PET-guided omission of radiotherapy in early-stage unfavourable Hodgkin lymphoma (GHSG HD17): a multicentre, open-label, randomised, phase 3 trial.
Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2). In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18-60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m2 intravenous cyclophosphamide on day 1, 35 mg/m2 intravenous doxorubicin on day 1, 200 mg/m2 intravenous etoposide on days 1-3, 100 mg/m2 oral procarbazine on days 1-7, 40 mg/m2 oral prednisone on days 1-14, 1·4 mg/m2 intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m2 intravenous bleomycin on day 8; ABVD consisted of 25 mg/m2 intravenous doxorubicin, 10 mg/m2 intravenous bleomycin, 6 mg/m2 intravenous vinblastine, and 375 mg/m2 intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680. Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7-61·2), 5-year progression-free survival was 97·3% (95% CI 94·5-98·7) in the standard combined-modality treatment group and 95·1% (92·0-97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226-1·211]). The between-group difference was 2·2% (95% CI -0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group. PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy. Deutsche Krebshilfe.


Functional differences between the N-terminal domains of mouse and human myosin binding protein-C.
The N-terminus of cMyBP-C can activate actomyosin interactions in the absence of Ca2+, but it is unclear which domains are necessary. Prior studies suggested that the Pro-Ala rich region of human cMyBP-C activated force in permeabilized human cardiomyocytes, whereas the C1 and M-domains of mouse cMyBP-C activated force in permeabilized rat cardiac trabeculae. Because the amino acid sequence of the P/A region differs between human and mouse cMyBP-C isoforms (46% identity), we investigated whether species-specific differences in the P/A region could account for differences in activating effects. Using chimeric fusion proteins containing combinations of human and mouse C0, Pro-Ala, and C1 domains, we demonstrate here that the human P/A and C1 domains activate actomyosin interactions, whereas the same regions of mouse cMyBP-C are less effective. These results suggest that species-specific differences between homologous cMyBP-C isoforms confer differential effects that could fine-tune cMyBP-C function in hearts of different species.


Effects of a Physical Activity Program on Cardiorespiratory Fitness and Pulmonary Function in Obese Women after Bariatric Surgery: a Pilot Study.
In severely obese individuals, reducing body weight induced by bariatric surgery is able to promote a reduction in comorbidities and improve respiratory symptoms. However, cardiorespiratory fitness (CRF) reflected by peak oxygen uptake (VO2peak) may not improve in individuals who remain sedentary post-surgery. The objective of this study was to evaluate the effects of a physical training program on CRF and pulmonary function in obese women after bariatric surgery, and to compare them to a control group. Twelve obese female candidates for bariatric surgery were evaluated in the preoperative, 3 months postoperative (3MPO), and 6 months postoperative (6MPO) periods through anthropometry, spirometry, and cardiopulmonary exercise testing (CPX). In the 3MPO period, patients were divided into control group (CG, n = 6) and intervention group (IG, n = 6). CG received only general guidelines while IG underwent a structured and supervised physical training program involving aerobic and resistance exercises, lasting 12 weeks. All patients had a significant reduction in anthropometric measurements and an increase in lung function after surgery, with no difference between groups. However, only IG presented a significant increase (p < 0.05) in VO2peak and total CPX duration of 5.9 mL/kg/min (23.8%) and 4.9 min (42.9%), respectively. Applying a physical training program to a group of obese women after 3 months of bariatric surgery could promote a significant increase in CRF only in the trained group, yet also showing that bariatric surgery alone caused an improvement in the lung function of both groups.


Prevalence of atopy in children with type 1 diabetes mellitus in central Taiwan.
Atopic diseases, including asthma, eczema and allergic rhinitis, are characterized by a chronic inflammatory reaction mediated by T helper 2 (Th2) cells, while type 1 diabetes mellitus (T1D) is mediated by T helper 1 (Th1) cells. The 'balance' between Th1 and Th2 cells appears to be vitally important. Hence, it is a plausible hypothesis that the prevalence in Th2-mediated disease would be lower in patients with Th1-mediated disease. The aim of this study was to compare the prevalence of atopic diseases between children with T1D and age-matched controls, and investigate possible factors that influence the prevalence of atopic disease. Parents of children with T1D in Taichung Veterans General Hospital were requested by pediatricians to complete the International Study of Asthma and Allergies in Childhood questionnaire on the prevalence of atopic diseases. Responses were compared with an age-matched control group. Questionnaires were evaluated from 100 T1D patients and 194 controls. After age-matching, the questionnaires of 54 T1D patients were included. Symptoms of asthma, allergic rhinitis and eczema were reported less often in the group of children with T1D compared with the control group (wheeze with exercise, p=0.044; nasal symptoms with itching eyes in the past 12 months, p=0.048; nasal allergy ever, p=0.038; skin rash in the past 12 months, p=0.044). In addition, the proportion of T1D patients with any asthmatic symptom (such as wheezing once in life, wheezing in the past 12 months, wheezing with exercise and dry cough at night in the past 12 months) was significantly lower than in controls (20.4% vs 36.6%, p=0.036). These results indicate that patients with T1D have a lower prevalence of atopic symptoms, especially asthma, which is consistent with the Th1/Th2 polarization concept. Environmental factors are another direct influence on the development of atopy in T1D patients.


Exposure to Persistent Organic Pollutants (POPs) and Their Relationship to Hepatic Fat and Insulin Insensitivity among Asian Indian Immigrants in the United States.
Persistent organic pollutants (POPs), such as dichlorodiphenyltrichloroethane (DDT) and other organochlorine compounds, are abundant in the environment and in foodstuffs from the Indian subcontinent. These environmental contaminants have been associated with a higher risk of diabetes in numerous studies. Asian Indians are well known to have a high risk of diabetes compared with other populations, and this risk is also found in migrant populations of Asian Indians in the United States, Europe, and elsewhere. We hypothesized that high plasma concentrations of POPs in Asian Indian migrants are linked to a variety of diabetes-related pathologies and explored the mechanism for the induction of these effects. We measured 30 environmental pollutants in plasma samples obtained from 147 participants in the Metabolic syndrome and Atherosclerosis in South Asians Living in America pilot study using a gas chromatography-tandem mass spectrometry analytical method that uses less than 0.5 mL of plasma. We found that plasma levels of o,p'-DDT and p,p'-DDT were independently associated with both body mass index (BMI) and waist circumference. Doubling the levels of the sums of these DDTs was associated with insulin insensitivity (-0.38 Matsuda index, p = 0.001), increased adiposity (1.26 kg/m2 BMI and 3.58 cm waist circumference increase, p < 0.0001), circulating insulin (12.9 mIU/L, p = 0.002), hepatic fat (-0.051 HU, p = 0.001), as well as increased odds of obesity (OR = 2.17, p < 0.001, BMI-based; OR = 2.37, p = 0.001, waist-based), prediabetes (OR = 1.55, p = 0.02), diabetes (OR = 1.72, p = 0.01), and fatty liver (OR = 1.66, p = 0.01) in multivariable models accounting for confounding by age, sex, years in the US, education, and fish protein. Furthermore, levels of DDTs were associated with increased hepatic fat and circulating insulin, independent of obesity and confounders. These findings suggest that exposure to DDTs may contribute to the risk of metabolic disease among Asian Indians by affecting hepatic fat levels independent of obesity.


Genipin protects the liver from ischemia/reperfusion injury by modulating mitochondrial quality control.
Hepatic ischemia and reperfusion (IR) injury is closely linked to oxidative mitochondrial damage. Since mitochondrial quality control (QC) plays a pivotal role in the recovery of impaired mitochondrial function, mitochondrial QC has emerged as a potential therapeutic target. Genipin, an iridoid compound from Gardenia jasminoides, has been showed antioxidant and anti-inflammatory properties. In this study, we investigated the hepatoprotective mechanism of genipin against IR-induced hepatic injury, particularly focusing on mitochondrial QC. Male C57BL/6 mice underwent liver ischemia for 60min, followed by reperfusion for 6h. Genipin (100mg/kg, i.p.) or vehicle (10% Tween 80 in saline) was administrated to mice 1h before ischemia. Liver and blood samples were collected 6h after reperfusion. Hepatic IR increased hepatocellular oxidative damage and induced mitochondrial dysfunction. These phenomena were ameliorated by genipin. Hepatic IR also increased the level of mitochondrial fission, such as dynamin-related protein 1 and the level of PINK1 protein expression. In contrast, hepatic IR decreased the levels of mitochondrial biogenesis related proteins (e.g., peroxisome proliferator-activated receptor gamma coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor A), mitophagy related proteins (e.g., Parkin), and fusion related protein (e.g., mitofusin 2). Furthermore, hepatic IR decreased the levels of sirtuin1 protein and phosphorylation of AMP-activated protein kinase. Genipin alleviated these IR-induced changes. These data indicate that genipin protects against IR-induced hepatic injury via regulating mitochondrial QC. (225/250).


Determination of interfacial shear strength between the glass fiber and primary coating in double-coated optical fibers from mechanical strip forces.
We propose a method of determining interfacial shear strength between the glass fiber and primary coating in double-coated optical fibers. A commercial stripper is used to mechanically strip the polymeric coatings. It consists of two hinged arms and a pair of blades with a semicircular bore. In the mechanical stripping process the relationship between the strip force and stripper displacement is measured. The interfacial shear strength between the glass fiber and primary coating is then determined from this relationship. The measured interfacial shear strength increases with the increasing stripping rate. It is found that measured results are compatible with theoretical results.


Ecological, social and biological risk factors for continued Trypanosoma cruzi transmission by Triatoma dimidiata in Guatemala.
Chagas disease transmission by Triatoma dimidiata persists in Guatemala and elsewhere in Central America under undefined ecological, biological and social (eco-bio-social) conditions. Eco-bio-social risk factors associated with persistent domiciliary infestation were identified by a cross-sectional survey and qualitative participatory methods. Quantitative and qualitative data were generated regarding Trypanosoma cruzi reservoirs and triatomine hosts. Blood meal analysis and infection of insects, dogs and rodents were determined. Based on these data, multimodel inference was used to identify risk factors for domestic infestation with the greatest relative importance (>0.75). Blood meal analysis showed that 64% of 36 bugs fed on chickens, 50% on humans, 17% on dogs; 24% of 34 bugs fed on Rattus rattus and 21% on Mus musculus. Seroprevalence among 80 dogs was 37%. Eight (17%) of 46 M. musculus and three (43%) of seven R. rattus from households with infected triatomines were infected with T. cruzi Distinct Typing Unit I. Results from interviews and participatory meetings indicated that vector control personnel and some householders perceived chickens roosting and laying eggs in the house as bug infestation risk factors. House construction practices were seen as a risk factor for bug and rodent infestation, with rodents being perceived as a pest by study participants. Multimodel inference showed that house infestation risk factors of high relative importance are dog density, mouse presence, interior wall plaster condition, dirt floor, tile roofing and coffee tree presence. Persistent house infestation is closely related to eco-bio-social factors that maintain productive T. dimidiata habitats associated with dogs, chickens and rodents. Triatomine, dog and rodent infections indicate active T. cruzi transmission. Integrated vector control methods should include actions that consider the role of peridomestic animals in transmission and community memberś level of knowledge, attitudes and practices associated with the disease and transmission process.


Characteristics of Effective Teachers of Invasive Bedside Procedures: A Multi-institutional Qualitative Study.
Faculty supervision of invasive bedside procedures (IBPs) in the ICU may enhance procedural education and ensure patient safety. However, there is limited research on teaching effectiveness in the ICU, and there are no best teaching practices regarding the supervision of IBPs. We conducted a multi-institutional qualitative study of pulmonary and critical care medicine faculty and fellows to better understand characteristics of effective IBP teachers. Separate focus groups (FGs) were conducted with fellows and faculty at four large academic institutions that were geographically distributed across the United States. FGs were facilitated by a trained investigator, audio-recorded, and transcribed verbatim for analysis. Themes were identified inductively and compared with constructs from social and situated learning theories. Data were analyzed between and across professional groups. Qualitative research software (NVivo; QSR International) was used to facilitate data organization and create an audit trail of the analysis. A multidisciplinary research team was engaged to minimize interpretive bias. Thirty-three faculty and 30 fellows participated. Inductive analysis revealed three categories of themes among successful IBP teachers: traits, behaviors, and context. Traits included calm demeanor, trust, procedural competence, and effective communication. Behaviors included leading preprocedure huddles to assess learners' experiences and define expectations; debriefing to provide feedback; and allowing appropriate autonomy. Context included learning climate, levels of distraction, patient acuity, and institutional culture. We identified specific traits and behaviors of effective IBP teachers that intersect with the practice environment, which highlights the challenge of teaching IBPs. Notably, FG participants emphasized interpersonal, more than technical, aspects of successful IBP teachers. These findings should inform future curricula on teaching IBPs in the ICU, standardize IBP teaching for pulmonary and critical care medicine fellows, and reduce patient injury from procedural complications.


Spliceosome Mutations in Uveal Melanoma.
Uveal melanoma (UM) is the most common primary intraocular malignancy of the eye. It has a high metastatic potential and mainly spreads to the liver. Genetics play a vital role in tumor classification and prognostication of UM metastatic disease. One of the driver genes mutated in metastasized UM is subunit 1 of splicing factor 3b (SF3B1), a component of the spliceosome complex. Recurrent mutations in components of the spliceosome complex are observed in UM and other malignancies, suggesting an important role in tumorigenesis. SF3B1 is the most common mutated spliceosome gene and in UM it is associated with late-onset metastasis. This review summarizes the genetic and epigenetic insights of spliceosome mutations in UM. They form a distinct subgroup of UM and have similarities with other spliceosome mutated malignancies.


Role of omega-6 and omega-3 fatty acids in fetal programming.
Maternal nutrition plays a critical role in fetal development and can influence adult onset of disease. Linoleic acid (LA) and alpha-linolenic acid (ALA) are major omega-6 (n-6) and n-3 polyunsaturated fatty acids (PUFA), respectively, that are essential in our diet. LA and ALA are critical for the development of the fetal neurological and immune systems. However, in recent years, the consumption of n-6 PUFA has increased gradually worldwide, and elevated n-6 PUFA consumption may be harmful to human health. Consumption of diets with high levels of n-6 PUFA before or during pregnancy may have detrimental effects on fetal development and may influence overall health of offspring in adulthood. This review discusses the role of n-6 PUFA in fetal programming, the importance of a balance between n-6 and n-3 PUFAs in the maternal diet, and the need of further animal models and human studies that critically evaluate both n-6 and n-3 PUFA contents in diets.


Early pregnancy factor suppresses experimental autoimmune encephalomyelitis induced in Lewis rats with myelin basic protein and in SJL/J mice with myelin proteolipid protein peptide 139-151.
Early pregnancy factor (EPF) is a secreted protein with immunosuppressive and growth factor properties. During pregnancy, it appears in maternal serum within 6-24 h of fertilization, is present for at least the first two-thirds of pregnancy in all species studied and is essential for embryonic survival. It is a homologue of chaperonin 10, a heat shock protein, but, unlike other members of this family, EPF has an extracellular role. As it has the ability to modulate CD4+ T cell-dependent immune responses, its role in treatment of experimental autoimmune encephalomyelitis (EAE) was investigated. EAE is a CD4+ T cell-mediated disease, the best available animal model of multiple sclerosis (MS). Two models of EAE were investigated, acute EAE induced in Lewis rats by inoculation with myelin basic protein (MBP-EAE) and chronic relapsing EAE induced in SJL/J mice by inoculation with myelin proteolipid protein peptide (residues 139-151) (PLP-EAE). EPF, delivered intraperitoneally or orally to rats or intraperitoneally to mice, suppressed clinical signs of disease. Mice with PLP-EAE were also treated with interferon-beta, with and without EPF. Both EPF and IFN-beta suppressed clinical signs of EAE and, when administered together, gave greater suppression than when given separately. These findings suggest that EPF may be a potential candidate for use in treatment of MS and may be of use in combined therapy with IFN-beta.


Factors influencing the decision to use hanging as a method of suicide: qualitative study.
Hanging is the most frequently used method of suicide in the UK and has high case fatality (>70%). To explore factors influencing the decision to use hanging. Semi-structured qualitative interviews with 12 men and 10 women who had survived a near-fatal suicide attempt. Eight respondents had attempted hanging. Data were analysed thematically and with constant comparison. Hanging was adopted or contemplated for two main reasons: the anticipated nature of a death from hanging; and accessibility. Those favouring hanging anticipated a certain, rapid and painless death with little awareness of dying and believed it was a 'clean' method that would not damage the body or leave harrowing images for others. Materials for hanging were easily accessed and respondents considered it 'simple' to perform without the need for planning or technical knowledge. Hanging was thus seen as the 'quickest' and 'easiest' method with few barriers to completion and sometimes adopted despite not being a first choice. Respondents who rejected hanging recognised it could be slow, painful and 'messy', and thought technical knowledge was needed for implementation. Prevention strategies should focus on countering perceptions of hanging as a clean, painless and rapid method that is easily implemented. However, care is needed in the delivery of such messages as some individuals could gain information that might facilitate fatal implementation. Detailed research needs to focus on developing and evaluating interventions that can manage this tension.


Safety of repeated yttrium-90 radioembolization.
Repeated radioembolization (RE) treatments carry theoretically higher risk of radiation-induced hepatic injury because of the liver's cumulative memory of previous exposure. We performed a retrospective safety analysis on patients who underwent repeated RE. From 2004 to 2011, a total of 247 patients were treated by RE. Eight patients (5 men, 3 women, age range 51-71 years) underwent repeated treatment of a targeted territory, all with resin microspheres (SIR-Spheres; Sirtex, Lane Cove, Australia). Adverse events were graded during a standardized follow-up. In addition, the correlation between the occurrence of RE-induced liver disease (REILD) and multiple variables was investigated in univariate and multivariate analyses in all 247 patients who received RE. Two patients died shortly after the second treatment (at 84 and 107 days) with signs and symptoms of REILD. Both patients underwent whole liver treatment twice (cumulative doses 3.08 and 2.66 GBq). The other 6 patients demonstrated only minor toxicities after receiving cumulative doses ranging from 2.41 to 3.88 GBq. All patients experienced objective tumor responses. In the whole population, multifactorial analysis identified three risk factors associated with REILD: repeated RE (p = 0.036), baseline serum total bilirubin (p = 0.048), and baseline serum aspartate aminotransferase (p = 0.043). Repeated RE proved to be the only independent risk factor for REILD in multivariate analysis (odds ratio 9.6; p = 0.002). Additionally, the administered activity per target volume (in GBq/L) was found to be an independent risk factor for REILD, but only in whole liver treatments (p = 0.033). The risk of REILD appears to be elevated for repeated RE. Objective tumor responses were observed, but establishment of safety limits will require improvement in dosimetric measurement and prediction.


Representative threats for research in public health surveillance.
A large number of biological agents can cause natural or bioterroristic disease outbreaks and each can present in a bewildering number of ways (e.g., a few cases versus many cases, confined to a building versus widely disseminated). This 'problem space' is a challenge for designers of early warning systems for disease outbreaks and the sheer size of this space is a barrier to progress. This paper addresses this problem by deriving nine categories of threats that represent a parsimonious characterization of the problem space. A literature search also identified one or more example outbreaks for each of the nine categories. These outbreaks have occurred in recent times and could be used by researchers in need of actual outbreak data for investigations of the role of different types of surveillance data and algorithms in outbreak detection. The methodological contribution of this research is a Criterion Set of threats for analysis and evaluation of detection systems. This set characterizes the problem space in a tractable manner with less loss of generality than analyses based on one or two selected diseases, which is representative of current analyses.


Complete genome sequence of the dissimilatory azo reducing thermophilic bacterium Novibacillus thermophiles SG-1.
With the isolation and identification of efficient azo-dye degradation bacteria, bioaugmentation with specific microbial strains has now become an effective strategy to promote the bioremediation of azo dye. However, Azo dye wastewater discharged at high temperature restricted the extensive application of the known mesophilic azoreducing microorganisms. Here we present the complete genome sequence of a bacterium capable of reducing azo dye under thermophilic condition, Novibacillus thermophiles SG-1 (=KCTC 33118T =CGMCC 1.12363T). The complete genome of strain SG-1 contains a circular chromosome of 3,629,225 bp with a G + C content of 50.44%. Genome analysis revealed that strain SG-1 possessed genes encoding riboflavin biosynthesis protein that would secrete riboflavin, which could act as electron shuttles to transport the electrons to extracellular azo dye in decolorization process. HPLC analysis showed that the concentration of riboflavin increased from 0.01 μM to 0.255 μM with the growth of strain SG-1 under azo dye reduction. Quantitative real-time PCR analysis further demonstrated that the gene encoding riboflavin biosynthesis protein would be involved in the azo dye decolorization. The results from this study would be beneficial to research the mechanism of anaerobic reduction of azo dye under thermophilic conditions.


Micron-sized PFOB liquid core droplets stabilized with tailored-made perfluorinated surfactants as a new class of endovascular sono-sensitizers for focused ultrasound thermotherapy.
The purpose of this study was to develop micron-sized droplet emulsions able to increase the heat deposition of high intensity focused ultrasound (HIFU), aiming to accelerate the tumour ablation in highly perfused organs with reduced side effects. The investigated droplets consisted of a perfluorooctyl bromide (PFOB) core coated with a biocompatible fluorinated surfactant called F-TAC. The novelty of this work relies on the use, for this application, of a high boiling point perfluorocarbon core (142 °C), combined with an in-house fluorinated surfactant to formulate the emulsion, yielding quasi-reversible strong interactions between the HIFU beam and the droplets. In order to fine-tune the emulsion size, surfactants with different hydrophobic/hydrophilic ratios were screened. Different concentrations of PFOB droplets were homogeneously embedded in two different MRI compatible materials, exhibiting either ultrasound (US) absorbing or non-absorbing properties. For the US absorbing TMM, the speed of sound at each droplet concentration was also assessed. These TMM were sonicated by 1 MHz HIFU with acoustical power of 94 W at two different duty cycles. The temperature elevation was monitored accurately by MRI proton shift resonance frequency in near real-time. The presence of sono-sensitive droplets induced a significant increase of the HIFU thermal effect that persisted under repeated sonication of the same locus. Optimal enhancement was observed at the lowest concentration tested (0.1%) with an additional temperature rise at the focal point of approximately 4 °C per applied kJ of acoustic energy corresponding to one order of magnitude augmentation of the thermal dose. Furthermore, no deformation of the heating pattern pre- or post-focal was observed.


Implications of the U.S. Food and Drug Administration warning against the use of sildenafil for the treatment of pediatric pulmonary hypertension.
Pulmonary arterial hypertension (PAH) contributes to disability and death in children with diverse cardiac, pulmonary, or systemic diseases, and therapeutic options are currently limited. Data from adult studies provide the basis for most PAH-specific therapies; however, many of these medications are commonly used in children on an off-label basis due to the life-threatening nature of PAH. Although currently approved for use in adult PAH, sildenafil is used extensively off-label for the treatment of neonates, infants, and children with PAH. Past studies have generally suggested favorable effects and outcomes in infants and young children with PAH, but these reports are generally uncontrolled observations, except for one single-center trial for persistent pulmonary hypertension of the newborn. Despite extensive clinical experience with sildenafil therapy in children and approval by the European Medicines Agency for its pediatric use in Europe, the U.S. Food and Drug Administration recently issued a warning against the use of sildenafil for pediatric PAH between 1 and 17 years of age due to an apparent increase in mortality during long-term therapy. Although these data are extremely limited, this U.S. Food and Drug Administration review challenges the pediatric PAH community to further assess the efficacy and safety of sildenafil, especially with chronic treatment. Although low doses of sildenafil are likely safe in pediatric PAH, further studies should carefully examine its role in the long-term therapy of children, especially with diverse causes of PAH. Pediatric patients with PAH require close surveillance and frequent monitoring, and persistent sildenafil monotherapy is likely insufficient with disease progression.


Target plasma factor levels for personalized treatment in haemophilia: a Delphi consensus statement.
Prophylactic replacement with factor concentrate is the optimal treatment for persons with severe haemophilia to avoid or minimize bleeding. This ultimately prevents or reduces joint disease and improves life expectancy and quality of life towards values matching those in the normal population. However, uncertainty still exists around the optimal regimens to be prescribed for prophylaxis. An increasing number of treating physicians and patients are showing interest in patient-tailored approaches to prophylaxis, which aim to harmonize the prophylaxis regimen with the patients' bleeding phenotype, levels of physical activity and a variety of other variables. A modified Delphi technique was adopted to generate consensus. The expert panel met in person to set the objectives, be trained on the Delphi technique and agree on the desired level of consensus. Three iterations were used to identify the targets, the scenarios and their combinations. Twenty-eight scenarios and eight target levels were identified and used to issue recommendations. The panel reached the desired level of consensus on positive or negative recommendations. Areas where consensus was not reached were identified and proposed as areas for future research. Prospective assessment of the validity of most of the proposed targets is recommended. We have generated, by expert consensus, target plasma levels of factor concentrate to be used to tailor treatment for persons with haemophilia.


Prenatal nutritional deficiency and risk of adult schizophrenia.
Converging evidence suggests that a neurodevelopmental disruption plays a role in the vulnerability to schizophrenia. The authors review evidence supporting in utero exposure to nutritional deficiency as a determinant of schizophrenia. We first describe studies demonstrating that early gestational exposure to the Dutch Hunger Winter of 1944--1945 and to a severe famine in China are each associated with an increased risk of schizophrenia in offspring. The plausibility of several candidate micronutrients as potential risk factors for schizophrenia and the biological mechanisms that may underlie these associations are then reviewed. These nutrients include folate, essential fatty acids, retinoids, vitamin D, and iron. Following this discussion, we describe the methodology and results of an epidemiologic study based on a large birth cohort that has tested the association between prenatal homocysteine, an indicator of serum folate, and schizophrenia risk. The study capitalized on the use of archived prenatal serum specimens that make it possible to obtain direct, prospective biomarkers of prenatal insults, including levels of various nutrients during pregnancy. Finally, we discuss several strategies for subjecting the prenatal nutritional hypothesis of schizophrenia to further testing. These approaches include direct assessment of additional prenatal nutritional biomarkers in relation to schizophrenia in large birth cohorts, studies of epigenetic effects of prenatal starvation, association studies of genes relevant to folate and other micronutrient deficiencies, and animal models. Given the relatively high prevalence of nutritional deficiencies during pregnancy, this work has the potential to offer substantial benefits for the prevention of schizophrenia in the population.


Characterization of the variable-number tandem repeats in vrrA from different Bacillus anthracis isolates.
PCR analysis of 198 Bacillus anthracis isolates revealed a variable region of DNA sequence differing in length among the isolates. Five polymorphisms differed by the presence of two to six copies of the 12-bp tandem repeat 5'-CAATATCAACAA-3'. This variable-number tandem repeat (VNTR) region is located within a larger sequence containing one complete open reading frame that encodes a putative 30-kDa protein. Length variation did not change the reading frame of the encoded protein and only changed the copy number of a 4-amino-acid sequence (QYQQ) from 2 to 6. The structure of the VNTR region suggests that these multiple repeats are generated by recombination or polymerase slippage. Protein structures predicted from the reverse-translated DNA sequence suggest that any structural changes in the encoded protein are confined to the region encoded by the VNTR sequence. Copy number differences in the VNTR region were used to define five different B. anthracis alleles. Characterization of 198 isolates revealed allele frequencies of 6.1, 17.7, 59.6, 5.6, and 11.1% sequentially from shorter to longer alleles. The high degree of polymorphism in the VNTR region provides a criterion for assigning isolates to five allelic categories. There is a correlation between categories and geographic distribution. Such molecular markers can be used to monitor the epidemiology of anthrax outbreaks in domestic and native herbivore populations.


Milk and cheese from cows fed calcium salts of palm and fish oil alone or in combination with soybean products.
Twenty cows were used in a randomized block design experiment for 6 wk to determine the influence of feeding partial ruminally inert Ca salts of palm and fish oil (Ca-PFO), alone or in combination with extruded full-fat soybeans or soybean oil, on milk fatty acid (FA) methyl esters composition and consumer acceptability of milk and Cheddar cheese. Cows were fed either a diet containing 44% forage and 56% concentrate (control) or a diet supplemented with 2.7% Ca-PFO (FO), 5% extruded full-fat soybeans + 2.7% Ca-PFO (FOESM), or 0.75% soybean oil + 2.7% Ca-PFO (FOSO). Total dietary FA content in the control, FO, FOESM, and FOSO diets were 4.61, 6.28, 6.77, and 6.62 g/100 g, respectively. There was no difference in nutrient intake, milk yield, or milk composition among treatments. Conjugated linoleic acid (CLA) C(18:2) cis-9, trans-11 isomer, C(18:1) trans-11 (VA), and total n-3 FA in milk from cows on the control, FO, FOESM, and FOSO treatments were 0.56, 1.20, 1.36, and 1.74; 3.29, 4.66, 6.34, and 7.81; 0.62, 0.69, 0.69, and 0.67 g/100 g of FA, respectively. Concentrations of CLA, VA, and total n-3 FA in cheese were similar to milk. A trained sensory panel detected no difference in flavors of milk and cheese, except for acid flavor below a slightly perceptible level in cheese from all treatments. Results suggest that feeding Ca-PFO alone or in combination with extruded full-fat soybeans or soybean oil enhanced the CLA, VA, total unsaturated and n-3 FA in milk and cheese without negatively affecting cow performance and consumer acceptability characteristics of milk and cheese.


A novel approach to the treatment of lower extremity lymphedema by transferring a vascularized submental lymph node flap to the ankle.
Vascularized groin lymph node flaps have been successfully transferred to the wrist to treat postmastecomy upper limb lymphedema. This study investigated the anatomy, mechanism and outcome of a novel vascularized submental lymph node (VSLN) flap transfer for the treatment of lower limb lymphedema. Bilateral regional submental flaps were dissected from three fresh adult cadavers for histological study. A unilateral submental flap was dissected in another six fresh cadavers after latex injection. The VSLN flap was transferred to the ankles of seven lower extremities in six patients with chronic lower extremity lymphedema. The mean patient age was 61 ± 9.4 years. The average duration of lymphedema symptoms was 71 ± 42.2 months. There was a mean of 3.3 ± 1.5 lymph nodes around the submental artery typically at the junction with the facial artery, on the six cadaveric histological sections. Mean of 2.3 ± 0.8 sizable lymph nodes were dissected and supplied by the submental artery in six cadaveric latex-injected submental flaps. All seven VSLN flaps survived. One flap required re-exploration for venous congestion but was successfully salvaged. There was no donor site morbidity. At a mean follow-up of 8.7 ± 4.2 months, the mean reduction of the leg circumference was 64 ± 11.5% above the knee, 63.7 ± 34.3% below the knee and 67.3 ± 19.2% above the ankle. The transfer of a vascularized submental lymph node flap to the ankle is a novel approach for the effective treatment of lower extremity lymphedema.


LPS and HIV gp120 modulate monocyte/macrophage CYP27B1 and CYP24A1 expression leading to vitamin D consumption and hypovitaminosis D in HIV-infected individuals.
Vitamin D deficiency is very common among HIV-infected subjects. We cross-sectionally evaluated the prevalence and risk factors for hypovitaminosis D in 91 HIV-infected Italian patients. We studied in a cohort of 91 HIV-infected Italian patients the metabolism of Vitamin D by evaluating the in vitro expression of CYP27B1, CYP24A1 and vitamin D receptor (VDR) by monocytes and macrophages stimulated with the viral envelope protein gp120 or lipopolysaccharide (LPS). The prevalence of vitamin D deficiency (25OHD < 10 ng/ml) and vitamin D insufficiency (25OHD 10-30 ng/ml) was 31% and 57%, respectively. In univariate analysis, female sex (p = 0.01), increasing age (p = 0.05), higher highly sensitive-C reactive protein (p = 0.025), higher parathyroid hormone (PTH) (p = 0.043) and lower BMI (p = 0.04) were associated with vitamin D deficiency. In multivariate analysis, the association was still significant only for PTH (p = 0.03) and female sex (p = 0.03). Monocyte stimulation with LPS (100 ng/ml) or gp120 (1 µg/ml) significantly upregulated CYP27B1 mRNA expression. Moreover, gp120 significantly increased VDR mRNA levels. On the contrary, neither LPS nor gp120 modified CYP24A1 levels. Macrophage stimulation with LPS (100 ng/ml) significantly upregulated CYP27B1 and CYP24A1 mRNA expression. When monocytes were cultured in the presence of 25OHD (40 ng/ml) and stimulated with LPS we detected significantly lower levels of 25OHD in the supernatant. Vitamin D deficiency was very common in our cohort of HIV-infected patients. Chronic inflammation, including residual viral replication, may contribute to hypovitaminosis D, by modulating vitamin D metabolism and catabolism. Systematic screening may help identifying subjects requiring supplementation.


The evaluation of thyroid diseases in patients with pemphigus vulgaris.
Thyroid disorders may affect all of the organ systems of the body and they are also highly associated with a wide variety of skin disorders. The aim of this study was to investigate the prevalence of thyroid function abnormalities and thyroid autoimmunity in patients with pemphigus vulgaris (PV) and to determine the association between thyroid disorders and clinical involvement and systemic corticosteroid treatment in patients with PV. The study consisted of eighty patients with PV and eighty healthy individuals. Thyroid functions (fT3, fT4, and TSH) and thyroid autoimmunity (anti-thyroid peroxidase (anti-TPO), and anti-thyroglobulin (anti-Tg) antibodies) were investigated in both groups. Primary thyroid disease (PTD) was diagnosed with one or more of the following diagnostic criteria: (i) positive antithyroid antibodies, (ii) primary thyroid function abnormalities. Significant changes in the serum thyroid profile were found in 16% (13/80) of the PV group and 5% (4/80) of the control group. Positive titers of antithyroid antibodies (anti-TPO and anti-Tg) were observed in 7 patients (9%) with PV and one in the control group (1,2%). Hashimoto thyroiditis was diagnosed in 9% of PV patients and it was found to be more prevalent in the mucosal form of PV. PTD was found in 13 of (%16) PV patients which was significantly high compared to controls. PTD was not found to be associated with systemic corticosteroid use. Free T3 levels were significantly lower in PV group compared to the control group and free T4 levels were significantly higher in PV group compared to the controls. PV may exist together with autoimmune thyroid diseases especially Hashimoto thyroiditis and primer thyroid diseases. Laboratory work-up for thyroid function tests and thyroid autoantibodies should be performed to determine underlying thyroid diseases in patients with PV.


Whole genome transcript profiling from fingerstick blood samples: a comparison and feasibility study.
Whole genome gene expression profiling has revolutionized research in the past decade especially with the advent of microarrays. Recently, there have been significant improvements in whole blood RNA isolation techniques which, through stabilization of RNA at the time of sample collection, avoid bias and artifacts introduced during sample handling. Despite these improvements, current human whole blood RNA stabilization/isolation kits are limited by the requirement of a venous blood sample of at least 2.5 mL. While fingerstick blood collection has been used for many different assays, there has yet to be a kit developed to isolate high quality RNA for use in gene expression studies from such small human samples. The clinical and field testing advantages of obtaining reliable and reproducible gene expression data from a fingerstick are many; it is less invasive, time saving, more mobile, and eliminates the need of a trained phlebotomist. Furthermore, this method could also be employed in small animal studies, i.e. mice, where larger sample collections often require sacrificing the animal. In this study, we offer a rapid and simple method to extract sufficient amounts of high quality total RNA from approximately 70 microl of whole blood collected via a fingerstick using a modified protocol of the commercially available Qiagen PAXgene RNA Blood Kit. From two sets of fingerstick collections, about 70 uL whole blood collected via finger lancet and capillary tube, we recovered an average of 252.6 ng total RNA with an average RIN of 9.3. The post-amplification yields for 50 ng of total RNA averaged at 7.0 ug cDNA. The cDNA hybridized to Affymetrix HG-U133 Plus 2.0 GeneChips had an average % Present call of 52.5%. Both fingerstick collections were highly correlated with r(2) values ranging from 0.94 to 0.97. Similarly both fingerstick collections were highly correlated to the venous collection with r(2) values ranging from 0.88 to 0.96 for fingerstick collection 1 and 0.94 to 0.96 for fingerstick collection 2. Our comparisons of RNA quality and gene expression data of the fingerstick method with traditionally processed sample workflows demonstrate excellent RNA quality from the capillary collection as well as very high correlations of gene expression data.


The Meniscus Tear: A Review of Stem Cell Therapies.
Meniscal injuries have posed a challenging problem for many years, especially considering that historically the meniscus was considered to be a structure with no important role in the knee joint. This led to earlier treatments aiming at the removal of the entire structure in a procedure known as a meniscectomy. However, with the current understanding of the function and roles of the meniscus, meniscectomy has been identified to accelerate joint degradation significantly and is no longer a preferred treatment option in meniscal tears. Current therapies are now focused to regenerate, repair, or replace the injured meniscus to restore its native function. Repairs have improved in technique and materials over time, with various implant devices being utilized and developed. More recently, strategies have applied stem cells, tissue engineering, and their combination to potentiate healing to achieve superior quality repair tissue and retard the joint degeneration associated with an injured or inadequately functioning meniscus. Accordingly, the purpose of this current review is to summarize the current available pre-clinical and clinical literature using stem cells and tissue engineering for meniscal repair and regeneration.


Dysregulated EGFR pathway in serum in early-stage breast cancer patients: A case control study.
The epidermal growth factor receptor (EGFR) and its ligands are involved in cancer pathogenesis and they might serve as circulating biomarkers. The current study aims to investigate if abnormal pre-treatment serum levels of EGFR and EGFR ligands are present in women with early-stage breast cancer and if up- or downregulation of EGFR and EGFR ligands occur in defined patient subgroups. Pre-treatment serum samples were obtained from 311 women with newly diagnosed early-stage breast cancer and from 419 healthy women and analysed for EGFR and the ligands: Epidermal growth factor (EGF), heparin-binding epidermal growth factor (HBEGF), betacellulin (BTC), amphiregulin (AREG), and transforming growth factor α (TGF-α). Previously, age-dependent 95% reference intervals for EGFR and the EGFR ligands have been established based on the healthy women population. S-EGFR, S-EGF, S-HBEGF, S-AREG, and S-TGFα were all significantly different in women with breast cancer compared to healthy women (p < 0.05). Elevated S-EGFR, according to the reference intervals, was present in 11.3% of breast cancer patients, whereas decreased S-EGF was found in 11.6%. Elevated S-EGFR was associated with estrogen receptor positivity of tumor (ER+) and a subgroup of ER + breast cancer patients showed markedly elevated S-EGFR (>120 ng/mL).


How Can Health Systems Better Prepare for the Next Pandemic? Lessons Learned From the Management of COVID-19 in Quebec (Canada).
The magnitude of the COVID-19 pandemic challenged societies around our globalized world. To contain the spread of the virus, unprecedented and drastic measures and policies were put in place by governments to manage an exceptional health care situation while maintaining other essential services. The responses of many governments showed a lack of preparedness to face this systemic and global health crisis. Drawing on field observations and available data on the first wave of the pandemic (mid-March to mid-May 2020) in Quebec (Canada), this article reviewed and discussed the successes and failures that characterized the management of COVID-19 in this province. Using the framework of Palagyi et al. on system preparedness toward emerging infectious diseases, we described and analyzed in a chronologically and narratively way: (1) how surveillance was structured; (2) how workforce issues were managed; (3) what infrastructures and medical supplies were made available; (4) what communication mechanisms were put in place; (5) what form of governance emerged; and (6) whether trust was established and maintained throughout the crisis. Our findings and observations stress that resilience and ability to adequately respond to a systemic and global crisis depend upon preexisting system-level characteristics and capacities at both the provincial and federal governance levels. By providing recommendations for policy and practice from a learning health system perspective, this paper contributes to the groundwork required for interdisciplinary research and genuine policy discussions to help health systems better prepare for future pandemics.


Pain perception after colorectal surgery: A propensity score matched prospective cohort study.
The purpose of this prospective cohort study was to compare multimodal pain management and pain perception after open vs. laparoscopic colorectal surgery within enhanced recovery care. Pain scores at rest and at mobilization were prospectively assessed in consecutive patients using Visual Analog Scales (VAS 0-10) and consumption of different analgesics was recorded daily until 96 hours postoperatively. Uni- and multivariate risk factors for pain peaks (≥ 4/10) were identified by logistic regression and compared between two propensity score matched groups (open vs. laparoscopic). 156 open and 176 laparoscopic procedures were included. Mean VAS scores were consistently < 3 until 96 hours at rest and at mobilization. Patients operated by laparoscopy experienced more pain peaks (≥ 4) within 24 hours (p < 0.05), while patients operated by open approach experienced more pain peaks (≥ 4) during mobilization at 72 hours (p < 0.05). Independent risk factors for insufficient pain control (≥ 4) within 24 hours from surgery were duration of the procedure (OR 3.37, 95%CI 2.03-5.59), emergency surgery (OR 3.01, 95%CI 1.72-5.31), wound infiltration (OR 3.23, 95%CI 0.97-10.70), age < 70 years (OR 2.03, 95% CI 1.18-3.48) and ASA I-II score (OR 2.06, 95% CI 1.19-3.56). The perioperative adding of lidocaine ± ketamine to opioids did not improve postoperative pain perception nor decrease morphine equivalents. In conclusion, overall pain scores were low after colorectal surgery. However, pain peaks remained a concern early after minimally invasive surgery and after epidural removal for open surgery. Multimodal strategies were not superior to opioids alone.


The influence of vitamin A supplementation on iron status.
Vitamin A (VA) and iron deficiencies are important nutritional problems, affecting particularly preschool children, as well as pregnant and lactating women. A PubMed (National Library of Medicine, National Institutes of Health, Bethesda, MD, USA) literature review was carried out to search for clinical trials published from 1992 to 2013 that assessed the influence of vitamin A supplementation on iron status. Simultaneous use of iron and vitamin A supplements seemed to be more effective to prevent iron deficiency anemia than the use of these micronutrients alone. Some studies did not include a placebo group and only a few of them assessed vitamin A status of the individuals at baseline. Moreover, the studies did not consider any inflammatory marker and a reasonable number of iron parameters. Another important limitation was the lack of assessment of hemoglobin variants, especially in regions with a high prevalence of anemia. Assessment of hemoglobin variants, inflammatory markers and anemia of chronic inflammation would be important to the studies investigated. Studies involving different populations are necessary to elucidate the interaction between the two micronutrients, especially regarding iron absorption and modulation of erythropoiesis.


Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development.
Fragile X syndrome (FXS) is considered the leading inherited cause of intellectual disability and autism. In FXS, the fragile X mental retardation 1 (FMR1) gene is silenced and the fragile X mental retardation protein (FMRP) is not expressed, resulting in the characteristic features of the syndrome. Despite recent advances in understanding the pathophysiology of FXS, there is still no cure for this condition; current treatment is symptomatic. Preclinical research is essential in the development of potential therapeutic agents. This review provides an overview of the preclinical evidence supporting metabotropic glutamate receptor 5 (mGluR5) antagonists as therapeutic agents for FXS. According to the mGluR theory of FXS, the absence of FMRP leads to enhanced glutamatergic signaling via mGluR5, which leads to increased protein synthesis and defects in synaptic plasticity including enhanced long-term depression. As such, efforts to develop agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. Animal models, particularly the Fmr1 knockout mouse model, have become invaluable in exploring therapeutic approaches on an electrophysiological, behavioral, biochemical, and neuroanatomical level. Two direct approaches are currently being investigated for FXS treatment: reactivating the FMR1 gene and compensating for the lack of FMRP. The latter approach has yielded promising results, with mGluR5 antagonists showing efficacy in clinical trials. Targeting mGluR5 is a valid approach for the development of therapeutic agents that target the underlying pathophysiology of FXS. Several compounds are currently in development, with encouraging results.


Cytoskeletal actin dynamics shape a ramifying actin network underpinning immunological synapse formation.
T cell activation and especially trafficking of T cell receptor microclusters during immunological synapse formation are widely thought to rely on cytoskeletal remodeling. However, important details on the involvement of actin in the latter transport processes are missing. Using a suite of advanced optical microscopes to analyze resting and activated T cells, we show that, following contact formation with activating surfaces, these cells sequentially rearrange their cortical actin across the entire cell, creating a previously unreported ramifying actin network above the immunological synapse. This network shows all the characteristics of an inward-growing transportation network and its dynamics correlating with T cell receptor rearrangements. This actin reorganization is accompanied by an increase in the nanoscale actin meshwork size and the dynamic adjustment of the turnover times and filament lengths of two differently sized filamentous actin populations, wherein formin-mediated long actin filaments support a very flat and stiff contact at the immunological synapse interface. The initiation of immunological synapse formation, as highlighted by calcium release, requires markedly little contact with activating surfaces and no cytoskeletal rearrangements. Our work suggests that incipient signaling in T cells initiates global cytoskeletal rearrangements across the whole cell, including a stiffening process for possibly mechanically supporting contact formation at the immunological synapse interface as well as a central ramified transportation network apparently directed at the consolidation of the contact and the delivery of effector functions.


Compass fundus automated perimetry.
Compass (CenterVue, Padova, Italy) is a fundus automated perimeter which has been introduced in the clinical practice for glaucoma management in 2014. The aim of the article is to review Compass literature, comparing its performances against Humphrey Field Analyzer (Zeiss Humphrey Systems, Dublin, CA, USA). Analyses on both normal and glaucoma subjects agree on the fact that Humphrey Field Analyzer and Compass are interchangeable, as the difference of their global indices is largely inferior than test -retest variability for Humphrey Field Analyzer. Compass also enables interesting opportunities for the assessment of morphology, and the integration between morphology and function on the same device. Visual field testing by standard automated perimetry is limited by a series of intrinsic factors related to the psychophysical nature of the examination; recent papers suggest that gaze tracking is closely related to visual field reliability. Compass, thanks to a retinal tracker and to the active dislocation of stimuli to compensate for eye movements, is able to provide visual fields unaffected by fixation instability. Also, the instrument is a true colour, confocal retinoscope and obtains high-quality 60° × 60° photos of the central retina and stereo-photos details of the optic nerve. Overlapping the image of the retina to field sensitivity may be useful in ascertaining the impact of comorbidities. In addition, the recent introduction of stereoscopic photography may be very useful for better clinical examination.


Safety of an ED High-Dose Opioid Protocol for Sickle Cell Disease Pain.
A nurse-initiated high dose, opioid protocol for vaso-occlusive crisis (VOC) was implemented. Total intravenous morphine sulfate equivalents (IVMSE) in mgs] and safety was evaluated. A medical record review was conducted for all ED visits in adult patients with VOC post protocol implementation. Opioids doses and routes administered during the ED stay, and six hours into the hospital admission were abstracted and total IVMSE administered calculated. Oxygen saturation (SPO2), respiratory rate (RR), administration of naloxone or vasoactive medications, evidence of respiratory arrest, or any other types of resuscitation effort were abstracted. A RR of <10 or SPO2 <92% were coded as abnormal. Descriptive statistics report the total dose. Logistic regression was used to predict abnormal events. Predictors were age, gender, ED dose (10 mg increments) administered, and time from 1st dose to discharge from ED. 72 patients, 603 visits, 276 admitted. The total (ED & hospital dose) mean (95% CI) mg IVMSE administered for all visits was 93 mg (CI 86, 100), ED visit 63 mg (CI 59, 67) and hospital 66 mg (CI 59, 72). The mean (SD) time from administration of 1st analgesic dose to discharge from the ED was 203 (143) minutes, (range = 30-1396 minutes). During two visits, patients experienced a RR <10; while 61 visits were associated with a SPO2 <92%. No medications were administered, or resuscitative measures required. Controlling for demographics and evaluated at the average total ED dose, the longer patients were in the ED, patients were 1.359 times more likely to experience an abnormal vital sign. Controlling for demographics and evaluated at the average total time in the ED, for every 10 mg increase in IVMSE, patients were 1.057 times more likely to experience an abnormal vital sign. The effect of ED dose on the odds of experiencing an abnormal vital sign decreased by a multiplicative factor of 0.0970 for every 1 hour increase in time until discharge. The larger the dose administered in less time, the more likely patients experienced an abnormal vital sign. High opioid doses were safely administered to patients with sickle cell disease.


Sperm competition and ejaculate economics.
Sperm competition was identified in 1970 as a pervasive selective force in post-copulatory sexual selection that occurs when the ejaculates of different males compete to fertilise a given set of ova. Since then, sperm competition has been much studied both empirically and theoretically. Because sperm competition often favours large ejaculates, an important challenge has been to understand the evolution of strategies through which males invest in sperm production and economise sperm allocation to maximise reproductive success under competitive conditions. Sperm competition mechanisms vary greatly, depending on many factors including the level of sperm competition, space constraints in the sperm competition arena, male mating roles, and female influences on sperm utilisation. Consequently, theoretical models of ejaculate economics are complex and varied, often with apparently conflicting predictions. The goal of this review is to synthesise the theoretical basis of ejaculate economics under sperm competition, aiming to provide empiricists with categorised model assumptions and predictions. We show that apparent contradictions between older and newer models can often be reconciled and there is considerable consensus in the predictions generated by different models. We also discuss qualitative empirical support for some of these predictions, and detail quantitative matches between predictions and observations that exist in the yellow dung fly. We argue that ejaculate economic theory represents a powerful heuristic to explain the diversity in ejaculate traits at multiple levels: across species, across males and within individual males. Future progress requires greater understanding of sperm competition mechanisms, quantification of trade-offs between ejaculate allocation and numbers of matings gained, further knowledge of mechanisms of female sperm selection and their associated costs, further investigation of non-sperm ejaculate effects, and theoretical integration of pre- and post-copulatory episodes of sexual selection.


What Went Wrong: Corona and the World after the Full Stop.
This article examines the global response to the Covid-19 pandemic. It argues that we urgently need to look beyond the virus if we want to understand the real seriousness of what is happening today. How did we end up in a space of thinking, acting, and feeling that has normalized extremes and is based on the assumption that biological life is an absolute value separate from politics? The author suggests that today's fear is fueled by mathematical disease modeling, neoliberal health policies, nervous media reporting, and authoritarian longings.


Disruption of β-catenin/CBP signaling inhibits human airway epithelial-mesenchymal transition and repair.
The epithelium of asthmatics is characterized by reduced expression of E-cadherin and increased expression of the basal cell markers ck-5 and p63 that is indicative of a relatively undifferentiated repairing epithelium. This phenotype correlates with increased proliferation, compromised wound healing and an enhanced capacity to undergo epithelial-mesenchymal transition (EMT). The transcription factor β-catenin plays a vital role in epithelial cell differentiation and regeneration, depending on the co-factor recruited. Transcriptional programs driven by the β-catenin/CBP axis are critical for maintaining an undifferentiated and proliferative state, whereas the β-catenin/p300 axis is associated with cell differentiation. We hypothesized that disrupting the β-catenin/CBP signaling axis would promote epithelial differentiation and inhibit EMT. We treated monolayer cultures of human airway epithelial cells with TGFβ1 in the presence or absence of the selective small molecule ICG-001 to inhibit β-catenin/CBP signaling. We used western blots to assess expression of an EMT signature, CBP, p300, β-catenin, fibronectin and ITGβ1 and scratch wound assays to assess epithelial cell migration. Snai-1 and -2 expressions were determined using q-PCR. Exposure to TGFβ1 induced EMT, characterized by reduced E-cadherin expression with increased expression of α-smooth muscle actin and EDA-fibronectin. Either co-treatment or therapeutic administration of ICG-001 completely inhibited TGFβ1-induced EMT. ICG-001 also reduced the expression of ck-5 and -19 independent of TGFβ1. Exposure to ICG-001 significantly inhibited epithelial cell proliferation and migration, coincident with a down regulation of ITGβ1 and fibronectin expression. These data support our hypothesis that modulating the β-catenin/CBP signaling axis plays a key role in epithelial plasticity and function.


Multiparametric MRI and CT models of infarct core and favorable penumbral imaging patterns in acute ischemic stroke.
Objective imaging methods to identify optimal candidates for late recanalization therapies are needed. The study goals were (1) to develop magnetic resonance imaging (MRI) and computed tomography (CT) multiparametric, voxel-based predictive models of infarct core and penumbra in acute ischemic stroke patients, and (2) to develop patient-level imaging criteria for favorable penumbral pattern based on good clinical outcome in response to successful recanalization. An analysis of imaging and clinical data was performed on 2 cohorts of patients (one screened with CT, the other with MRI) who underwent successful treatment for large vessel, anterior circulation stroke. Subjects were divided 2:1 into derivation and validation cohorts. Pretreatment imaging parameters independently predicting final tissue infarct and final clinical outcome were identified. The MRI and CT models were developed and validated from 34 and 32 patients, using 943 320 and 1 236 917 voxels, respectively. The derivation MRI and 2-branch CT models had an overall accuracy of 74% and 80%, respectively, and were independently validated with an accuracy of 71% and 79%, respectively. The imaging criteria of (1) predicted infarct core ≤90 mL and (2) ratio of predicted infarct tissue within the at-risk region ≤70% identified patients as having a favorable penumbral pattern with 78% to 100% accuracy. Multiparametric voxel-based MRI and CT models were developed to predict the extent of infarct core and overall penumbral pattern status in patients with acute ischemic stroke who may be candidates for late recanalization therapies. These models provide an alternative approach to mismatch in predicting ultimate tissue fate.


Dioxin exposure and cancer risk in the Seveso Women's Health Study.
2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD), a widespread environmental contaminant, disrupts multiple endocrine pathways. The International Agency for Research on Cancer classified TCDD as a known human carcinogen, based on predominantly male occupational studies of increased mortality from all cancers combined. After a chemical explosion on 10 July 1976 in Seveso, Italy, residents experienced some of the highest levels of TCDD exposure in a human population. In 1996, we initiated the Seveso Women's Health Study (SWHS), a retrospective cohort study of the reproductive health of the women. We previously reported a significant increased risk for breast cancer and a nonsignificant increased risk for all cancers combined with individual serum TCDD, but the cohort averaged only 40 years of age in 1996. Herein we report results for risk of cancer from a subsequent follow-up of the cohort in 2008. In 1996, we enrolled 981 women who were 0-40 years of age in 1976, lived in the most contaminated areas, and had archived sera collected near the explosion. Individual TCDD concentration was measured in archived serum by high-resolution mass spectrometry. A total of 833 women participated in the 2008 follow-up study. We examined the relation of serum TCDD with cancer incidence using Cox proportional hazards models. In total, 66 (6.7%) women had been diagnosed with cancer. The adjusted hazard ratio (HR) associated with a 10-fold increase in serum TCDD for all cancers combined was significantly increased [adjusted HR = 1.80; 95% confidence interval (CI): 1.29, 2.52]. For breast cancer, the HR was increased, but not significantly (adjusted HR = 1.44; 95% CI: 0.89, 2.33). Individual serum TCDD is significantly positively related with all cancer incidence in the SWHS cohort, more than 30 years later. This all-female study adds to the epidemiologic evidence that TCDD is a multisite carcinogen.


Chemical characterization, antioxidant and cytotoxic activities of Brazilian red propolis.
Propolis is known for a long time for its health benefits and biological activities. Here, the red variety from the northeast of Brazil was chemically analyzed and extracts were investigated regarding their antioxidant and antitumor activity. Hydroalcoholic extracts, obtained from the red propolis, revealed polyphenol content, 2,2-diphenyl-1-picrylhydrazyl scavenging potential and enzymatic activities for catalase-like and superoxide dismutase-like. Cytotoxic activity was evaluated for human laryngeal epidermoid carcinoma cell (Hep-2), human cervical adenocarcinoma (HeLa) and human normal epithelial embryonic kidney (Hek-293). Survival analysis for non-tumor cell line showed greater IC50 compared to tumor cell lines, suggesting an increased sensitivity that may correlate with the higher proliferative index of the tumor vs. normal cells. Our results indicate that the Brazilian red propolis is capable of inhibiting cancer cell growth and constitutes an excellent source of antioxidant and antitumor natural agent.


Expression of neuropilin-1 in high-grade dysplasia, invasive cancer, and metastases of the human gastrointestinal tract.
Neuropilin-1 (NRP-1) functions as an axonal guidance molecule in the developing nervous system, and recent work has identified NRP-1 up-regulation in several cancers, including neuroblastomas and breast carcinoma. We examined for the first time NRP-1 expression in a large variety of gastrointestinal carcinomas and precursor lesions to determine whether NRP-1 up-regulation correlated with invasive growth in this system. Protein expression and localization of NRP-1 were studied by immunolabeling and semiquantification in >300 dysplastic, invasive, and metastatic lesions of the gastrointestinal tract, and confirmation of NRP-1 protein expression was performed by Western blot analysis on pancreatic cancer cell lines. NRP-1 expression was limited within normal tissues of the gastrointestinal tract, with prominent labeling present only in endothelial cells, pancreatic islet cells, and the most apical colonic epithelium. Invasive cancer of the esophagus, gallbladder, ampulla of Vater, pancreas (endocrine and exocrine), and colon, however, all demonstrated striking NRP-1 expression. NRP-1 was also identified in precursor lesions of gastrointestinal adenocarcinomas, such as Barrett esophagus and colorectal adenomas. Within the spectrum of precursor lesions, a progressive increase in both intensity and area of expression was evident during histologic progression from low-grade to high-grade dysplasia. Notably, the most intense up-regulation of NRP-1 was apparent at or around the point of invasion, with focal expression of NRP-1 at levels equivalent to the invasive cancer (2- to 3-fold increase). Prominent labeling for NRP-1 was apparent in primary invasive cancers, liver metastases, and a subset of lymph node metastases, with a 2- to 3-fold increase of NRP-1 over dysplastic lesions. We conclude that increased expression of NRP-1 occurs in gastrointestinal adenocarcinomas and in a subset of high-grade precursor lesions. This up-regulation appears to parallel invasive behavior and may therefore be used as a potential marker for cancer aggressiveness in this system.


Reconstruction of the original mycoflora in pelleted feed by PCR-SSCP and qPCR.
Ground feeds for pigs were investigated for fungal contamination before and after pelleting (subsamples in total n = 24) by cultural and molecular biological methods. A fungal-specific primer pair ITS1/ITS5.8R was used to amplify fungal DNA; PCR products were processed for the PCR-SSCP method. In the resulting acrylamide gel, more than 85% of DNA bands of ground feeds were preserved after pelleting. Twenty-two DNA bands were sequenced; all represented fungal DNA. The level of fungal DNA in ground feed samples was equivalent to 4.77-5.69 log10 CFU g(-1) , calculated by qPCR using a standard curve of Aspergillus flavus. In pelleted feed, the level of fungal DNA was in average ± 0.07 log10 different from ground feed. Quantified by cultural methods, the fresh ground feeds contained up to 4.51 log10 CFU g(-1) culturable fungi, while there was < 2.83 log10 CFU g(-1) detected in pelleted feeds. This result shows that, while the process of pelleting reduced the amount of living fungi dramatically, it did not affect the total fungal DNA in feed. Thus, the described methodology was able to reconstruct the fungal microbiota in feeds and reflected a considerable fungal contamination of raw materials such as grains.


Relationship between viral load and behavioral measures of adherence to antiretroviral therapy in children living with human immunodeficiency virus in Latin America.
Few studies have examined antiretroviral therapy adherence in Latin American children. Standardized behavioral measures were applied to a large cohort of human immunodeficiency virus-infected children in Brazil, Mexico, and Peru to assess adherence to prescribed antiretroviral therapy doses during the three days prior to study visits, assess timing of last missed dose, and evaluate the ability of the adherence measures to predict viral suppression. Time trends in adherence were modeled using a generalized estimating equations approach to account for possible correlations in outcomes measured repeatedly in the same participants. Associations of adherence with human immunodeficiency virus viral load were examined using linear regression. Mean enrollment age of the 380 participants was 5 years; 57.6% had undetectable' viral load (<400 copies/mL). At enrollment, 90.8% of participants were perfectly (100%) adherent, compared to 87.6% at the 6-month and 92.0% at the 12-month visit; the proportion with perfect adherence did not differ over time (p=0.1). Perfect adherence was associated with a higher probability of undetectable viral load at the 12-month visit (odds ratio=4.1, 95% confidence interval: 1.8-9.1; p<0.001), but not at enrollment or the 6-month visit (p>0.3). Last time missed any antiretroviral therapy dose was reported as "never" for 52.0% at enrollment, increasing to 60.7% and 65.9% at the 6- and 12-month visits, respectively (p<0.001 for test of trend). The proportion with undetectable viral load was higher among those who never missed a dose at enrollment and the 12-month visit (p≤0.005), but not at the 6-month visit (p=0.2). While antiretroviral therapy adherence measures utilized in this study showed some association with viral load for these Latin American children, they may not be adequate for reliably identifying non-adherence and consequently children at risk for viral resistance. Other strategies are needed to improve the evaluation of adherence in this population.


Histamine-1 receptor antagonism for treatment of insomnia.
To evaluate the literature regarding the use of histamine-1 (H(1)) receptor antagonists and to describe their role in the treatment of insomnia in adult patients, including the elderly. Literature was identified via PubMed and Medline through April 1, 2012, using the search terms insomnia and sleep, each individually combined with histamine antagonist, tricyclic antidepressant, trazodone, mirtazapine, doxepin, amitriptyline, nortriptyline, trimipramine, doxylamine, diphenhydramine, and antihistamine. Data included randomized double-blind trials that statistically evaluated H(1) receptor antagonist treatment in patients with insomnia compared with a placebo control or Food and Drug Administration-approved insomnia treatment. Trials selected evaluated sleep latency, wake after sleep onset, total sleep time, number of awakenings, and/or sleep efficiency in a subjective or objective manner. A total of 65 trials were evaluated, and 16 met inclusion criteria. With the exception of low-dose doxepin (Silenor-Somaxon), trials evaluating the clinical effectiveness of H(1) receptor antagonists show mixed results and are limited by sample size and generalizability. Large, randomized, appropriately controlled trials are lacking, making it difficult to define the safety and efficacy of these agents. In contrast, low-dose doxepin has been shown to provide consistent sleep benefit compared with placebo. Over-the-counter antihistamines may have a role for short-term insomnia treatment in younger adults, but tolerance develops rapidly. Mirtazapine should not be used solely for the treatment of insomnia. Sedating antidepressants can be considered after failure of first-line insomnia treatments. Patients taking these agents chronically should be evaluated for continued efficacy and potential harm. Low-dose doxepin may have a unique role in the treatment of insomnia in elderly patients given its tolerability, documented efficacy, and lack of important adverse effects.


A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress.
Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, we identified salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha). Salubrinal also blocks eIF2alpha dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2alpha dephosphorylation may be useful in diseases involving ER stress or viral infection. More broadly, salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events.


Transport- and diffusion-based optical tomography in small domains: a comparative study.
We compare reconstructions based on the radiative transport and diffusion equations in optical tomography for media of small sizes. While it is well known that the diffusion approximation is less accurate to describe light propagation in such media, it has not yet been shown how this inaccuracy affects the images obtained with model-based iterative image reconstructions schemes. Using synthetic nondifferential data we calculate the error in the reconstructed images of optical properties as functions of source modulation frequency, noise level in measurement, and diffusion extrapolation length. We observe that the differences between diffusion and transport reconstructions are large when high modulation frequencies and noise-free data are used in the reconstructions. When the noise in data reaches a certain level, approximately 12% in our simulations, the differences between diffusion- and transport-based reconstructions become almost indistinguishable. Given that state-of-the-art optical imaging systems operate at much lower noise levels, the benefits of transport-based reconstructions of small imaging domains can be realized with most of the currently available systems. However, transport-based reconstructions are considerably slower than diffusion-based reconstructions.


Changes in cortical oscillations linked to multisensory modulation of nociception.
Pain can be modulated by several contextual factors. For example, simply viewing one's own body can reduce pain, suggesting that the visual context may influence the processing of nociceptive stimuli. We studied changes in electroencephalographic (EEG) oscillatory activity related to visual modulation of nociception, comparing cortical oscillations during innocuous or noxious contact heat, while participants viewed either their own hand or a neutral object at the same location. Viewing the body compared with viewing the object reduced the intensity ratings of noxious stimuli, but not of innocuous heat. Time-frequency analysis of EEG data revealed that noxious, as opposed to warm, stimulation was associated with reduced beta (15-25 Hz) power. Classically, such decreases in oscillatory power indicate increases in sensory cortical activation. These event-related oscillatory changes were moreover modulated by the visual context; viewing one's own body increased noxious stimulation-induced beta oscillatory activity bilaterally, relative to viewing a neutral object, possibly indicating inhibition of cortical nociceptive processing. These results demonstrate that visual-nociceptive interactions involve changes in sensorimotor EEG rhythms.


Diagnosing hyperuniformity in two-dimensional, disordered, jammed packings of soft spheres.
Hyperuniformity characterizes a state of matter for which (scaled) density fluctuations diminish towards zero at the largest length scales. However, the task of determining whether or not an image of an experimental system is hyperuniform is experimentally challenging due to finite-resolution, noise, and sample-size effects that influence characterization measurements. Here we explore these issues, employing video optical microscopy to study hyperuniformity phenomena in disordered two-dimensional jammed packings of soft spheres. Using a combination of experiment and simulation we characterize the possible adverse effects of particle polydispersity, image noise, and finite-size effects on the assignment of hyperuniformity, and we develop a methodology that permits improved diagnosis of hyperuniformity from real-space measurements. The key to this improvement is a simple packing reconstruction algorithm that incorporates particle polydispersity to minimize the free volume. In addition, simulations show that hyperuniformity in finite-sized samples can be ascertained more accurately in direct space than in reciprocal space. Finally, our experimental colloidal packings of soft polymeric spheres are shown to be effectively hyperuniform.


Rapid isolation of Arabidopsis chloroplasts and their use for in vitro protein import assays.
In vitro chloroplast protein import assays have been performed since the late 1970s, initially with plant species (e.g., pea and spinach) that readily provide an abundant source of starting material and also, subsequently, a good yield of chloroplasts for import assays. However, the sequencing of the Arabidopsis genome paved the way for an additional model system that is more amenable to genetic analysis, as a complement to the more biochemically orientated models such as pea and spinach. A prerequisite for this change was an efficient and reliable protocol for the isolation of chloroplasts for use in protein import assays, enabling biochemical approaches to be combined with the genetic potential of the plant. The method described here was developed as a rapid and low-cost procedure that can be accessed by everyone due to its simplicity. Despite its rapidity and simplicity, the method yields highly pure chloroplasts, and in addition works well with mutant plants that exhibit pale or chlorotic phenotypes. The protocol is also optimized for work with material from young plants (10-14 days old), when protein import is believed to be at its peak, and so plant growth can be conducted in vitro on Murashige and Skoog medium. The isolation method has been used not only for protein import assays, but also for proteomic analysis and further subfractionation studies.


Suppression of inflammatory immune responses in celiac disease by experimental hookworm infection.
We present immunological data from two clinical trials where the effect of experimental human hookworm (Necator americanus) infection on the pathology of celiac disease was evaluated. We found that basal production of Interferon- (IFN-)γ and Interleukin- (IL-)17A from duodenal biopsy culture was suppressed in hookworm-infected participants compared to uninfected controls. Increased levels of CD4+CD25+Foxp3+ cells in the circulation and mucosa are associated with active celiac disease. We show that this accumulation also occurs during a short-term (1 week) oral gluten challenge, and that hookworm infection suppressed the increase of circulating CD4+CD25+Foxp3+ cells during this challenge period. When duodenal biopsies from hookworm-infected participants were restimulated with the immunodominant gliadin peptide QE65, robust production of IL-2, IFN-γ and IL-17A was detected, even prior to gluten challenge while participants were strictly adhering to a gluten-free diet. Intriguingly, IL-5 was produced only after hookworm infection in response to QE65. Thus we hypothesise that hookworm-induced TH2 and IL-10 cross-regulation of the TH1/TH17 inflammatory response may be responsible for the suppression of these responses during experimental hookworm infection.


Reduced fields of view are neither necessary nor sufficient for distance underestimation but reduce precision and may cause calibration problems.
Watt et al. (Exp Brain Res, 2000, 135:411-416) suggested that a reduced field of view causes objects to appear closer than their physical distance. This suggestion is based on the observation that individuals terminated open-loop prehension prematurely when pretending to grasp a paper rectangle initially viewed through a reduced field of view. We tested Watt et al.'s suggestion in an open-loop pointing task. In experiment 1, 21 participants pointed at targets in three locations (20, 30 and 40 cm relative to the starting position) in three viewing conditions (full, 16 degrees and 4 degrees field of view). No difference in accuracy was found between conditions but the reduced field of view led to an increase in end-point variability across trials. We interpret these results as indicating that a reduced field of view decreases precision but does not necessarily affect object localisation. In experiment 2, we asked participants to reach-and-grasp a real object under the same three open-loop viewing conditions but without vision following movement onset. The experimental design ensured that haptic feedback was available, which could be used to calibrate reaching movements. We found that the reduced field of view caused no changes in grasp but we observed changes in the transport kinematics consistent with increased variability in the perceptual estimate of target location. Notably there were no changes in the spatial path (expected from movements to a closer location). In experiment 3, we repeated the Watt et al. design but removed vision and forced participants to rely on memory. In this condition we found the same undershoots as described by Watt et al. We conclude that a reduced field of view is neither necessary nor sufficient for underestimation and suggest that a reduced field of view decreases precision. This can cause participants to undershoot and/or alter the movement kinematics but we argue that such findings cannot be ascribed unambiguously to perceptual underestimation as they may reflect strategic alterations in behaviour.


Scholarly activity in family medicine residency programs: a national survey.
In 2006, the Family Medicine Review Committee (RC) began requiring resident scholarly activity. This study sought to (1) determine how resident scholarly activity requirements and productivity changed after this alteration, (2) delineate characteristics of scholarship within family medicine residencies, and (3) determine the factors within programs that are associated with resident scholarly productivity. We sent a 38-item electronic survey to all 450 US family medicine program directors. Multivariate analysis was performed to determine significant predictors of scholarship. Fifty-five percent of surveys were returned; 42.8% of programs modified scholarship requirements after 2006, and 48.6% required resident scholarship in 1997 versus 89.6% in 2009. A total of 76.6% have research curricula versus 51.5% in 1997; 87.5% report that <25% of residents authored publications within 2 years, yet 46.1% of programs report >50% of residents conducted research during that same time. Three factors were associated with ≥25% of residents publishing within 2 years: "Residency director publishing" (OR=4.1, 95% CI=1.5-11.5), "≥6 faculty publications within 2 years" (OR=7.8, 95% CI=3.0-20.3), and "Residency opened before 1980" (OR=3.7, 95% CI=1.4-9.6). Five factors were associated with participation by ≥50% of program's residents in a research project: "Resident recognition for scholarship" (OR=2.2, 95% CI=1.1-4.1), "Dedicated resident time for research" (OR=2.3, 95% CI=1.2-4.4), "Local Research Day" (OR=2.5, 95% CI=1.3-5.1), "Academic advancement linked to scholarship" (OR=1.9, 95% CI=0.9-3.9), and "Residency director performs research" (OR=2.7, 95% CI=1.4-5.1). Many family medicine residency programs have increased resident scholarly activity requirements since 2006. To date, these changes have not increased scholarly output, and most programs have low resident scholarship. This study confirms that dedicating resources and time to research combined with active faculty scholarship will likely increase resident scholarly production.


Posterior consistency in conditional distribution estimation.
A wide variety of priors have been proposed for nonparametric Bayesian estimation of conditional distributions, and there is a clear need for theorems providing conditions on the prior for large support, as well as posterior consistency. Estimation of an uncountable collection of conditional distributions across different regions of the predictor space is a challenging problem, which differs in some important ways from density and mean regression estimation problems. Defining various topologies on the space of conditional distributions, we provide sufficient conditions for posterior consistency focusing on a broad class of priors formulated as predictor-dependent mixtures of Gaussian kernels. This theory is illustrated by showing that the conditions are satisfied for a class of generalized stick-breaking process mixtures in which the stick-breaking lengths are monotone, differentiable functions of a continuous stochastic process. We also provide a set of sufficient conditions for the case where stick-breaking lengths are predictor independent, such as those arising from a fixed Dirichlet process prior.


Time-Efficiency Analysis Comparing Digital and Conventional Workflows for Implant Crowns: A Prospective Clinical Crossover Trial.
To compare time-efficiency in the production of implant crowns using a digital workflow versus the conventional pathway. This prospective clinical study used a crossover design that included 20 study participants receiving single-tooth replacements in posterior sites. Each patient received a customized titanium abutment plus a computer-aided design/computer-assisted manufacture (CAD/CAM) zirconia suprastructure (for those in the test group, using digital workflow) and a standardized titanium abutment plus a porcelain-fused-to-metal crown (for those in the control group, using a conventional pathway). The start of the implant prosthetic treatment was established as the baseline. Time-efficiency analysis was defined as the primary outcome, and was measured for every single clinical and laboratory work step in minutes. Statistical analysis was calculated with the Wilcoxon rank sum test. All crowns could be provided within two clinical appointments, independent of the manufacturing process. The mean total production time, as the sum of clinical plus laboratory work steps, was significantly different. The mean ± standard deviation (SD) time was 185.4 ± 17.9 minutes for the digital workflow process and 223.0 ± 26.2 minutes for the conventional pathway (P = .0001). Therefore, digital processing for overall treatment was 16% faster. Detailed analysis for the clinical treatment revealed a significantly reduced mean ± SD chair time of 27.3 ± 3.4 minutes for the test group compared with 33.2 ± 4.9 minutes for the control group (P = .0001). Similar results were found for the mean laboratory work time, with a significant decrease of 158.1 ± 17.2 minutes for the test group vs 189.8 ± 25.3 minutes for the control group (P = .0001). Only a few studies have investigated efficiency parameters of digital workflows compared with conventional pathways in implant dental medicine. This investigation shows that the digital workflow seems to be more time-efficient than the established conventional production pathway for fixed implant-supported crowns. Both clinical chair time and laboratory manufacturing steps could be effectively shortened with the digital process of intraoral scanning plus CAD/CAM technology.


Assessing the impact of total quality management and organizational culture on multiple outcomes of care for coronary artery bypass graft surgery patients.
To assess the impact of total quality management (TQM) and organizational culture on a comprehensive set of endpoints of care for coronary artery bypass graft surgery (CABG) patients, including risk-adjusted adverse outcomes, clinical efficiency, patient satisfaction, functional health status, and cost of care. Prospective cohort study of 3,045 eligible CABG patients from 16 hospitals using risk-adjusted clinical outcomes, functional health status, patient satisfaction, and cost measures. Implementation of TQM was measured by a previously validated instrument based on the Baldridge national quality award criteria. Organizational culture was measured by a previously validated 20-item instrument. Generalized estimating equations were used to control for potential selection bias, repeated measures, and intraclass correlation. A 2- to 4-fold difference in all major clinical CABG care endpoints was observed among the 16 hospitals, but little of this variation was associated with TQM or organizational culture. Patients receiving CABG from hospitals with high TQM scores were more satisfied with their nursing care (P = 0.005) but were more likely to have lengths of stay >10 days (P = 0.0003). A supportive group culture was associated with shorter postoperative intubation times (P = 0.01) but longer operating room times (P = 0.004). A supportive group culture was also associated with higher patient physical (P = 0.005) and mental (P = 0.01) functional health status scores 6 months after CABG. There was little effect of TQM and organizational culture on multiple endpoints of care for CABG patients. There is a need to examine further the relationships among individual professional skills and motivations, group and microsystem team processes, specifically tailored interventions, and organization-wide culture, decision support processes, and incentives. Assessing the impact of such multifaceted approaches is an important area for further research.


Is privacy privacy?
This position paper observes how different technical and normative conceptions of privacy have evolved in parallel and describes the practical challenges that these divergent approaches pose. Notably, past technologies relied on intuitive, heuristic understandings of privacy that have since been shown not to satisfy expectations for privacy protection. With computations ubiquitously integrated in almost every aspect of our lives, it is increasingly important to ensure that privacy technologies provide protection that is in line with relevant social norms and normative expectations. Similarly, it is also important to examine social norms and normative expectations with respect to the evolving scientific study of privacy. To this end, we argue for a rigorous analysis of the mapping from normative to technical concepts of privacy and vice versa. We review the landscape of normative and technical definitions of privacy and discuss specific examples of gaps between definitions that are relevant in the context of privacy in statistical computation. We then identify opportunities for overcoming their differences in the design of new approaches to protecting privacy in accordance with both technical and normative standards.This article is part of a discussion meeting issue 'The growing ubiquity of algorithms in society: implications, impacts and innovations'.


Push-pull type meso-ester substituted BODIPY near-infrared dyes as contrast agents for photoacoustic imaging.
A series of push-pull type meso-ester substituted BODIPY dyes 1-4 with intense near-infrared absorption, largely enhanced photoacoustic (PA) activity and excellent photo-stability were synthesized. The impact of the electronic structure on the PA activity was also discussed. Moreover, the in vitro and in vivo PA imaging were investigated, which suggested a passive targeting capacity in the tumor site.