGlu were specific for the l-isomers. Pteroylglutamate, aminopterin, and amethopterin did not interfere with the uptake. Tetrahydrofolate competed with the uptake of folinate. The transport of folinate and 5-CH(3)-H(4)PteGlu at 37 C conformed to Michaelis-Menten kinetics; apparent K(m) for both compounds was 4.0 x 10(-7)m, and the V(max) for folinate was 1.0 x 10(-10) moles per min per mg (dry weight) and for 5-CH(3)-H(4)PteGlu it was 1.6 x 10(-10) moles per min per mg (dry weight). Both compounds accumulated in the intracellular pool at a concentration about 80- to 140-fold higher than that in the external medium. Folinate inhibited competitively the uptake of 5-CH(3)-H(4)PteGlu with a K(i) of 0.4 x 10(-7)m. Unlike 5-CH(3)-H(4)PteGlu, which accumulated only at 37 C, folinate was also taken up at 0 C by a glucose- and temperature-independent process, which was not affected by the metabolic inhibitors mentioned above. Since at 0 C the intracellular concentration of folinate was also considerably higher than the external, binding of the substrate to some cellular component is assumed. The finding of an efficient transport system for l-5-CH(3)-H(4)PteGlu is of special interest, since this compound has no growth-promoting activity for P. cerevisiae.


Lack of stearoyl-CoA desaturase 1 upregulates basal thermogenesis but causes hypothermia in a cold environment.
Stearoyl-CoA desaturase (SCD) is a microsomal enzyme involved in the biosynthesis of oleate and palmitoleate. Mice with a targeted disruption of the SCD1 isoform (SCD1-/-) exhibit reduced adiposity and increased energy expenditure. To address whether the energy expenditure is attributable to increased thermogenesis, we investigated the effect of SCD1 deficiency on basal and cold-induced thermogenesis. SCD1-/- mice have increased expression of uncoupling proteins in brown adipose tissue (BAT) relative to controls. The beta3-adrenergic receptor (beta3-AR) expression was increased and the phosphorylation of cAMP response element binding protein and the protein level of peroxisome proliferator-activated receptor-gamma coactivator-1alpha were increased in the SCD1-/- mice. Both lipolysis and fatty acid oxidation were increased in the SCD1-/- mice. When exposed to 4 degrees C, SCD1-/- mice showed hypothermia, hypoglycemia, and depleted liver glycogen. High levels of dietary oleate partially compensated for the hypothermia and rescued plasma glucose and liver glycogen. These results suggest that SCD1 deficiency stimulates basal thermogenesis through the upregulation of the beta3-AR-mediated pathway and a subsequent increase in lipolysis and fatty acid oxidation in BAT. The hypothermia and hypoglycemia in cold-exposed SCD1-/- mice and the compensatory recovery by oleate indicate an important role of SCD1 gene expression in thermoregulation.


Some novel classifiers designed using prototypes extracted by a new scheme based on self-organizing feature map.
We propose two new comprehensive schemes for designing prototype-based classifiers. The scheme addresses all major issues (number of prototypes, generation of prototypes, and utilization of the prototypes) involved in the design of a prototype-based classifier. First we use Kohonen's self-organizing feature map (SOFM) algorithm to produce a minimum number (equal to the number of classes) of initial prototypes. Then we use a dynamic prototype generation and tuning algorithm (DYNAGEN) involving merging, splitting, deleting, and retraining of the prototypes to generate an adequate number of useful prototypes. These prototypes are used to design a "1 nearest multiple prototype (1-NMP)" classifier. Though the classifier performs quite well, it cannot reasonably deal with large variation of variance among the data from different classes. To overcome this deficiency we design a "1 most similar prototype (1-MSP)" classifier. We use the prototypes generated by the SOFM-based DYNAGEN algorithm and associate with each of them a zone of influence. A norm (Euclidean)-induced similarity measure is used for this. The prototypes and their zones of influence are fine-tuned by minimizing an error function. Both classifiers are trained and tested using several data sets, and a consistent improvement in performance of the latter over the former has been observed. We also compared our classifiers with some benchmark results available in the literature.


Hpa2 required by HrpF to translocate Xanthomonas oryzae transcriptional activator-like effectors into rice for pathogenicity.
Xanthomonas oryzae pv. oryzicola, the causative agent of bacterial leaf streak, injects a plethora of effectors through the type III secretion system (T3SS) into rice cells to cause disease. The T3SS, encoded by the hrp genes, is essential for the pathogen to elicit the hypersensitive response (HR) in nonhost tobacco and for pathogenicity in host rice. Whether or not a putative lytic transglycosylase, Hpa2, interacts with a translocon protein, HrpF, to facilitate bacterial pathogenicity remains unknown. Here we demonstrated that both the hpa2 and hrpF genes are required for the pathogenicity of X. oryzae pv. oryzicola strain RS105 in rice but not for HR induction in tobacco. The expression of hpa2 was positively regulated by HrpG and HrpD6 but not by HrpX. In vivo secretion and subcellular localization analyses confirmed that Hpa2 secretion is dependent on HpaB (a T3SS exit protein) and that Hpa2 binds to the host cell membrane. Protein-protein assays demonstrated that Hpa2 interacts with HrpF. In planta translocation of AvrXa10 indicated that the mutation in hpa2 and hrpF inhibits the injection of the HpaB-dependent transcriptional activator-like (TAL) effector into rice. These findings suggest that Hpa2 and HrpF form a complex to translocate T3S effectors into plant cells for pathogenesis in host rice.


Aortic cell apoptosis in rat primary aldosteronism model.
This study aimed to determine whether aldosterone could induce vascular cell apoptosis in vivo. Thirty-two male rats were randomly divided into 4 groups: vehicle (control), aldosterone, aldosterone plus eplerenone or hydralazine. They were then implanted with an osmotic mini-pump that infused either aldosterone or the vehicle. Systolic blood pressure (SBP) was measured weekly by the tail-cuff method. After 8 weeks, plasma aldosterone concentration (PAC) and renin activity (PRA) were determined by radioimmunoassay. Aortic apoptosis was examined by TUNEL assay. The levels of cytochrome c and caspase-3 were determined by Western blotting and the expression of Bax and Bcl-2 was detected by immunohistochemistry and Western blotting. The results showed that as compared with control group, aldosterone-infused rats exhibited: (1) an increase in SBP; (2) significantly elevated PAC with depressed PRA; (3) elevated aortic vascular cell apoptosis accompanied with higher levels of cytochrome c and activated caspase-3; and (4) significantly up-regulated Bax protein with down-regulated Bcl-2. These effects of aldosterone were significantly inhibited after co-administration with eplerenone but not with hydralazine. It was concluded that aldosterone induced vascular cell apoptosis by its direct effect on the aorta via mineralocorticoid receptors and independently of blood pressure, which may contribute to aldosterone-mediated vascular injury.


Crystallization and preliminary diffraction analysis of truncated human pleckstrin.
Pleckstrin is a major substrate of protein kinase C in platelets and leukocytes and appears to play an important role in exocytosis through a currently unknown mechanism. Pleckstrin function is regulated by phosphorylation, which is thought to cause dissociation of pleckstrin dimers, thereby facilitating phosphoinositide interactions and membrane localization. Evidence also exists suggesting that phosphorylation causes a subtle conformational change in pleckstrin. Structural studies of pleckstrin have been initiated in order to characterize these structural changes and ultimately advance understanding of pleckstrin function. Here, the crystallization and preliminary X-ray diffraction analysis of a truncated version of pleckstrin consisting of the N-terminal PH domain, the protein kinase C phosphorylation sites and the DEP domain (NPHDEP) are reported. In addition, the oligomeric state and phospholipid-binding properties of NPHDEP were analyzed. This work demonstrates that NPHDEP behaves as a monomer in solution and suggests that all three pleckstrin domains contribute to the dimerization interface. Furthermore, based on the binding properties of NPHDEP, the C-terminal PH domain appears to increase the specificity of pleckstrin for phosphoinositides. This work represents a significant step towards determining the structure of pleckstrin.


Lessons learnt from an outbreak of COVID-19 in a workplace providing an essential service, Thames Valley, England 2020: Implications for investigation and control.
Human behavioural factors are an important consideration in the response to COVID-19 outbreaks. Prior to the emergence of highly infectious variants of SARS-CoV-2 and implementation of vaccination programmes, we conducted a study to explore the role of behavioural factors influencing transmission at an essential services workplace during an outbreak of COVID-19. Observational cohort study. In response to a COVID-19 outbreak in November 2020 at an office-based call centre workplace providing an essential service in Thames Valley, we designed and conducted an anonymous staff questionnaire to explore potential behavioural factors of staff behaviour that influence transmission. A total of 45 staff (27%) tested positive for SARS-CoV-2 over a six-week period between 26 October and 14 December 2020. The online questionnaire was cascaded to 168 staff members; the response rate was 41%. Self-reported use of hand sanitiser, face masks and cleaning of equipment in line with workplace guidance was 86%, 66% and 63% respectively. On the same behaviours, respondents reported that 33%, 31% and 14% of their colleagues followed the recommendations. Almost two thirds of respondents (63%) reported that they were unable to maintain social distancing at the workplace, primarily due to operational constraints. Prevention and control of COVID-19 outbreaks at workplaces providing an essential service is challenging. Operational requirements, often compounded by reduced staff availability, impede implementation of more robust control measures. Ongoing assessment of human behavioural factors in the control of COVID-19 outbreaks at workplaces in the post-vaccine era is essential.


Radiation dose from single-heartbeat coronary CT angiography performed with a 320-detector row volume scanner.
To determine radiation doses from coronary computed tomographic (CT) angiography performed by using a 320-detector row volume scanner and evaluate how the effective dose depends on scan mode and the calculation method used. Radiation doses from coronary CT angiography performed by using a volume scanner were determined by using metal-oxide-semiconductor field-effect transistor detectors positioned in an anthropomorphic phantom physically and radiographically simulating a male or female human. Organ and effective doses were determined for six scan modes, including both 64-row helical and 280-row volume scans. Effective doses were compared with estimates based on the method most commonly used in clinical literature: multiplying dose-length product (DLP) by a general conversion coefficient (0.017 or 0.014 mSv.mGy(-1).cm(-1)), determined from Monte Carlo simulations of chest CT by using single-section scanners and previous tissue-weighting factors. Effective dose was reduced by up to 91% with volume scanning relative to helical scanning, with similar image noise. Effective dose, determined by using International Commission on Radiological Protection publication 103 tissue-weighting factors, was 8.2 mSv, using volume scanning with exposure permitting a wide reconstruction window, 5.8 mSv with optimized exposure and 4.4 mSv for optimized 100-kVp scanning. Estimating effective dose with a chest conversion coefficient resulted in a dose as low as 1.8 mSv, substantially underestimating effective dose for both volume and helical coronary CT angiography. Volume scanning markedly decreases coronary CT angiography radiation doses compared with those at helical scanning. When conversion coefficients are used to estimate effective dose from DLP, they should be appropriate for the scanner and scan mode used and reflect current tissue-weighting factors. (c) RSNA, 2010.


Interactive effects of warming and invertebrate grazing on the outcomes of competitive fungal interactions.
Saprotrophic fungal community composition, determined by the outcomes of competitive mycelial interactions, represents a key determinant of woodland carbon and nutrient cycling. Atmospheric warming is predicted to drive changes in fungal community composition. Grazing by invertebrates can also exert selective pressures on fungal communities and alter the outcome of competitive fungal interactions; their potential to do so is determined by grazing intensity. Temperature regulates the abundance of soil collembola, but it remains unclear whether this will alter the top-down determination of fungal community composition. We use soil microcosms to explore the direct (via effects on interacting fungi) and indirect (by influencing top-down grazing pressures) effects of a 3 °C temperature increase on the outcomes of competitive interactions between cord-forming basidiomycete fungi. By differentially affecting the fungal growth rates, warming reversed the outcomes of specific competitive interactions. Collembola populations also increased at elevated temperature, and these larger, more active, populations exerted stronger grazing pressures. Consequently, grazing mitigated the effects of temperature on these interactions, restoring fungal communities to those recorded at ambient temperature. The interactive effects of biotic and abiotic factors are a key in determining the functional and ecological responses of microbial communities to climate change.


The effect of upper dorsal thoracoscopic sympathectomy on the total amount of body perspiration.
Thoracoscopic T2-T3 sympathectomy is the treatment of choice for primary palmar hyperhidrosis (PPH); however, compensatory hyperhidrosis (CH) is a disturbing sequela of this operation, the mechanism of which is poorly understood. This study was conducted to evaluate the effect of heat stress on total body perspiration after thoracoscopic T2-T3 sympathectomy, and determine its correlation with CH. A total of 17 patients with PPH who underwent bilateral T2-T3 sympathectomy were subjected to heat stress induced by a 10-min sauna bath (ambient temperature 70 degrees C), 1 day before and 1 month after surgery. The naked body weight was recorded before and immediately following the sauna bath, and the patients were followed up to assess whether CH had developed and the degree of its severity. Postoperatively, the amount of perspiration increased in 13 patients and decreased in 1. The amount of perspiration induced by the sauna bath ranged from 60 to 480 g, with a mean value of 185.29 +/- 125.80 g, before the operation, and from 60 to 540 g, with a mean value of 265.88 +/- 154.05 g, after the operation (P = 0.0113). There was no correlation between the degree of alteration in total body perspiration and the development of CH. Performing thoracoscopic T2-T3 sympathectomy for PPH affects the total body sweating response to heat; however, the development of CH does not correlate with this alteration.


Characteristics of antibodies adsorbed on the DNA immunoadsorbent, agarose poly-L-lysine-DNA.
Agarose-poly-L-lysine (Ag-(lys)n-DNA) has been used to bind DNA for assay of anti-DNA antibodies (ab). In this work, an algorithmic approach has been used to classify antinuclear ab (ANA) as being directed against native DNA (dsDNA), denatured DNA (ssDNA), DNA-protein complexes (deoxyribonucleoprotein; DNP), and against antigens which are independent of DNA (iDNA). These ab were subjected to Ag-(lys)n-DNA, and the selectivity of this adsorbent for the various specificities of ab was determined. The DNA on the columns was left untreated or treated with S1 nuclease, this being effected either by treating the DNA prior to introducing it onto the columns or by adding S1 nuclease to the columns after the DNA was bound. Ag-(lys)n-DNA adsorbs ab directed against ssDNA and DNP as well as ab to dsDNA; iDNA ab are not adsorbed. S1 nuclease treatment does not effectively remove ssDNA regions from the Ag-(lys)n-DNA, but it does result in the abolition of the adsorption of a population of ab which are in the anti-DNP sera and contribute to the total ANA load. While anti-iDNA ab are not adsorbed onto the columns, they do contribute to the ANA titer, unlike anti-ssDNA ab which are adsorbed onto the Ag-(lys)n-DNA but do not contribute to the ANA titer. We conclude that Ag-(lys)n-DNA bears antigenic sites for dsDNA, ssDNA, and DNP ab and suggest that our understanding of the characteristic ab-binding profile of this versatile immunoadsorbent may have applications in the study of autoimmune diseases.


Beginning the discussion of commercialism in dentistry.
There is increasing concern over commercialism in dentistry. Multiple factors contribute to this trend, which has the potential for fragmenting the profession, exacerbating the access issue, and eroding the public's confidence in dentistry. There are both positive and negative aspects of commercialism. Positive approaches for promoting oral health in the face of commercialism hold the greatest promise. The core theme in the recommendations from Ethics Summit on Commercialism is that competent, comprehensive, and continuous oral health care is appropriate and should be promoted to the American public.


Social Dancing and Incidence of Falls in Older Adults: A Cluster Randomised Controlled Trial.
The prevention of falls among older people is a major public health challenge. Exercises that challenge balance are recognized as an efficacious fall prevention strategy. Given that small-scale trials have indicated that diverse dance styles can improve balance and gait of older adults, two of the strongest risk factors for falls in older people, this study aimed to determine whether social dance is effective in i) reducing the number of falls and ii) improving physical and cognitive fall-related risk factors. A parallel two-arm cluster randomized controlled trial was undertaken in 23 self-care retirement villages (clusters) around Sydney, Australia. Eligible villages had to have an appropriate hall for dancing, house at least 60 residents, and not be currently offering dance as a village activity. Retirement villages were randomised using a computer generated randomisation method, constrained using minimisation. Eligible participants had to be a resident of the village, be able to walk at least 50 m, and agree to undergo physical and cognitive testing without cognitive impairment. Residents of intervention villages (12 clusters) were offered twice weekly one-hour social dancing classes (folk or ballroom dancing) over 12 mo (80 h in total). Programs were standardized across villages and were delivered by eight dance teachers. Participants in the control villages (11 clusters) were advised to continue with their regular activities. falls during the 12 mo trial and Trail Making Tests. The Physiological Performance Assessment (i.e., postural sway, proprioception, reaction time, leg strength) and the Short Physical Performance Battery; health-related physical and mental quality of life from the Short-Form 12 (SF-12) Survey. Data on falls were obtained from 522 of 530 (98%) randomised participants (mean age 78 y, 85% women) and 424 (80%) attended the 12-mo reassessment, which was lower among folk dance participants (71%) than ballroom dancing (82%) or control participants (82%, p = 0.04). Mean attendance at dance classes was 51%. During the period, 444 falls were recorded; there was no significant difference in fall rates between the control group (0.80 per person-year) and the dance group (1.03 per person-year). Using negative binomial regression with robust standard errors the adjusted Incidence Rate Ratio (IRR) was 1.19 (95% CI: 95% CI = 0.83, 1.71). In exploratory post hoc subgroup analysis, the rate of falls was higher among dance participants with a history of multiple falls (IRR = 2.02, 95% CI: 1.15, 3.54, p = 0.23 for interaction) and with the folk dance intervention (IRR = 1.68, 95% CI: 1.03, 2.73). There were no significant between-group differences in executive function test (TMT-B = 2.8 s, 95% CI: -6.2, 11.8). Intention to treat (ITT) analysis revealed no between-group differences at 12-mo follow-up in the secondary outcome measures, with the exception of postural sway, favouring the control group. Exploratory post hoc analysis by study completers and style indicated that ballroom dancing participants apparently improved their gait speed by 0.07 m/s relative to control participants (95% CI: 0.00, 0.14, p = 0.05). Study limitations included allocation to style based on logistical considerations rather than at random; insufficient power to detect differential impacts of different dance styles and smaller overall effects; variation of measurement conditions across villages; and no assessment of more complex balance tasks, which may be more sensitive to changes brought about by dancing. Social dancing did not prevent falls or their associated risk factors among these retirement villages' residents. Modified dance programmes that contain "training elements" to better approximate structured exercise programs, targeted at low and high-risk participants, warrant investigation. The Australian New Zealand Clinical Trials Registry ACTRN12612000889853.


Development of a proficiency testing program for HPV serology assays used to evaluate antibody responses in vaccine trials.
In this study, a proficiency panel was created for evaluation of assay performance and inter- and intra-laboratory assay comparisons, especially the ability to accurately measure negative, low, intermediate, and high levels of HPV type-specific antibodies. Comprised of 80 deidentified samples, this panel is designed for individual labs to evaluate assay performance characteristics on a biennial basis, to promote standardization of methodology and harmonization of data from human papillomavirus (HPV) serology tests in vaccine trials. The proficiency panel was qualified using 2 types of assays (singleplex Enzyme-Linked Immunosorbent Assays [ELISAs] or Multiplex antibody-binding assays and Pseudovirion-based neutralization assays [PBNAs]) in 10 laboratories from 7 countries, monitoring HPV antibody responses for up to 9 HPV types and using 3 different analysis methods. Sensitivity, specificity, and correlations (concordance, accuracy, and precision) were evaluated for each HPV type. In laboratories that tested all 80 samples, results from most (74/80) samples were reported with 100% accuracy across all 9 HPV types. The average sensitivity and specificity for singleplex and multiplex antibody binding assays ranged from 86.7% to 98.3% (sensitivity) and 84.2% to 94.3% (specificity), while the average sensitivity and specificity for the Pseudovirion (PsV)-based neutralization assays (PBNA) ranged from 87.6% to 99.4% (sensitivity) and 52.4% to 94.4% (specificity). This proficiency panel will help with assessing performance characteristics of HPV serology assays used in clinical trial studies and assure the data generated from these assays is harmonized.


[Ehlers-Danlos syndrome, with special emphasis in the joint hypermobility syndrome].
There is an urgent need to increase the awareness on the Joint Hyper mobility Syndrome QHS). This is a congenital and prevalent emergent condition that is frequently undiagnosed and that causes significant health problems. Besides recurrent muscular-skeletal problems and signs and symptoms derived from tissue fragility, adolescents and young adults may develop osteoporosis, early osteoarthritis or dysautonomia, that are common in the disease, and deteriorate quality of life. Many JHS patients have signs and symptoms suggestive of fibromyalgia and are usually misdiagnosed. Physicians should be able to differentiate the less severe form of JHS from the Vascular Ehlers-Danlos Syndrome, to diagnose it before the appearance of serious complications and even death. The study of these diseases is a promising area for genomic and rheumatologic research.


Systematic Review Checklist: A Standardized Technique for Assessing and Reporting Reviews of Life Cycle Assessment Data.
Systematic review, including meta-analysis, is increasingly utilized in life cycle assessment (LCA). There are currently no widely recognized guidelines for designing, conducting, or reporting systematic reviews in LCA. Other disciplines such as medicine, ecology, and software engineering have both recognized the utility of systematic reviews and created standardized protocols for conducting and reporting systematic reviews. Based largely on the 2009 Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, which updated the preferred format for reporting of such reviews in biomedical research, we provide an introduction to the topic and a checklist to guide the reporting of future LCA reviews in a standardized format. The standardized technique for assessing and reporting reviews of LCA (STARR-LCA) checklist is a starting point for improving the utility of systematic reviews in LCA.


Oral papillomatosis caused by Enhydra lutris papillomavirus 1 (ElPV-1) in southern sea otters (Enhydra lutris nereis) in California, USA.
The southern sea otter (Enhydra lutris nereis) is a threatened marine sentinel. During postmortem investigations of stranded sea otters from 2004 to 2013 in California, US, papillomas were detected in the oral cavity of at least seven otters via necropsy and histopathology. Next-generation sequencing of viral particles purified from a single papilloma revealed a novel papillomavirus, Enhydra lutris papillomavirus 1 (ElPV-1). The genome of ElPV-1 was obtained, representing the first fully sequenced viral genome from southern sea otters. Phylogenetic analysis of the entire L1 gene, as well as a concatenated protein identities plot of all papillomaviral genes revealed that ElPV-1 is a λ-papillomavirus, related to a raccoon papillomavirus (Procyon lotor papillomavirus type 1) and a canine oral papillomavirus. Immunohistochemical staining, using a cross-reactive bovine papillomavirus antibody, suggested that ElPV-1 is present in intranuclear inclusions and intracytoplasmic keratin granules. Virus-infected cells were scattered throughout the stratum granulosum and stratum spinosum of the gingival and buccal papillomas. Using ElPV-1-specific PCR, we confirmed viral DNA in oral papillomas from all seven stranded sea otters, with identical L1 sequences. This virus is associated with the development of oral papillomatosis in southern sea otters.


Beyond an AFLP genome scan towards the identification of immune genes involved in plague resistance in Rattus rattus from Madagascar.
Genome scans using amplified fragment length polymorphism (AFLP) markers became popular in nonmodel species within the last 10 years, but few studies have tried to characterize the anonymous outliers identified. This study follows on from an AFLP genome scan in the black rat (Rattus rattus), the reservoir of plague (Yersinia pestis infection) in Madagascar. We successfully sequenced 17 of the 22 markers previously shown to be potentially affected by plague-mediated selection and associated with a plague resistance phenotype. Searching these sequences in the genome of the closely related species Rattus norvegicus assigned them to 14 genomic regions, revealing a random distribution of outliers in the genome (no clustering). We compared these results with those of an in silico AFLP study of the R. norvegicus genome, which showed that outlier sequences could not have been inferred by this method in R. rattus (only four of the 15 sequences were predicted). However, in silico analysis allowed the prediction of AFLP markers distribution and the estimation of homoplasy rates, confirming its potential utility for designing AFLP studies in nonmodel species. The 14 genomic regions surrounding AFLP outliers (less than 300 kb from the marker) contained 75 genes encoding proteins of known function, including nine involved in immune function and pathogen defence. We identified the two interleukin 1 genes (Il1a and Il1b) that share homology with an antigen of Y. pestis, as the best candidates for genes subject to plague-mediated natural selection. At least six other genes known to be involved in proinflammatory pathways may also be affected by plague-mediated selection.


Variational Bayesian Parameter Estimation Techniques for the General Linear Model.
Variational Bayes (VB), variational maximum likelihood (VML), restricted maximum likelihood (ReML), and maximum likelihood (ML) are cornerstone parametric statistical estimation techniques in the analysis of functional neuroimaging data. However, the theoretical underpinnings of these model parameter estimation techniques are rarely covered in introductory statistical texts. Because of the widespread practical use of VB, VML, ReML, and ML in the neuroimaging community, we reasoned that a theoretical treatment of their relationships and their application in a basic modeling scenario may be helpful for both neuroimaging novices and practitioners alike. In this technical study, we thus revisit the conceptual and formal underpinnings of VB, VML, ReML, and ML and provide a detailed account of their mathematical relationships and implementational details. We further apply VB, VML, ReML, and ML to the general linear model (GLM) with non-spherical error covariance as commonly encountered in the first-level analysis of fMRI data. To this end, we explicitly derive the corresponding free energy objective functions and ensuing iterative algorithms. Finally, in the applied part of our study, we evaluate the parameter and model recovery properties of VB, VML, ReML, and ML, first in an exemplary setting and then in the analysis of experimental fMRI data acquired from a single participant under visual stimulation.