Integrin Regulation during Leukocyte Recruitment.
Integrins are recognized as vital players in leukocyte recruitment. Integrin malfunction causes severe disease patterns characterized by the inability to fight pathogens. Although inflammatory reactions are beneficial and necessary for host defense, these reactions have to be controlled to prevent tissue destruction and harmful sequelae. In this review, we discuss the different signaling pathways leading to the change of integrin adhesiveness in neutrophils, monocytes, and lymphocytes. We thereby focus on the importance of integrin activation for the different steps of the leukocyte recruitment cascade, including rolling, adhesion, postadhesion strengthening, intravascular crawling, and transmigration, as each step necessitates the proper functioning of a distinct set of integrin molecules that has to be activated specifically. Additionally, we discuss endogenous mechanisms that balance and counteract integrin activation and limit leukocyte recruitment at the site of inflammation. Further insight into these complex mechanisms may provide new approaches for developing new anti-inflammatory therapies.


Integrative nonpharmacologic behavioral interventions for the management of cancer-related fatigue.
Cancer-related fatigue (CRF) is a debilitating, multi-faceted biopsychosocial symptom experienced by the majority of cancer survivors during and after treatment. CRF begins after diagnosis and frequently persists long after treatments end, even when the cancer is in remission. The etiological pathopsychophysiology underlying CRF is multifactorial and not well delineated. Mechanisms may include abnormal accumulation of muscle metabolites, dysregulation of the homeostatic status of cytokines, irregularities in neuromuscular function, abnormal gene expression, inadequate ATP synthesis, serotonin dysregulation, abnormal vagal afferent nerve activation, as well as an array of psychosocial mechanisms, including self-efficacy, causal attributions, expectancy, coping, and social support. An important first step in the management of CRF is the identification and treatment of associated comorbidities, such as anemia, hypothyroidism, pain, emotional distress, insomnia, malnutrition, and other comorbid conditions. However, even effective clinical management of these conditions will not necessarily alleviate CRF for a significant proportion of cancer survivors. For these individuals, intervention with additional therapeutic modalities may be required. The National Comprehensive Cancer Network guidelines recommend that integrative nonpharmacologic behavioral interventions be implemented for the effective management of CRF. These types of interventions may include exercise, psychosocial support, stress management, energy conservation, nutritional therapy, sleep therapy, and restorative therapy. A growing body of scientific evidence supports the use of exercise and psychosocial interventions for the management of CRF. Research on these interventions has yielded positive outcomes in cancer survivors with different diagnoses undergoing a variety of cancer treatments. The data from trials investigating the efficacy of other types of integrative nonpharmacologic behavioral therapies for the management of CRF, though limited, are also encouraging. This article provides an overview of current research on the relative merits of integrative nonpharmacologic behavioral interventions for the effective clinical management of CRF and makes recommendations for future research. Disclosure of potential conflicts of interest is found at the end of this article.


Decision Support Systems in Health Care - Velocity of Apriori Algorithm.
The amount of stored data in health information systems can reach tera- and petabytes and application of specific algorithms in the field of data mining makes finding useful information suitable for making quality business decisions. A frequently used method for determining the rules of the relationship between attributes is the Association rule by applying Apriori algorithm. Lack of basic Apriori algorithm is derived from the slow work due to multiple scanned data sets. By examining the speed of generating the basic rules in relation to the improved Apriori algorithm by using software RapidMiner confirmed that the time required to generate rules for Improved algorithm is shorter, the rules are quickly generated particularly for large data sets, which is an advantage for making decisions.


Cognitive and Ocular Factors Jointly Determine Pupil Responses under Equiluminance.
Changes in pupil diameter can reflect high-level cognitive signals that depend on central neuromodulatory mechanisms. However, brain mechanisms that adjust pupil size are also exquisitely sensitive to changes in luminance and other events that would be considered a nuisance in cognitive experiments recording pupil size. We implemented a simple auditory experiment involving no changes in visual stimulation. Using finite impulse-response fitting we found pupil responses triggered by different types of events. Among these are pupil responses to auditory events and associated surprise: cognitive effects. However, these cognitive responses were overshadowed by pupil responses associated with blinks and eye movements, both inevitable nuisance factors that lead to changes in effective luminance. Of note, these latter pupil responses were not recording artifacts caused by blinks and eye movements, but endogenous pupil responses that occurred in the wake of these events. Furthermore, we identified slow (tonic) changes in pupil size that differentially influenced faster (phasic) pupil responses. Fitting all pupil responses using gamma functions, we provide accurate characterisations of cognitive and non-cognitive response shapes, and quantify each response's dependence on tonic pupil size. These results allow us to create a set of recommendations for pupil size analysis in cognitive neuroscience, which we have implemented in freely available software.


BSACI guidelines for the management of rhinosinusitis and nasal polyposis.
This guidance for the management of patients with rhinosinusitis and nasal polyposis has been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI). The recommendations are based on evidence and expert opinion and are evidence graded. These guidelines are for the benefit of both adult physicians and paediatricians treating allergic conditions. Rhinosinusitis implies inflammation of the nose and sinuses which may or may not have an infective component and includes nasal polyposis. Acute rhinosinusitis lasts up to 12 weeks and resolves completely. Chronic rhinosinusitis persists over 12 weeks and may involve acute exacerbations. Rhinosinusitis is common, affecting around 15% of the population and causes significant reduction in quality of life. The diagnosis is based largely on symptoms with confirmation by nasendoscopy. Computerized tomography scans and magnetic resonance imaging are abnormal in approximately one third of the population so are not recommended for routine diagnosis but should be reserved for those with acute complications, diagnostic uncertainty or failed medical therapy. Underlying conditions such as immune deficiency, Wegener's granulomatosis, Churg-Strauss syndrome, aspirin hypersensitivity and allergic fungal sinusitis may present as rhinosinusitis. There are few good quality trials in this area but the available evidence suggests that treatment is primarily medical, involving douching, corticosteroids, antibiotics, anti-leukotrienes, and anti-histamines. Endoscopic sinus surgery should be considered for complications, anatomical variations causing local obstruction, allergic fungal disease or patients who remain very symptomatic despite medical treatment. Further well conducted trials in clearly defined patient groups are needed to improve management.


Hydrogen mapping of the lunar south pole using the LRO neutron detector experiment LEND.
Hydrogen has been inferred to occur in enhanced concentrations within permanently shadowed regions and, hence, the coldest areas of the lunar poles. The Lunar Crater Observation and Sensing Satellite (LCROSS) mission was designed to detect hydrogen-bearing volatiles directly. Neutron flux measurements of the Moon's south polar region from the Lunar Exploration Neutron Detector (LEND) on the Lunar Reconnaissance Orbiter (LRO) spacecraft were used to select the optimal impact site for LCROSS. LEND data show several regions where the epithermal neutron flux from the surface is suppressed, which is indicative of enhanced hydrogen content. These regions are not spatially coincident with permanently shadowed regions of the Moon. The LCROSS impact site inside the Cabeus crater demonstrates the highest hydrogen concentration in the lunar south polar region, corresponding to an estimated content of 0.5 to 4.0% water ice by weight, depending on the thickness of any overlying dry regolith layer. The distribution of hydrogen across the region is consistent with buried water ice from cometary impacts, hydrogen implantation from the solar wind, and/or other as yet unknown sources.


The influence of thalamic GABA transmission on the susceptibility of adult rats to flurothyl induced seizures.
There is considerable evidence that thalamic nuclei are involved in the propagation and regulation of seizures. In the present study, we investigated the possible role in seizure mechanisms of GABAergic transmission in two thalamic nuclei, the posterior nucleus (PO) and the ventromedial nucleus (VM). Several GABAergic drugs were bilaterally microinfused into PO or VM of adult rats via chronically implanted cannulae, before testing the rats' susceptibility to seizures induced by flurothyl. In PO, infusions of the GABA elevating agent gamma-vinyl-GABA (20 micrograms) or of the GABAA receptor agonist muscimol (100 ng) suppressed both clonic and tonic seizures. Infusions into PO of the GABAA receptor antagonist bicuculline (100 ng) facilitated both these seizure types. Administration of the GABAB receptor agonist baclofen (200 ng) also suppressed clonic seizure susceptibility. Drug infusions into VM, however, did not significantly modify the susceptibility to seizures. These findings lead us to conclude that GABAergic transmission in the vicinity of the PO, but perhaps not in VM, affects flurothyl seizure susceptibility. We hypothesize that GABA synapses in PO may be part of a seizure propagation or control circuit including striatum, substantia nigra, and superior colliculus.


Loss of Mecp2 in substantia nigra dopamine neurons compromises the nigrostriatal pathway.
Mutations in the methyl-CpG-binding protein 2 (MeCP2) result in Rett syndrome (RTT), an X-linked disorder that disrupts neurodevelopment. Girls with RTT exhibit motor deficits similar to those in Parkinson's disease, suggesting defects in the nigrostriatal pathway. This study examined age-dependent changes in dopamine neurons of the substantia nigra (SN) from wild-type, presymptomatic, and symptomatic Mecp2(+/-) mice. Mecp2(+) neurons in the SN in Mecp2(+/-) mice were indistinguishable in morphology, resting conductance, and dopamine current density from neurons in wild-type mice. However, the capacitance, total dendritic length, and resting conductance of Mecp2(-) neurons were less than those of Mecp2(+) neurons as early as 4 weeks after birth, before overt symptoms. These differences were maintained throughout life. In symptomatic Mecp2(+/-) mice, the current induced by activation of D(2) dopamine autoreceptors was significantly less in Mecp2(-) neurons than in Mecp2(+) neurons, although D(2) receptor density was unaltered in Mecp2(+/-) mice. Electrochemical measurements revealed that significantly less dopamine was released after stimulation of striatum in adult Mecp2(+/-) mice compared to wild type. The decrease in size and function of Mecp2(-) neurons observed in adult Mecp2(+/-) mice was recapitulated in dopamine neurons from symptomatic Mecp2(-/y) males. These results show that mutation in Mecp2 results in cell-autonomous defects in the SN early in life and throughout adulthood. Ultimately, dysfunction in terminal dopamine release and D(2) autoreceptor-dependent currents in dopamine neurons from symptomatic females support the idea that decreased dopamine transmission due to heterogeneous Mecp2 expression contributes to the parkinsonian features of RTT in Mecp2(+/-) mice.


Factors influencing the delivery of abortion services in Ontario: a descriptive study.
Although Canadian women have had the right to obtain legal induced abortions for the past decade, access to the procedure is still limited and controversial in many areas. Chiefs of obstetrics and gynecology, chiefs of staff, directors of nursing and other health professionals at 163 general hospitals in Ontario, Canada, were asked to provide information on issues concerning the availability of abortion services of their facility. The hospital participation rate was 97% and the individual response rate was 75%. Nearly one-half (48%) of hospitals perform abortions. Approximately 36% of these hospitals do so up to a maximum gestational age of 12 weeks, 23% to a maximum of 13-16 weeks, 37% to a maximum of 17-20 weeks and 4% at greater than 20 weeks. Hospital factors, including resources and policies, did not significantly influence whether abortions are provided. However, these factors did affect the number performed, whether there were gestational limitations and the choice of procedure. About 13% of provider hospitals indicated that staff training contributes to the existence of gestational age limits, and 24% said that it directly influences procedure choice. Only 18% of hospitals reported that their physicians have received additional training outside of their medical school or medical residency education to learn abortion techniques or to gain new skills. Forty-five percent of hospitals that provide abortions had experienced harassment within the past two years, and 15% reported that this harassment has directly affected their staff members' willingness to provide abortions. Based upon the provision of obstetric care, many hospitals in Ontario that are capable of offering abortion services do not. Some of the reasons for this failure are related to the procedure itself, while others may be related to resource issues that affect the delivery of other medical services as well. Variation in the availability of abortions is due to a shortage of clinicians performing the procedure, and training directly influences gestational limits and procedural choices.


Characteristics of Prostate Cancer by Opportunistic Screening in Korean Men with a Prostate-Specific Antigen Level Less Than 4.0 ng per Milliliter.
Background/Aims/Objectives: We studied the detection rate of prostate cancer (PCa) among Korean men with a prostate-specific antigen (PSA) level of less than 4.0 ng/mL. A total of 1,680 men with PSA ≤4 ng/mL had a prostate biopsy from January 2004 to December 2014. The differences in clinical factors were analyzed and their independent predictive implications were evaluated. PCa was diagnosed in 331 (19.6%) and 99 of these 331 cancers (14.9%) had a Gleason score of 7 or higher. The detection rate of PCa increased from 6.67% (≤0.5 ng/mL) to 20.36% (3.01-3.9 ng/mL). There were significant differences in age 65.7 vs. 62.1 years, prostate volume 33.4 vs. 38.2 g, PSA density 0.10 vs. 0.08 ng/mL/mL between men with and without PCa. On multivariable analysis, age and prostate volume were the best independent discriminative parameters. When comparing PCa patients with a Gleason score less than 6 to those with a 7 or higher, patients with a Gleason score 7 or higher were older (67.2 vs. 64.8 years). Even when the PSA level is less than 4 ng/mL, PCas, including high-grade cancers, were detected in a significant number of men. In this group, patients with PCa were older and had a smaller prostate volume and high-grade cancers were detected more frequently in older cancer patients.


Graduated compression and its relation to venous refilling time.
Graduated compression is important in improving venous function, but the pressure profiles of different brands of stockings in situ and effects on a direct measure of venous function have not been investigated. The pressure profiles of 15 different types of below knee compression stockings were established with a medical stocking tester in 13 healthy volunteers. Analysis of variance was performed for each stocking separately, considering the factors of size of stocking, site of measurement, and their interaction. The criteria used to define satisfactory function were that the stockings should have a significant linear trend with site--that is, graduation--and no other significant effects. Only five types of stockings met these standards. Venous function was then assessed by photoplethysmography in 19 patients with defined venous abnormalities. For each patient the effect on venous refilling time of three satisfactory and three unsatisfactory stockings was assessed. The three satisfactory stockings gave refilling times that were not significantly different from normal in patients with both superficial and deep vein incompetence, while refilling times with the three unsatisfactory stockings remained significantly below normal in all patients with deep vein incompetence; one stocking had no significant effect on refilling times in either group. Functional testing of compression hosiery should form part of future British Standards specifications.


Community treatment orders: exploring the paradox of personalisation under compulsion.
The introduction of supervised community treatment, delivered through community treatment orders (CTOs) in England and Wales, contrasts with the policy of personalisation, which aims to provide service users autonomy and choice over services. This article draws upon findings from a primarily qualitative study which included 72 semi-structured interviews (conducted between January and December 2012) with practitioners, service users and nearest relatives situated within a particular NHS Trust. The article also refers to a follow-on study in which 30 Approved Mental Health Practitioners were interviewed. The studies aimed to develop a better understanding of how compulsory powers are being used in the community, within a policy context that emphasises personalisation and person-centred care in service delivery. Findings from the interview data (which were analysed thematically) suggest that service users were often inadequately informed about the CTO and their legal rights. Furthermore, they tended to be offered little, or no, opportunity to make choices and have involvement in the making of the CTO and setting of conditions. Retrospectively, however, restrictions were often felt beneficial to recovery, and service users reported greater involvement in decisions at review stage. Areas of good practice are identified through which person-centred care can be better incorporated into the making of CTOs.


High and Sustained Participation in a Multi-year Voluntary Performance Measurement Initiative Among Primary Care Teams.
The province of Ontario, Canada has made major investments in interdisciplinary primary care teams. There is interest in both demonstrating and improving the quality of care they provide. Challenges include lack of consensus on the definition of quality and evidence that the process of measuring quality can be counter-productive to actually achieving it. This study describes how primary care teams in Ontario voluntarily measured quality at the team level. Data for this 4-year observational study came from electronic medical records (EMRs), patient surveys and administrative reports. Descriptive statistics were calculated for individual measures (eg, access, preventive interventions) and composite indicators of quality and healthcare system costs. Repeated measures identified patient and practice characteristics related to quality and cost outcomes. Teams participated in an average of 5 of 8 possible iterations of the reporting process. There was variation between teams. For example, cervical cancer screening rates ranged from 21 to 86% of eligible patients. Rural teams had significantly better performance on some indicators (eg, continuity) and worse on others (eg, cancer screening). There were some statistical but small changes in performance over time. High, sustained voluntary participation suggests that the initiative served a need for the primary care teams involved. The absence of robust data standards suggests that these standards were not crucial to achieve participation. The constant level of performance might mean that measurement has not yet led to improvement or that measures used might not accurately reflect improvement. The data reinforce the need to consider differences between rural and urban settings. They also suggest that further analysis is needed to identify characteristics that teams can change to improve the quality of care their patients experience. The study describes a practical, sustainable real-world approach to performance measurement in primary care that was attractive to interdisciplinary teams.


Familial hematuria; clinico-pathological correlations.
The findings are reported in 38 patients with familial hematuria. In 10 of the 24 families investigated, a familial incidence of hematuria was revealed only by routine urinalysis in first-degree relatives. Where there was either neurosensory deafness of heavy proteinuria in the patient or family, or a history of chronic renal failure in the family, the patient generally ran a progressive clinical course. Light microscopy (LM) of renal biopsy specimens revealed little abnormality in young children, but segmental glomerular sclerosis was frequently observed in older patients. The most characteristic change, observed on electron microscopy (EM) in 27 out of 31 renal biopsies was complex replication of the lamina densa of the capillary basement membrane, to form a "basket weave" pattern. Families with and without deafness (groups 1 and 2) were both considered to fall within the spectrum of Alport's syndrome, although the presence of deafness adversely affected the prognosis. In contrast, patients from families showing neither deafness, heavy proteinuria nor chronic renal failure (group 3) ran a non-progressive course. Their biopsies showed little or no glomerular changes other than attenuation of the lamina densa on EM. In Alport's syndrome, deafness, heavy proteinuria, segmental sclerosis and foam cells were not often present before the age of 10 years, whereas the "basket weave" alteration of the lamina densa was found in all three children biopsied under 5 years of age. We therefore emphasize the importance of EM in the differential diagnosis from benign familial hematuria.


Measurement of surface plasmon correlation length differences using Fibonacci deterministic hole arrays.
Using terahertz (THz) transmission measurements through two-dimensional Fibonacci deterministic subwavelength hole arrays fabricated in metal foils, we find that the surface plasmon-polariton (SPP) correlation lengths for aperiodic resonances are smaller than those associated with the underlying grid. The enhanced transmission spectra associated with these arrays contain two groups of Fano-type resonances: those related to the two-dimensional Fibonacci structure and those related to the underlying hole grid array upon which the aperiodic Fibonacci array is built. For both groups the destructive interference frequencies at which transmission minima occur closely match prominent reciprocal vectors in the hole array (HA) structure-factor in reciprocal space. However the Fibonacci-related transmission resonances are much weaker than both their calculated Fourier intensity in k space and the grid-related resonances. These differences may arise from the complex, multi-fractal dispersion relations and scattering from the underlying grid arrays. We also systematically studied and compared the transmission resonance strength of Fibonacci HA and periodic HA lattices as a function of the number of holes in the array structure. We found that the Fibonacci-related resonance strengths are an order of magnitude weaker than that of the periodic HA, consistent with the smaller SPP correlation length for the aperiodic structure.


Echinococcus multilocularis in North America: the great unknown.
Over the last decade, studies have begun to shed light on the distribution and genetic characterization of Echinococcus multilocularis, the causative agent of alveolar echinococcosis (AE), in North America. Recent findings indicate that the parasite is likely expanding its range in the central region of the United States and Canada and that invasions of European strains might have occurred. In our review, we present the available data on E. multilocularis infections in wild and domestic animals and humans in North America and emphasize the lack of knowledge on the distribution of the parasite in wild and domestic hosts. Furthermore, we stress the need to better understand the complexity of host communities and their roles in shaping the transmission and distribution of the parasite. We hypothesize that a lack of knowledge about AE by North American physicians might result in the misdiagnosis of cases and an underestimation of disease incidence. The endemic presence of the parasite in urban areas and a recent human case in Alberta, Canada, suggest that the scientific community may need to reconsider the local public health risks, re-assess past cases that might have been overlooked and increase surveillance efforts to identify new cases of human AE.


Massive steroids do not reduce the zone of injury after penetrating spinal cord injury.
The National Acute Spinal Cord Injury Study II concluded in 1990 that high-dose methylprednisolone (MP) improved neurologic recovery after acute spinal cord injury (ASCI). We tested this conclusion by analysis of 54 patients with ASCI; 25 patients were treated without MP before 1990 whereas 29 patients were treated with MP after 1990. Neurologic deficit was assessed regularly, in most cases daily. Motor and sensory scores on admission, and best results at one-half week (days 2 to 4), 1 week (days 6 to 10), 2 weeks (days 11 to 21), 1 month, and 2 months were noted for both groups. Motor assessment was recorded in 22 muscle segments on a scale of 0 (complete deficit) to 5 (normal); the range, thus, was 0 to 110. The 23 patients with closed injuries demonstrated no difference in improvement with or without MP. In contrast, MP was associated with impaired improvement in the patients with penetrating wounds; the 15 patients with no MP therapy had an admission motor score of 49, which increased by 6.9 at one-half week, whereas the 16 patients treated with MP had an admission motor score of 48, which decreased by 0.3 at one-half week (p = 0.03). The neural status seen by day 4 persisted throughout the next 2 months. Changes in sensation paralleled the changes in motor function. We conclude that MP therapy for penetrating ASCI may impair recovery of neurologic function.


Adherence to guidelines for youths with diabetes mellitus.
To describe demographic and clinical characteristics associated with self-reported receipt of tests and measurements recommended by the American Diabetes Association (ADA) for children and youths with diabetes. The study included 1514 SEARCH for Diabetes in Youth study participants who completed a survey about diabetes care received. Quality-of-care measures were based on ADA guidelines for eye examinations and glycohemoglobin (hemoglobin A1c [HbA1c]), lipid level, microalbuminuria, and blood pressure measurements, and a composite variable of these 5 indicators was created. Multivariate logistic regression models were used to assess the association of selected demographic and clinical characteristics with the reported receipt of all recommended tests and measurements according to age and diabetes type subgroups. Overall, 95% of the participants reported having their blood pressure checked at all or most visits, 88% had lipid levels measured, 83% had kidney function tested, 68% underwent HbA1c testing, and 66% underwent an eye examination, in accordance with ADA recommendations. Participants aged 18 years or older, particularly those with type 2 diabetes, tended to have fewer tests of all kinds performed. Age and family income emerged as important correlates of overall quality of care in multivariate models; older age and lower income were associated with not meeting guidelines. Although there was relatively good adherence to ADA-recommended guidelines for most indicators, efforts are needed to improve rates of HbA1c testing and eye examinations, particularly among older youths.


Tailoring Intensity of Active Surveillance for Low-Risk Prostate Cancer Based on Individualized Prediction of Risk Stability.
Active surveillance is increasingly recognized as the preferred standard of care for men with low-risk prostate cancer. However, active surveillance requires repeated assessments, including prostate-specific antigen tests and biopsies that may increase anxiety, risk of complications, and cost. To identify and validate clinical parameters that can identify men who can safely defer follow-up prostate cancer assessments. The Canary Prostate Active Surveillance Study (PASS) is a multicenter, prospective active surveillance cohort study initiated in July 2008, with ongoing accrual and a median follow-up period of 4.1 years. Men with prostate cancer managed with active surveillance from 9 North American academic medical centers were enrolled. Blood tests and biopsies were conducted on a defined schedule for least 5 years after enrollment. Model validation was performed among men at the University of California, San Francisco (UCSF) who did not enroll in PASS. Men with Gleason grade group 1 prostate cancer diagnosed since 2003 and enrolled in PASS before 2017 with at least 1 confirmatory biopsy after diagnosis were included. A total of 850 men met these criteria and had adequate follow-up. For the UCSF validation study, 533 active surveillance patients meeting the same criteria were identified. Exclusion criteria were treatment within 6 months of diagnosis, diagnosis before 2003, Gleason grade score of at least 2 at diagnosis or first surveillance biopsy, no surveillance biopsy, or missing data. Active surveillance for prostate cancer. Time from confirmatory biopsy to reclassification, defined as Gleason grade group 2 or higher on subsequent biopsy. A total of 850 men (median [interquartile range] age, 64 [58-68] years; 774 [91%] White) were included in the PASS cohort. A total of 533 men (median [interquartile range] age, 61 [57-65] years; 422 [79%] White) were included in the UCSF cohort. Parameters predictive of reclassification on multivariable analysis included maximum percent positive cores (hazard ratio [HR], 1.30 [95% CI, 1.09-1.56]; P = .004), history of any negative biopsy after diagnosis (1 vs 0: HR, 0.52 [95% CI, 0.38-0.71]; P < .001 and ≥2 vs 0: HR, 0.18 [95% CI, 0.08-0.4]; P < .001), time since diagnosis (HR, 1.62 [95% CI, 1.28-2.05]; P < .001), body mass index (HR, 1.08 [95% CI, 1.05-1.12]; P < .001), prostate size (HR, 0.40 [95% CI, 0.25-0.62]; P < .001), prostate-specific antigen at diagnosis (HR, 1.51 [95% CI, 1.15-1.98]; P = .003), and prostate-specific antigen kinetics (HR, 1.46 [95% CI, 1.23-1.73]; P < .001). For prediction of nonreclassification at 4 years, the area under the receiver operating curve was 0.70 for the PASS cohort and 0.70 for the UCSF validation cohort. This model achieved a negative predictive value of 0.88 (95% CI, 0.83-0.94) for those in the bottom 25th percentile of risk and of 0.95 (95% CI, 0.89-1.00) for those in the bottom 10th percentile. In this study, among men with low-risk prostate cancer, heterogeneity prevailed in risk of subsequent disease reclassification. These findings suggest that active surveillance intensity can be modulated based on an individual's risk parameters and that many men may be safely monitored with a substantially less intensive surveillance regimen.


Clinal population divergence in an adaptive parental environmental effect that adjusts seed banking.
Bet-hedging via between-year seed dormancy is a costly strategy for plants in unpredictable environments. Theoretically, fitness costs can be reduced through a parental environmental effect when the environment is partly predictable. We tested whether populations from environments that differ in predictability diverged in parental effects on seed dormancy. Common garden-produced seeds of the two annual plant species Biscutella didyma and Bromus fasciculatus collected along an aridity gradient were grown under 12 irrigation treatments. Offspring germination was evaluated and related to environmental correlations between generations and their fitness consequences at the four study sites. One species exhibited strong seed dormancy that increased with unpredictability in seasonal precipitation. The parental effect on seed dormancy also increased proportionally with the environmental correlation between precipitation in the parental season and seedling density in the following season; this correlation increased from mesic to arid environments. Because fitness was negatively related to density, this parental effect may be adaptive. However, the lack of dormancy in the second species indicates that bet-hedging is not the only strategy for annual plants in arid environments. Our results provide the first evidence for clinal variation in the relative strength of parental effects along environmental gradients.


Association between prenatal exposure to perfluorinated compounds and symptoms of infections at age 1-4years among 359 children in the Odense Child Cohort.
Perfluorinated alkylated substances (PFAS) are persistent industrial chemicals that have resulted in global environmental exposures. Previous epidemiological studies have reported possible effects on the immune system after developmental PFAS exposure, but the possible impact on childhood infectious disease is unclear. To investigate the association between prenatal exposure to PFAS and symptoms of infections at age 1-4years. The Odense Child Cohort is an on-going prospective study on children's health, where serum concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorodecanoic acid (PFDA) and perfluorononanoic acid (PFNA) were measured in 649 pregnant women before gestational week 16. Of these women, 359 reported on symptoms of infection in their child every two weeks for a one-year period. The association between prenatal exposure to PFAS and the symptoms was estimated using a logistic regression model and a negative binomial regression model. For the latter, the outcome was reported as an incidence rate-ratio (IRR), and all models were adjusted for maternal age, educational level, parity and child age. On average, the children experienced symptoms of infection 23% of the time during one year. PFOS exposure in the high tertile compared to the low tertile was associated with a statistically significant increased proportion of days with fever (IRR: 1.65 (95% CI: 1.24, 2.18), P-trend<0.001) and an increased odds of experiencing days with fever above the median (OR: 2.35 (95% CI: 1.31, 4.11). The latter tendency was also apparent for PFOA (OR: 1.97 (95% CI: 1.07, 3.62). Further, higher concentrations of PFOS and PFOA tended to increase the number of episodes of co-occurrence of fever and coughing and fever and nasal discharge during the one-year study period. We found a positive association between prenatal exposure to PFOS and PFOA and the prevalence of fever, which may be a sensitive marker of infection. This finding is in agreement with an immunotoxic effect of prenatal exposure to PFAS. The wider implications for childhood infectious disease deserve attention.


Cytosolically expressed PrP GPI-signal peptide interacts with mitochondria.
We previously reported that PrP GPI-anchor signal peptide (GPI-SP) is specifically degraded by the proteasome. Additionally, we showed that the point mutation P238S, responsible for a genetic form of prion diseases, while not affecting the GPI-anchoring process, results in the accumulation of PrP GPI-SP, suggesting the possibility that PrP GPI-anchor signal peptide could play a role in neurodegenerative prion diseases. We now show that PrP GPI-SP, when expressed as a cytosolic peptide, is able to localize to the mitochondria and to induce mitochondrial fragmentation and vacuolarization, followed by loss in mitochondrial membrane potential, ultimately resulting in apoptosis. Our results identify the GPI-SP of PrP as a novel candidate responsible for the impairment in mitochondrial function involved in the synaptic pathology observed in prion diseases, establishing a link between PrP GPI-SP accumulation and neuronal death.


Cavernous Sinus Thrombosis due to Streptococcus mitis and Staphylococcus lugdunensis.
Cavernous Sinus Thrombosis (CST) is a rare, life-threatening condition that may result from the direct spread of infection from the nose, ears, teeth or sinuses. It is most commonly caused by Staphylococcus aureus and Streptococcus sp. We present a case of CST caused by Strepotococcus mitis and Staphylococcus lugdunensis. Early surgical intervention with aggressive medical management is needed as the syndrome carries a high mortality. To our knowledge this is the first case of CST associated with these two organisms.


Clinical significance of enteroviruses in serious summer febrile illnesses of children.
Enteroviruses are common causes of aseptic meningitis and nonspecific febrile illnesses in young children. During the summer-fall months, enterovirus-infected children are frequently evaluated in emergency room settings to rule out bacterial sepsis and/or meningitis. We sought to determine the clinical significance of enterovirus infections in children evaluated for serious febrile illnesses in pediatric emergency rooms during the summer-fall season. Children admitted to emergency rooms at four university teaching hospitals during a single summer-fall season who required blood culture and/or lumbar puncture to rule out bacterial sepsis/meningitis were prospectively studied. An extensive questionnaire was administered, and specimens of cerebrospinal fluid, serum, urine and throat were tested for enteroviruses by viral culture and PCR. Patients were followed to determine the duration, management and outcome of their illnesses. Of 203 patients studied 173 had no apparent explanation for their illness (e.g. bacterial sepsis, bacterial urinary tract infection, etc.). Of those 173 patients 79 (46%) were infected with enteroviruses, including 33 of 47 (70%) patients with aseptic meningitis, 13 of 25 (52%) patients with nonspecific febrile episodes and 33 of 101 (33%) patients with fever and focal findings (P < 0.0001 for aseptic meningitis vs. fever and focal findings; P = 0.0001 for aseptic meningitis vs. combined nonspecific febrile episodes and fever/focal patients). Among 119 hospitalized patients 65 (55%) were enterovirus-infected. Children < or =90 days of age were more likely to be enterovirus-infected (66 of 122; 54%) than children older than 90 days (13 of 51; 25%) (P = 0.0001). Enterovirus-infected children were more likely to be hospitalized as a result of the current emergency room visit (65 of 79 vs. 54 of 94; P = 0.0005) and were more likely to have had an additional hospitalization for the same illness (10 of 79 vs. 1 of 94; P = 0.003). Enterovirus-infected patients also had a shorter period from illness onset to presentation. Enterovirus-infected children were indistinguishable from those without enterovirus infection in their symptoms at onset, signs at presentation and total duration of illness (>7 days in both groups). Enterovirus-infected children were almost all treated with antibiotics (78 of 79; 99%), with 74 of 79 (94%) receiving parenteral antibiotics for a mean of 3.6 days. During the summer-fall months, 39% (79 of 203) of children for whom blood cultures and/or lumbar punctures were performed for suspected bacterial infection had enterovirus infection identified as the only explanation for their illness. Of those patients with no alternative diagnosis, enterovirus infection was confirmed in 46% (79 of 179). The majority of those patients requiring hospitalization were infected with enteroviruses. The use of PCR increases the number of children for whom a specific etiology of illness can be determined and may in the future reduce the hospitalization and use of unnecessary antibiotics in patients with enterovirus infections.


Dosimetry-based therapy in metastatic breast cancer patients using 90Y monoclonal antibody 170H.82 with autologous stem cell support and cyclosporin A.
Radioimmunoconjugates of 170H.82 (m170), a panadenocarcinoma monoclonal antibody, are effective for imaging primary and metastatic breast cancer. To evaluate m170 as a targeting agent for therapy, we developed (111)In- and 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10 tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-m170 immunoconjugates with 99% purity by molecular sieving and immunoreactivity comparable to unmodified antibody. (111)In-m170 pharmacokinetic studies were performed prior to each therapy to determine the maximum dose of 90Y-m170 that could be administered without exceeding a limit of 800 rad to the liver, lungs, or kidneys or 250 rad to the whole body or bone marrow for each of three cycles of treatment. Peripheral blood stem cells (PBSCs) were harvested and cyclosporin A (5 mg/kg twice daily) was administered as strategies to ameliorate myelosuppression and prevent the development of HAMA, respectively. An (111)In imaging/pharmacokinetic study was performed, and the 90Y dose was calculated and administered. The liver was the 90Y dose-limiting organ. The mean and range of calculated doses (in rad/mCi) for the five patients evaluated were as follows: whole body, 2.3 (2.1-2.4); liver, 17.8 (12.7-22.2); lung, 6.4 (4.8-7.2); kidney, 6.9 (6.3-11.5); marrow, 3.6 (1.9-4.4); and tumors (n = 25), 71.5 (14.1-141.5). Of the three patients treated, with doses of 37, 54, and 57 mCi of 90Y, one had a partial response, one had measurable tumor reduction but less than a partial response, and one had stable disease for more than 1 month. PBSCs prevented prolonged myelosuppression. The therapeutic responses, coupled with an absence, thus far, of significant adverse sequelae, suggest that this dosimetry-based approach combined with PBSCs may lead to effective therapy when higher 90Y doses are reached.


Methodological Comparisons of Heart Rate Variability Analysis in Patients With Type 2 Diabetes and Angiotensin Converting Enzyme Polymorphism.
Angiotensin converting enzyme (ACE) polymorphism has been shown to be important in hypertension progression and also in diabetes complications, especially associated with heart disease. Heart rate variability (HRV) is an established measure for classification of autonomic function regulating heart rate, based on the interbeat interval time series derived from a raw ECG recording. Results of this paper show that the length (number of interbeat intervals) and preprocessing of the tachogram affect the HRV analysis outcome. The comparison was based on tachogram lengths of 250, 300, 350, and 400 RR-intervals and five preprocessing approaches. An automated adaptive preprocessing method for the heart rate biosignal and tachogram length of 400 interbeat intervals provided the best classification. HRV results differed for the Type 2 Diabetes Mellitus (T2DM) group between the I/I genotype and the I/D and D/D genotypes, whereas for controls there was no significant difference in HRV between genotypes. Selecting an appropriate length of recording and automated preprocessing has confirmed that there is an effect of ACE polymorphism including the I/I genotype and that I/I should not be combined with I/D genotype in determining the extent of autonomic modulation of the heart rate.


Tools, harmonization and standardization procedures of the impact and outcome evaluation indices obtained during a kindergarten-based, family-involved intervention to prevent obesity in early childhood: the ToyBox-study.
The ToyBox-intervention is a kindergarten-based, family-involved intervention targeting multiple lifestyle behaviours in preschool children, their teachers and their families. This intervention was conducted in six European countries, namely Belgium, Bulgaria, Germany, Greece, Poland and Spain. The aim of this paper is to provide a descriptive overview of the harmonization and standardization procedures of the baseline and follow-up evaluation of the study (and substudies). Steps related to the study's operational, standardization and harmonization procedures as well as the impact and outcome evaluation assessment tools used are presented. Experiences from the project highlight the importance of safeguarding the measurement process to minimize data heterogeneity derived from potential measurement error and country-by-country differences. In addition, it was made clear that continuing quality control and support is an important component of such studies. For this reason, well-supported communication channels, such as regular email updates and teleconferences, and regular internal and external meetings to ensure smooth and accurate implementation were in place during the study. The ToyBox-intervention and its harmonized and standardized procedures can serve as a successful case study for future studies evaluating the efficacy of similar interventions.


Evaluation of two matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) systems for the identification of Candida species.
Candida spp. are responsible for severe infections in immunocompromised patients and those undergoing invasive procedures. The accurate identification of Candida species is important because emerging species can be associated with various antifungal susceptibility spectra. Conventional methods have been developed to identify the most common pathogens, but have often failed to identify uncommon species. Several studies have reported the efficiency of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for the identification of clinically relevant Candida species. In this study, we evaluated two commercially available MALDI-TOF systems, Andromas™ and Bruker Biotyper™, for Candida identification in routine diagnosis. For this purpose, we investigated 1383 Candida isolates prospectively collected in eight hospital laboratories during routine practice. MALDI-TOF MS results were compared with those obtained using conventional phenotypic methods. Analysis of rDNA gene sequences with internal transcribed regions or D1-D2 regions is considered the reference standard for identification. Both MALDI-TOF MS systems could accurately identify 98.3% of the isolates at the species level (1359/1383 for Andromas™; 1360/1383 for Bruker Biotyper™) vs. 96.5% for conventional techniques. Furthermore, whereas conventional methods failed to identify rare or emerging species, these were correctly identified by MALDI-TOF MS. Both MALDI-TOF MS systems are accurate and cost-effective alternatives to conventional methods for mycological identification of clinically relevant Candida species and should improve the diagnosis of fungal infections as well as patient management.


Understanding and responding to the cost and health impact of short-term health staffing in remote and rural Aboriginal and Torres Strait Islander community-controlled health services: a mixed methods study protocol.
Access to high-quality primary healthcare is limited for remote residents in Australia. Increasingly, remote health services are reliant on short-term or 'fly-in, fly-out/drive-in, drive-out' health workforce to deliver primary healthcare. A key strategy to achieving health service access equity, particularly evident in remote Australia, has been the development of Aboriginal Community Controlled Health Services (ACCHSs). This study aims to generate new knowledge about (1) the impact of short-term staffing in remote and rural ACCHSs on Aboriginal and Torres Strait Islander communities; (2) the potential mitigating effect of community control; and (3) effective, context-specific evidence-based retention strategies. This paper describes a 3-year, mixed methods study involving 12 ACCHSs across three states. The methods are situated within an evidence-based programme logic framework for rural and remote primary healthcare services. Quantitative data will be used to describe staffing stability and turnover, with multiple regression analyses to determine associations between independent variables (population size, geographical remoteness, resident staff turnover and socioeconomic status) and dependent variables related to patient care, service cost, quality and effectiveness. Qualitative assessment will include interviews and focus groups with clinical staff, clinic users, regionally-based retrieval staff and representatives of jurisdictional peak bodies for the ACCHS sector, to understand the impact of short-term staff on quality and continuity of patient care, as well as satisfaction and acceptability of services. The study has ethics approval from the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (project number DR03171), Central Australian Human Research Ethics Committee (CA-19-3493), Western Australian Aboriginal Health Ethics Committee (WAAHEC-938) and Far North Queensland Human Research Ethics Committee (HREC/2019/QCH/56393). Results will be disseminated through peer-reviewed journals, the project steering committee and community/stakeholder engagement activities to be determined by each ACCHS.


Multimodal communication and language origins: integrating gestures and vocalizations.
The presence of divergent and independent research traditions in the gestural and vocal domains of primate communication has resulted in major discrepancies in the definition and operationalization of cognitive concepts. However, in recent years, accumulating evidence from behavioural and neurobiological research has shown that both human and non-human primate communication is inherently multimodal. It is therefore timely to integrate the study of gestural and vocal communication. Herein, we review evidence demonstrating that there is no clear difference between primate gestures and vocalizations in the extent to which they show evidence for the presence of key language properties: intentionality, reference, iconicity and turn-taking. We also find high overlap in the neurobiological mechanisms producing primate gestures and vocalizations, as well as in ontogenetic flexibility. These findings confirm that human language had multimodal origins. Nonetheless, we note that in great apes, gestures seem to fulfil a carrying (i.e. predominantly informative) role in close-range communication, whereas the opposite holds for face-to-face interactions of humans. This suggests an evolutionary shift in the carrying role from the gestural to the vocal stream, and we explore this transition in the carrying modality. Finally, we suggest that future studies should focus on the links between complex communication, sociality and cooperative tendency to strengthen the study of language origins.


Pentoxifylline for intermittent claudication.
Intermittent claudication (IC) is a symptom of peripheral arterial occlusive disease (PAD). It is associated with high morbidity and mortality. Pentoxifylline is one of many drugs used to treat IC. Pentoxifylline decreases blood viscosity, improves erythrocyte flexibility, and increases microcirculatory flow and tissue oxygen concentration.Many studies have evaluated the efficacy of pentoxifylline in treating PAD but the results of these studies are very variable. To determine the efficacy of pentoxifylline in improving the walking capacity (that is pain-free walking distance and the total (absolute, maximum) walking distance) of patients with stable intermittent claudication, Fontaine stage II. The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched January 2011) and CENTRAL (2011, Issue 1). In addition, we searched MEDLINE (Week 2 January 2011) and EMBASE (2011 Week 03). ClinicalTrials.gov and Current Controlled Trials were searched for ongoing or unpublished trials. All double blind, randomised controlled trials (RCTs) comparing pentoxifylline to placebo or any other pharmacological intervention in patients with IC Fontaine stage II. Included studies were assessed separately by two review authors. Data were matched and disagreements resolved by discussion. The quality of the studies was assessed using the Jadad score and the Cochrane risk of bias tool. Results relating to pain-free walking distance (PFWD) and total walking distance (TWD) were collected. Studies were compared based on the duration and dose of pentoxifylline. Twenty-three studies with 2816 participants were included in this review. There was considerable heterogeneity between the included studies with regards to multiple variables including duration of treatment, dose of pentoxifylline, baseline walking distance and patient characteristics, and therefore pooled analysis was not possible. The quality of the included studies was generally low. There was very large variability in the reported findings between the individual studies. In a total of 17 studies which compared pentoxifylline with placebo, of which 14 reported TWD and 11 reported PFWD, the difference in percentage improvement in TWD for pentoxifylline over placebo ranged from 1.2% to 155.9%, and for PFWD the difference ranged from -33.8% to 73.9%. Testing for statistical significance of these results was generally not possible due to the lack of data. There was no statistically significant difference in ankle brachial pressure index (ABI) between the pentoxifylline and placebo groups. Pentoxifylline was generally well tolerated. Given the generally poor quality of the published studies and the large degree of heterogeneity in the interventions and the results, the overall benefit of pentoxifylline for patients with Fontaine class II intermittent claudication remains uncertain. Pentoxifylline is generally well tolerated. Based on the totality of the available evidence, it is possible that pentoxifylline could have a place in the treatment of IC as a means of improving walking distance and as a complimentary treatment assuming all other essential measures such as lifestyle change, exercise and treatment for secondary prevention have been taken into account. However, the response to pentoxifylline should be assessed on an individual basis.


Transsexual prostitution in New Zealand: predominance of persons of Maori extraction.
Information concerning the racial distribution, family background, sexual history, education, and employment status of 27 New Zealand, male-to-female preoperative transsexual prostitutes was obtained by interview and questionnaire. Subjects lived in Wellington, New Zealand, and Sydney, Australia. Subjects recalled childhoods with maternal dominance, paternal absence, being youngest sons, and being dressed in girls' clothes by female relatives. Further, an early history of homosexual intercourse and cross-dressing behavior occurred significantly often. Moreover, it was apparent that the Maori race, which forms 9.0% of the total New Zealand population, was disproportionately represented; approximately 90% of the transsexual prostitute population in Wellington is Maori. Various explanations are offered for the racial inequality. It is concluded that cultural influences have an effect on the number of transsexual prostitutes in New Zealand. Further research is needed to assess whether these factors also influence the etiology and development of transsexualism.


Analysis of Tie2-expressing monocytes (TEM) in patients with colorectal cancer.
Tie2-expressing monocytes (TEM) promote tumor angiogenesis and growth in experimental cancer models. The role of TEM in cancer patients is unknown. We studied TEM in healthy volunteers and colorectal cancer (CRC) patients. Although TEM were detectable in the blood and tumor lesions of CRC patients, their frequency and functional phenotype showed no correlation with levels of angiopoietin-2 or vascular endothelial growth factor, microvessel density, tumor markers, tumor stage, or outcome of antiangiogenic therapy. These unexpected findings are at odds with murine tumor models and question the diagnostic or therapeutic value of TEM in human cancer.


Regulation of enzyme activities in Drosophila: genetic variation affecting induction of glucose 6-phosphate and 6-phosphogluconate dehydrogenase in larvae.
The genetic basis of modulation by dietary sucrose of the enzyme activities glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) activities in third instar larvae of Drosophila melanogaster was investigated, using isogenic lines derived from wild populations. Considerable genetically determined variation in response was detected among lines that differed only in their third chromosome constitution. Comparison of cross-reacting material between a responding and a nonresponding line showed that the G6PD activity variation is due to changes in G6PD protein level. These differences in responses are localized in the fat body, with 300 mM sucrose in the diet resulting in a sixfold stimulation of G6PD activity and a fourfold one of 6PGD in the line showing the strongest response. In this tissue, the responses of the two enzymes are closely correlated with one another. Using recombinant lines, we obtained data that suggested the existence of more than one gene on chromosome III involved in the regulation of G6PD in the fat body, and at least one of these genes affects the level of 6PGD as well.


The Acute COPD Exacerbation Prediction Tool (ACCEPT): a modelling study.
Accurate prediction of exacerbation risk enables personalised care for patients with chronic obstructive pulmonary disease (COPD). We developed and validated a generalisable model to predict individualised rate and severity of COPD exacerbations. In this risk modelling study, we pooled data from three COPD trials on patients with a history of exacerbations. We developed a mixed-effect model to predict exacerbations over 1 year. Severe exacerbations were those requiring inpatient care. Predictors were history of exacerbations, age, sex, body-mass index, smoking status, domiciliary oxygen therapy, lung function, symptom burden, and current medication use. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE), a multicentre cohort study, was used for external validation. The development dataset included 2380 patients, 1373 (58%) of whom were men. Mean age was 64·7 years (SD 8·8). Mean exacerbation rate was 1·42 events per year and 0·29 events per year were severe. When validated against all patients with COPD in ECLIPSE (mean exacerbation rate was 1·20 events per year, 0·27 events per year were severe), the area-under-curve (AUC) was 0·81 (95% CI 0·79-0·83) for at least two exacerbations and 0·77 (95% CI 0·74-0·80) for at least one severe exacerbation. Predicted exacerbation and observed exacerbation rates were similar (1·31 events per year for all exacerbations and 0·25 events per year for severe exacerbations vs 1·20 events per year and 0·27 events per year). In ECLIPSE, in patients with previous exacerbation history (mean exacerbation rate was 1·82 events per year, 0·40 events per year were severe), AUC was 0·73 (95% CI 0·70-0·76) for two or more exacerbations and 0·74 (95% CI 0·70-0·78) for at least one severe exacerbation. Calibration was accurate for severe exacerbations (predicted 0·37 events per year vs observed 0·40 events per year) and all exacerbations (predicted 1·80 events per year vs observed 1·82 events per year). This model can be used as a decision tool to personalise COPD treatment and prevent exacerbations. Canadian Institutes of Health Research.


Impact of preoperative calculation of nephron volume loss on future of partial nephrectomy techniques; planning a strategic roadmap for improving functional preservation and securing oncological safety.
To assess the correlation of the resected and ischaemic volume (RAIV), which is a preoperatively calculated volume of nephron loss, with the amount of postoperative renal function (PRF) decline after minimally invasive partial nephrectomy (PN) in a multi-institutional dataset. We identified 348 patients from March 2005 to December 2013 at six institutions. Data on all cases of laparoscopic (n = 85) and robot-assisted PN (n = 263) performed were retrospectively gathered. Univariable and multivariable linear regression analyses were used to identify the associations between various time points of PRF and the RAIV, as a continuous variable. The mean (sd) RAIV was 24.2 (29.2) cm3 . The mean preoperative estimated glomerular filtration rate (eGFR) and the eGFRs at postoperative day 1, 6 and 36 months after PN were 91.0 and 76.8, 80.2 and 87.7 mL/min/1.73 m2 , respectively. In multivariable linear regression analysis, the amount of decline in PRF at follow-up was significantly correlated with the RAIV (β 0.261, 0.165, 0.260 at postoperative day 1, 6 and 36 months after PN, respectively). This study has the limitation of its retrospective nature. Preoperatively calculated RAIV significantly correlates with the amount of decline in PRF during long-term follow-up. The RAIV could lead our research to the level of prediction of the amount of PRF decline after PN and thus would be appropriate for assessing the technical advantages of emerging techniques.


The landscape of somatic copy-number alteration across human cancers.
A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappaBeta pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.


T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection.
Innate and adaptive defense mechanisms protect the respiratory system from attack by microbes. Here, we present evidence that the bitter taste receptor T2R38 regulates the mucosal innate defense of the human upper airway. Utilizing immunofluorescent and live cell imaging techniques in polarized primary human sinonasal cells, we demonstrate that T2R38 is expressed in human upper respiratory epithelium and is activated in response to acyl-homoserine lactone quorum-sensing molecules secreted by Pseudomonas aeruginosa and other gram-negative bacteria. Receptor activation regulates calcium-dependent NO production, resulting in stimulation of mucociliary clearance and direct antibacterial effects. Moreover, common polymorphisms of the TAS2R38 gene were linked to significant differences in the ability of upper respiratory cells to clear and kill bacteria. Lastly, TAS2R38 genotype correlated with human sinonasal gram-negative bacterial infection. These data suggest that T2R38 is an upper airway sentinel in innate defense and that genetic variation contributes to individual differences in susceptibility to respiratory infection.


Genome-Wide Analysis of Domain-Swap Predicted Products in the Genome of Anti-Stress Medicinal Plant: Ocimum tenuiflorum.
Computational approaches to high-throughput data are gaining importance because of explosion of sequences in the post-genomic era. This explosion of sequence data creates a huge gap among the domains of sequence structure and function, since the experimental techniques to determine the structure and function are very expensive, time taking, and laborious in nature. Therefore, there is an urgent need to emphasize on the development of computational approaches in the field of biological systems. Engagement of proteins in quaternary arrangements, such as domain swapping, might be relevant for higher compatibility of such genes at stress conditions. In this study, the capacity to engage in domain swapping was predicted from mere sequence information in the whole genome of holy Basil (Ocimum tenuiflorum), which is well known to be an anti-stress agent. Approximately, one-fourth of the proteins of O tenuiflorum are predicted to undergo three-dimensional (3D)-domain swapping. Furthermore, function annotation was carried out on all the predicted domain-swap sequences from the O tenuiflorum and Arabidopsis thaliana for their distribution in different Pfam protein families and gene ontology (GO) terms. These domain-swapped protein sequences are associated with many Pfam protein families with a wide range of GO annotation terms. A comparative analysis of domain-swap-predicted sequences in O tenuiflorum with gene products in A thaliana reveals that around 26% (2522 sequences) are close homologues across the 2 genomes. Functional annotation of predicted domain-swapped sequences infers that predicted domain-swap sequences are involved in diverse molecular functions, such as in gene regulation of abiotic stress conditions and adaptation to different environmental niches. Finally, the positively predicted sequences of A thaliana and O tenuiflorum were also examined for their presence in stress regulome, as recorded in our STIFDB database, to check the involvement of these proteins in different abiotic stresses.


The next step in health behavior research: the need for ecological moderation analyses - an application to diet and physical activity at childcare.
The ecological perspective holds that human behavior depends on the interaction of different environmental factors and personal characteristics, but it lacks validation and operationalization. In the current paper, an ecological view was adopted to examine the interactive impact of several ecological systems on children's dietary intake and physical activity at childcare or similar facilities. The ecological view was operationalized into three types of interaction: 1) interaction between types of childcare environment (physical, social, political, economic); 2) interaction between micro-systems (the childcare and home environment) in meso-systems; and 3) interaction between childcare environment and child characteristics. The predictive value of each of these interactions was tested based on a systematic review of the literature. Several studies support the hypothesis that the influence of the childcare environment on children's physical activity and diet is moderated by child characteristics (age, gender), but interaction between environmental types as well as between micro-systems is hardly examined in the field of behavioral nutrition and physical activity. Qualitative studies and general child development research provide some valuable insights, but we advocate quantitative research adopting an ecological perspective on environmental influences. Empirical studies operationalizing a true ecological view on diet and physical activity are scarce. Theorizing and assessment of interaction is advocated to become common practice rather than an exception in behavioral nutrition and physical activity research, in order to move the field forward.


Population structure of Atlantic mackerel (Scomber scombrus).
Atlantic mackerel (Scomber scombrus) occurs on both sides of the north Atlantic and has traditionally been grouped into 5 spawning components, some of which were thought to be isolated natal homing stocks. Previous studies have provided no evidence for cross Atlantic migration and no or weak support for isolated spawning components within either side of the North Atlantic. We question the de-facto accepted hypothesis of isolation between spawning components on the basis of spawning and age distribution data. The spawning intensities, proxied by larval abundances, are negatively correlated between the North Sea and Celtic Sea, which indicates that the two spawning components may be connected by straying individuals. This finding is based on unique larvae samples collected before the collapse of North Sea component, thus showing that the exchange is not a recent phenomenon due to the collapse. The analyses of old as well as more recent age distributions show that strong year classes spread into other areas where they spawn as adults ("twinning"). Our findings are in accordance with the lack of solid evidence for stock separation from previous analyses of tagging data, genetics, ectoparasite infections, otolith shapes, and blood phenotypes. Because no method has been able to identify the origin of spawning mackerel unequivocally from any of the traditional spawning components, and in the light of our results, we conclude that straying outweighs spatial segregation. We propose a new model where the population structure of mackerel is described as a dynamic cline, rather than as connected contingents. Temporal changes in hydrography and mackerel behavior may affect the steepness of the cline at various locations. The new interpretation of the population structure of Atlantic mackerel has important implications for research, assessment and management.


Further development and validation of the Unhelpful Thoughts and Beliefs About Stuttering (UTBAS) scales: relationship to anxiety and social phobia among adults who stutter.
In an initial validation study, the Unhelpful Thoughts and Beliefs About Stuttering (UTBAS I) scale, demonstrated excellent psychometric properties as a self-report measure of the frequency of unhelpful cognitions associated with social anxiety for adults who stutter. The aim was to further validate the original UTBAS I scale, and to develop two additional scales to assess beliefs (UTBAS II) and anxiety (UTBAS III) associated with negative thoughts. A total of 140 adults seeking speech-restructuring treatment for stuttering completed the original UTBAS I scale, the newly developed UTBAS II and III scales, and self-report measures of psychological functioning. Participants also completed a first-stage screener for the presence of anxious personality disorder, and a diagnostic assessment to evaluate the presence of social phobia, according to criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the International Classification of Diseases (ICD-10). The mean UTBAS I score for the present sample did not differ significantly from the mean score reported in the original UTBAS I validation study. Convergent validity was confirmed by significant correlations between the UTBAS Total score and all anxiety-related measures. Discriminant validity was established by the absence of strong correlations between the UTBAS Total score and some of the self-report measures of unrelated constructs, although it was found to tap into the negative cognitions associated with depression and life problems. Approximately one-quarter of participants met criteria for a diagnosis of DSM-IV or ICD-10 social phobia (23.5% and 27.2% respectively), and nearly one-third met first-stage screening criteria for anxious personality disorder (30%). The mean UTBAS scores for participants who met criteria for these disorders were significantly higher than scores for participants who did not, confirming known-groups validity. The present study demonstrates the validity and utility of the UTBAS scales in assessing negative cognitions associated with speech-related anxiety among adults who stutter. Results also confirm previous evidence of a high rate of social phobia among adults who stutter, and reveal that the UTBAS discriminates between adults with and without social phobia. In terms of clinical applications, the UTBAS scales could be used to screen for indicators of social phobia among adults who stutter, and may prove useful in identifying negative cognitions which have the potential to impact treatment outcomes.


Fullerene modification CdSe/TiO2 and modification of photocatalytic activity under visible light.
CdSe, CdSe-TiO2, and CdSe-C60/TiO2 composites were prepared using sol-gel method, and their photocatalytic activity was evaluated by measuring the degradation of rhodamine B solutions under visible light. The surface area, surface structure, crystal phase, and elemental identification of these composites were characterized by nitrogen adsorption isotherms, scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX), and UV-visible (vis) absorption spectrophotometry. XRD showed that the CdSe-C60/TiO2 composite contained a typical single and clear anatase phase. SEM of the CdSe-C60/TiO2 composites revealed a homogenous composition in the particles. EDX revealed the presence of C and Ti with strong Cd and Se peaks in the CdSe-C60/TiO2 composite. The degradation of dye was determined by UV-vis spectrophotometry. An increase in photocatalytic activity was observed and attributed to an increase in the photoabsorption effect by fullerene and the cooperative effect of the CdSe. The repeatability of photocatalytic activity was also tested in order to investigate the stability of C60 and CdS-C60/TiO2 composites.


Strand-specific RNA-seq reveals ordered patterns of sense and antisense transcription in Bacillus anthracis.
Although genome-wide transcriptional analysis has been used for many years to study bacterial gene expression, many aspects of the bacterial transcriptome remain undefined. One example is antisense transcription, which has been observed in a number of bacteria, though the function of antisense transcripts, and their distribution across the bacterial genome, is still unclear. Single-stranded RNA-seq results revealed a widespread and non-random pattern of antisense transcription covering more than two thirds of the B. anthracis genome. Our analysis revealed a variety of antisense structural patterns, suggesting multiple mechanisms of antisense transcription. The data revealed several instances of sense and antisense expression changes in different growth conditions, suggesting that antisense transcription may play a role in the ways in which B. anthracis responds to its environment. Significantly, genome-wide antisense expression occurred at consistently higher levels on the lagging strand, while the leading strand showed very little antisense activity. Intrasample gene expression comparisons revealed a gene dosage effect in all growth conditions, where genes farthest from the origin showed the lowest overall range of expression for both sense and antisense directed transcription. Additionally, transcription from both strands was verified using a novel strand-specific assay. The variety of structural patterns we observed in antisense transcription suggests multiple mechanisms for this phenomenon, suggesting that some antisense transcription may play a role in regulating the expression of key genes, while some may be due to chromosome replication dynamics and transcriptional noise. Although the variety of structural patterns we observed in antisense transcription suggest multiple mechanisms for antisense expression, our data also clearly indicate that antisense transcription may play a genome-wide role in regulating the expression of key genes in Bacillus species. This study illustrates the surprising complexity of prokaryotic RNA abundance for both strands of a bacterial chromosome.


Heterogeneity of Glycan Processing on Trimeric SARS-CoV-2 Spike Protein Revealed by Charge Detection Mass Spectrometry.
The heterogeneity associated with glycosylation of the 66 N-glycan sites on the protein trimer making up the spike (S) region of the SARS-CoV-2 virus has been assessed by charge detection mass spectrometry (CDMS). CDMS allows simultaneous measurement of the mass-to-charge ratio and charge of individual ions, so that mass distributions can be determined for highly heterogeneous proteins such as the heavily glycosylated S protein trimer. The CDMS results are compared to recent glycoproteomics studies of the structure and abundance of glycans at specific sites. Interestingly, average glycan masses determined by "top-down" CDMS measurements are 35-47% larger than those obtained from the "bottom-up" glycoproteomics studies, suggesting that the glycoproteomic measurements underestimated the abundances of larger, more-complex glycans. Moreover, the distribution of glycan masses determined by CDMS is much broader than the distribution expected from the glycoproteomics studies, assuming that glycan processing on each trimer is not correlated. The breadth of the glycan mass distribution therefore indicates heterogeneity in the extent of glycan processing of the S protein trimers, with some trimers being much more heavily processed than others. This heterogeneity may have evolved as a way of further confounding the host's immune system.


Efficacy and safety of oral NSAIDs and analgesics in the management of osteoarthritis: Evidence from real-life setting trials and surveys.
Non-steroidal anti-inflammatory drugs (NSAIDs) are at the cornerstone of treatment for osteoarthritis (OA). In recent years, the widespread use of oral NSAIDs has been called into question due to the appearance of significant upper gastrointestinal (GI) complications and cardiovascular (CV) adverse events (AEs). However, NSAIDs are non-homogeneous, and there are noticeable differences between them in AE risk for GI and CV events. Nevertheless, if properly prescribed oral NSAIDs can provide an effective and safe treatment for OA in real-life situations. The identification of patients with significant CV and/or GI risk is critical, and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm provides guidance on appropriate treatments for OA patients with elevated risk. Among non-selective NSAIDs, ibuprofen and naproxen seem preferable to diclofenac, the latter being associated with higher CV risk. Recommendation has been made by some that naproxen may be the preferred agent in patients at high CV risk because of its lower risk of CV events. Low dose celecoxib (200mg/day) is also associated with a lower risk of CV events compared with other coxibs. In addition, drugs with a demonstrated low GI risk profile may be of benefit, such as coxibs and nabumetone. Among patients who fail to respond adequately to sequential ESCEO algorithm Step 1 and Step 2 treatments, the short-term use of weak opioids, such as tramadol, for severely symptomatic OA patients is recommended. Although studies exploring the efficacy of tramadol in OA are limited, there is good evidence that tramadol works if prescribed properly. The sustained-release (SR) formulation of tramadol is preferred as it avoids the peak plasma concentrations reached with immediate-release tramadol, and is believed to reduce the incidence of AEs. Furthermore, slow upwards titration of tramadol SR is recommended to improve tolerability and minimize treatment discontinuations.


TRPA1 in bradykinin-induced mechanical hypersensitivity of vagal C fibers in guinea pig esophagus.
Bradykinin (BK) activates sensory nerves and causes hyperalgesia. Transient receptor potential A1 (TRPA1) is expressed in sensory nerves and mediates cold, mechanical, and chemical nociception. TRPA1 can be activated by BK. TRPA1 knockout mice show impaired responses to BK and mechanical nociception. However, direct evidence from sensory nerve terminals is lacking. This study aims to determine the role of TRPA1 in BK-induced visceral mechanical hypersensitivity. Extracellular recordings of action potentials from vagal nodose and jugular neurons are performed in an ex vivo guinea pig esophageal-vagal preparation. Peak frequencies of action potentials of afferent nerves evoked by esophageal distension and chemical perfusion are recorded and compared. BK activates most nodose and all jugular C fibers. This activation is repeatable and associated with a significant increase in response to esophageal distension, which can be prevented by the B2 receptor antagonist WIN64338. TRPA1 agonist allyl isothiocyanate (AITC) activates most BK-positive nodose and jugular C fibers. This is associated with a transient loss of response to mechanical distensions and desensitization to a second AITC perfusion. Desensitization with AITC and pretreatment with TRPA1 inhibitor HC-030031 both inhibit BK-induced mechanical hypersensitivity but do not affect BK-evoked activation in nodose and jugular C fibers. In contrast, esophageal vagal afferent Adelta fibers do not respond to BK or AITC and fail to show mechanical hypersensitivity after BK perfusion. This provides the first evidence directly from visceral sensory afferent nerve terminals that TRPA1 mediates BK-induced mechanical hypersensitivity. This reveals a novel mechanism of visceral peripheral sensitization.


A Single Human VH-gene Allows for a Broad-Spectrum Antibody Response Targeting Bacterial Lipopolysaccharides in the Blood.
B cell receptors (BCRs) display a combination of variable (V)-gene-encoded complementarity determining regions (CDRs) and adaptive/hypervariable CDR3 loops to engage antigens. It has long been proposed that the former tune for recognition of pathogens or groups of pathogens. To experimentally evaluate this within the human antibody repertoire, we perform immune challenges in transgenic mice that bear diverse human CDR3 and light chains but are constrained to different human VH-genes. We find that, of six commonly deployed VH sequences, only those CDRs encoded by IGHV1-2∗02 enable polyclonal antibody responses against bacterial lipopolysaccharide (LPS) when introduced to the bloodstream. The LPS is from diverse strains of gram-negative bacteria, and the VH-gene-dependent responses are directed against the non-variable and universal saccrolipid substructure of this antigen. This reveals a broad-spectrum anti-LPS response in which germline-encoded CDRs naturally hardwire the human antibody repertoire for recognition of a conserved microbial target.


The use of blood biomarkers to predict poor outcome after acute transient ischemic attack or ischemic stroke.
The prediction of death or disability ("poor outcome") after stroke by validated clinical models might be improved by the addition of blood biomarker measurements. We investigated whether such measurements improved the classification of patients into 4 categories of predicted risk of poor outcome: very high, intermediate high, intermediate low, and very low. We prospectively recruited symptomatic patients within 24 hours of ischemic cerebrovascular events. We measured clinical prognostic variables in each patient. We drew blood soon after admission and measured markers of inflammation, thrombosis, cardiac strain, and cerebral damage. We assessed poor outcome at 3 months with the modified Rankin Scale and recovery of symptoms at 24 hours. We measured the association between blood marker levels and poor outcome after adjustment for stroke severity and age with multivariate logistic regression. Where these associations were statistically significant, we calculated the net reclassification index. We recruited 270 patients with acute ischemic cerebrovascular events. At 3 months, 112 patients had a poor outcome. After adjustment for stroke severity and age, only interleukin-6 and N-terminal pro-brain natriuretic peptide were significantly associated with poor outcome. The addition of either interleukin-6 or N-terminal pro-brain natriuretic peptide to National Institutes of Health Stroke Scale and age did not improve the prediction of a poor outcome. Neither interleukin-6 nor N-terminal pro-brain natriuretic peptide had sufficient predictive power to be of clinical use to predict poor outcome after stroke. The search for better markers to improve the classification of patients across clinically relevant boundaries of predicted probabilities of outcome events needs to continue.


Characterization of Borrelia lusitaniae sp. nov. by 16S ribosomal DNA sequence analysis.
We determined the complete sequence of the rrs gene from five strains of genomic species PotiB2. Both distance and parsimony methods were used to infer the evolutionary relationships of the rrs gene sequence of this genomic species in comparison with the rrs gene sequence of Borrelia valaisiana and the rrs gene sequences of Borrelia burgdorferi sensu lato species obtained from sequence databases. The phylogenetic analysis revealed that the genomic species PotiB2 strains clustered in a separate lineage, which was consistent with data from previous DNA-DNA hybridization experiments (D. Postic, M. V. Assous, P. A. D. Grimont, and G. Baranton, Int. J. Syst. Bacteriol. 44:743-752, 1994). A PCR-restriction fragment length polymorphism analysis was used to identify genomic species PotiB2 and to differentiate it from B. burgdorferi sensu lato species. Moreover, signature nucleotide positions were identified for each B. burgdorferi sensu lato species. In accordance with DNA relatedness values, our findings suggest that genomic species PotiB2 can be more clearly defined and identified, and we propose that it should be referred to as a new species, Borrelia lusitaniae. The type strain is PotiB2.


Epigenetic Modulation as a Therapeutic Prospect for Treatment of Autoimmune Rheumatic Diseases.
Systemic inflammatory rheumatic diseases are considered as autoimmune diseases, meaning that the balance between recognition of pathogens and avoidance of self-attack is impaired and the immune system attacks and destroys its own healthy tissue. Treatment with conventional Disease Modifying Antirheumatic Drugs (DMARDs) and/or Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) is often associated with various adverse reactions due to unspecific and toxic properties of those drugs. Although biologic drugs have largely improved the outcome in many patients, such drugs still pose significant problems and fail to provide a solution to all patients. Therefore, development of more effective treatments and improvements in early diagnosis of rheumatic diseases are badly needed in order to increase patient's functioning and quality of life. The reversible nature of epigenetic mechanisms offers a new class of drugs that modulate the immune system and inflammation. In fact, epigenetic drugs are already in use in some types of cancer or cardiovascular diseases. Therefore, epigenetic-based therapeutics that control autoimmunity and chronic inflammatory process have broad implications for the pathogenesis, diagnosis, and management of rheumatic diseases. This review summarises the latest information about potential therapeutic application of epigenetic modification in targeting immune abnormalities and inflammation of rheumatic diseases.


Combined Chlorophyll Fluorescence and Transcriptomic Analysis Identifies the P3/P4 Transition as a Key Stage in Rice Leaf Photosynthetic Development.
Leaves are derived from heterotrophic meristem tissue that, at some point, must make the transition to autotrophy via the initiation of photosynthesis. However, the timing and spatial coordination of the molecular and cellular processes underpinning this switch are poorly characterized. Here, we report on the identification of a specific stage in rice (Oryza sativa) leaf development (P3/P4 transition) when photosynthetic competence is first established. Using a combined physiological and molecular approach, we show that elements of stomatal and vascular differentiation are coordinated with the onset of measurable light absorption for photosynthesis. Moreover, by exploring the response of the system to environmental perturbation, we show that the earliest stages of rice leaf development have significant plasticity with respect to elements of cellular differentiation of relevance for mature leaf photosynthetic performance. Finally, by performing an RNA sequencing analysis targeted at the early stages of rice leaf development, we uncover a palette of genes whose expression likely underpins the acquisition of photosynthetic capability. Our results identify the P3/P4 transition as a highly dynamic stage in rice leaf development when several processes for the initiation of photosynthetic competence are coordinated. As well as identifying gene targets for future manipulation of rice leaf structure/function, our data highlight a developmental window during which such manipulations are likely to be most effective.


Exercise ASKARI SERPENT: enabling clinical data collection during exercises and operations to support future contingency planning and assurance of category-based reporting systems.
Exercise ASKARI SERPENT (Ex AS) is a British Army exercise that provides primary healthcare (PHC) to Kenyan civilians in support of local health authorities. It is conducted in partnership with the Kenya Defence Force Medical Services (KDFMS). Accurate epidemiological data is critical in planning the exercise and for any future short-notice contingency operations in similar environments. This paper reports epidemiological data for Ex AS using a novel data collection system. PHC on Ex AS was delivered by trained and validated combat medical technicians (CMTs) using a set of Read-coded protocols. The CMTs were also directly supported and supervised by medical officers and nurses. A total of 3093 consultations were conducted over a 16-day period. Of these, 2707 (87.5%) consultations fell within the remit of the CMT protocols, with only 386 consultations (12.5%) being conducted exclusively by the medical officers or nurses. A Read-coded matrix built on CMT protocols is a simple and useful tool, particularly in civilian populations, for collecting morbidity data with the vast majority of conditions accounted for in the protocols. It is anticipated that such a system can better inform training, manning, medical material and pharmaceutical procurement than current category-based morbidity surveillance systems such as EPINATO (NATO epidemiological data). There is clear advantage to directly linking data capture to treatment algorithms. Accuracy, both in terms of numbers and condition, is likely improved. Data is also captured contemporaneously rather than after indeterminate time. Read coding has the added benefit of being an established electronic standard. In addition, the system would support traditional reporting methods such as EPINATO by providing increased assurance.


Treatment of Symptomatic Convergence Insufficiency in Children Enrolled in the Convergence Insufficiency Treatment Trial-Attention & Reading Trial: A Randomized Clinical Trial.
These data confirm the effectiveness of office-based vergence/accommodative therapy for improving convergence in children with symptomatic convergence insufficiency. They also highlight the importance of using a primary outcome measure that is as objective as possible rather than relying solely on self-reported symptoms for studies of binocular vision in children. The purpose of this study was to report changes in clinical signs and symptoms of convergence insufficiency (secondary outcome measures) from a multicenter clinical trial (Convergence Insufficiency Treatment Trial-Attention & Reading Trial [CITT-ART]) evaluating the effectiveness of vergence/accommodative therapy for improving reading and attention in children with symptomatic convergence insufficiency. Three hundred eleven children aged 9 to 14 years with symptomatic convergence insufficiency were randomly assigned to 16 weeks of office-based vergence/accommodative therapy or to placebo therapy. Improvements in (1) near point of convergence (NPC), (2) positive fusional vergence (PFV), and (3) self-reported symptoms (Convergence Insufficiency Symptom Survey [CISS] score) were compared after 16 weeks of treatment. Mean NPC improved 10.4 cm in the vergence/accommodative and 6.2 cm in the placebo therapy group (mean difference of -4.2 cm [95% confidence interval {CI}, -5.2 to -3.2 cm; P < .001]); mean PFV increased 23.2 and 8.8Δ in the vergence/accommodative and placebo therapy groups, respectively (mean difference of 14.4Δ [95% CI, 12.1 to 16.8Δ; P < .001]). The mean CISS score improved 11.8 and 10.4 points in the vergence/accommodative and placebo therapy groups, respectively (mean difference of 1.5 points [95% CI, -3.8 to +0.8 points; P = .21]). Our results demonstrate that office-based vergence/accommodative therapy is effective for improving the NPC and PFV in children with symptomatic convergence insufficiency. However, given that both treatment groups had a similar reduction in self-reported symptoms, it may not be prudent to use the CISS alone as a measure of successful treatment.


Hepatocellular Carcinoma Is Associated With Gut Microbiota Profile and Inflammation in Nonalcoholic Fatty Liver Disease.
The gut-liver axis plays a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), which is the third leading cause of hepatocellular carcinoma (HCC) worldwide. However, the link between gut microbiota and hepatocarcinogenesis remains to be clarified. The aim of this study was to explore what features of the gut microbiota are associated with HCC in patients with cirrhosis and NAFLD. A consecutive series of patients with NAFLD-related cirrhosis and HCC (group 1, 21 patients), NAFLD-related cirrhosis without HCC (group 2, 20 patients), and healthy controls (group 3, 20 patients) was studied for gut microbiota profile, intestinal permeability, inflammatory status, and circulating mononuclear cells. We finally constructed a model depicting the most relevant correlations among these features, possibly involved in hepatocarcinogenesis. Patients with HCC showed increased levels of fecal calprotectin, while intestinal permeability was similar to patients with cirrhosis but without HCC. Plasma levels of interleukin 8 (IL8), IL13, chemokine (C-C motif) ligand (CCL) 3, CCL4, and CCL5 were higher in the HCC group and associated with an activated status of circulating monocytes. The fecal microbiota of the whole group of patients with cirrhosis showed higher abundance of Enterobacteriaceae and Streptococcus and a reduction in Akkermansia. Bacteroides and Ruminococcaceae were increased in the HCC group, while Bifidobacterium was reduced. Akkermansia and Bifidobacterium were inversely correlated with calprotectin concentration, which in turn was associated with humoral and cellular inflammatory markers. A similar behavior was also observed for Bacteroides. Conclusion: Our results suggest that in patients with cirrhosis and NAFLD the gut microbiota profile and systemic inflammation are significantly correlated and can concur in the process of hepatocarcinogenesis.


Strategic funding priorities in the pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT).
Substantial changes in Pharmaceutical R&D strategy are required to address existing issues of low productivity, imminent patent expirations and pressures on pricing. Moves towards personalized healthcare and increasing diversity in the nature of portfolios including the rise of biopharmaceuticals however have the potential to provide considerable challenges to the establishment of cost effective and robust supply chains. To guarantee product quality and surety of supply for essential medicines it is necessary that manufacturing science keeps pace with advances in pharmaceutical R&D. In this position paper, the EUFEPS QbD and PAT Sciences network make recommendations that European industry, academia and health agencies focus attention on delivering step changes in science and technology in a number of key themes. These subject areas, all underpinned by the sciences allied to QbD and PAT, include product design and development for personalized healthcare, continuous-processing in pharmaceutical product manufacture, quantitative quality risk assessment for pharmaceutical development including life cycle management and the downstream processing of biopharmaceutical products. Plans are being established to gain commitment for inclusion of these themes into future funding priorities for the Innovative Medicines Initiative (IMI).


Thermally induced mode coupling in rare-earth doped fiber amplifiers.
We present a simple semianalytical model of thermally induced mode coupling in multimode rare-earth doped fiber amplifiers. The model predicts that power can be transferred from the fundamental mode to a higher-order mode when the operating power exceeds a certain threshold, and thus provides an explanation of recently reported mode instability in such fiber amplifiers under high average-power operation. We apply our model to a simple step-index fiber design, and investigate how the power threshold depends on various design parameters of the fiber.